Proteopedia - User contributions [en]

TET Enzymes

2016-04-28T11:52:49Z

Madelyn Kasprzak:

== TET Enzymes==

TET enzymes are a family of [[Dioxygenase|dioxygenases]] that are involved in the process of oxidizing methylated cytosine. Members of this family include ten-eleven translocation methylcytosine dioxygenase 1 (<scene name='72/728164/Naegleria_gruberi_tet1/1'>TET1</scene>), methylcytosine dioxygenase <scene name='72/728164/Human_tet2_5fc/1'>TET2</scene>, and methylcytosine dioxygenase <scene name='72/728164/Xenopus_tropicalis_tet3_dna/1'>TET3</scene>. The gene for the first of these proteins, TET1, was identified when it was determined to be fused to the ''Mixed Lineage Leukemia'' (MLL) gene as a result of a translocation event that occurred between chromosomes ten and eleven (hence the name). <ref>DOI 10.1038/sj.leu.2402834</ref>

<div style="width:auto;clear:both;">
== Structure ==
<div style="width:66%;float:left;">

The TET enzymes have a cysteine-rich region closely followed by a double stranded beta-helix (DSBH) domain near their C-terminus.<ref name='Kinney et al.'>DOI 10.1007/978-1-4419-9967-2_3</ref> The DSBH domain contains three <scene name='72/728164/Two_iron_binding_residues/1'>Fe<sup>(II)</sup> binding sites</scene> and an <scene name='72/728164/2-oxoglutarate_binding_site/1'>α-ketoglutarate binding site</scene>.<ref name='Kinney et al.' /> For all α-ketoglutarate oxygenases, including TET enzymes, the DSBH domain and the preceding cysteine-rich region perform the main catalytic activity for these enzymes.

In addition, TET1 has a CXXC-type zinc finger domain near the N-terminus. However, the TET1 CXXC domain lacks the conserved lysine-phenylalanine-glycine-glycine (KFGG) motif commonly seen within the CXXC domains of other DNA binding proteins, such as DNA methyltransferase-1 (DNMT1). A study conducted by Frauer et al. in 2011 showed that the isolated CXXC domain of TET1 has no DNA binding activity, which agrees with the evidence suggesting that the KFGG motif increases affinity for unmethylated DNA.<ref name='Frauer et al.'>DOI 10.1371/journal.pone.0016627</ref> Frauer et al. also speculated that the CXXC domain of TET1 may be involved with protein-protein interactions instead of DNA binding.<ref name='Frauer et al.' />
</div>
<div style="width:33%;float:right;clear:right;border:1px solid black;">
<StructureSection load='5d9y' size='335' side='right' caption='Human TET2 in complex with DNA containing 5fC.' scene=''></StructureSection>
</div>

</div>

== Function ==
===Common Function===

All three TET enzymes and their isoforms are involved in the biochemical pathway that converts 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC). They also regulate the further conversions of 5hmC to 5-formylcytosine (5fC) and then 5fC to 5-carboxylcytosine (5caC).<ref name='He et al.'>DOI: 10.1126/science.1210944</ref> Although experimental data shows that TET3 does so to a lesser extent than TET1 and TET2.<ref name='He et al.' />

While the oxidation performed by TET enzymes was originally thought to be a source of DNA damage, new research has implied that this catalytic activity may actually be the initial steps of a process of DNA demethylation. This hypothesized DNA demethylation pathway starts with the conversion of 5mC to 5caC after several rounds of oxidation by TET enzymes. The next step is the removal of the modified cytosine base by thymine DNA glycosylase (TDG) which leaves an abasic site on the DNA. The last step is then the process of base excision repair in which a new unmodified cytosine is regenerated at the site, thus completing the process of DNA demethylation.<ref name='He et al.' /><ref name='Rahul M. Kohli & Yi Zhang'>DOI 10.1038/nature12750</ref>

[[Image:nsmb.2437-F1.jpg|395px|left|thumb|Cycle of DNA methylation and demethylation by DNA methyltransferases (DNMTs) and TET proteins.<ref>DOI 10.1038/nsmb.2437</ref>]]

===Specific Functions===
Experimental data shows that the TET genes have different expression patterns and at different levels, which indicates that each of the TET enzymes do not fully overlap in their functionality.

TET1 is usually expressed in fetal heart, lung, and brain tissue and in adult skeletal muscle, thymus, and ovary. It is not generally expressed in adult heart, lung, and brain tissue. Moreover, studies have shown that TET1 expression in adult brain tissue is correlated with brain cancer. This occurs through TET1’s indirect activation of brain cancer-related genes such as EGFR, AKT3, CDK6, CCND2, and BRAF through creation of 5hmC which recruits the CHTOP-methylosome complex that activates these genes.<ref>DOI 10.1016/j.celrep.2014.08.071</ref>

TET2 is broadly expressed, but it is especially highly expressed in hematopoietic cells, which develop into blood cells. Regarding this, it is suggested that TET2 plays a role in hematopoiesis due to the presence of TET2 mutations in many myelodysplastic syndromes.<ref name='Delhommeau et al.'>DOI 10.1056/NEJMoa0810069</ref><ref>DOI 10.1038/ng.391</ref>

TET3 is highly expressed in zygotes and is involved with epigenetic chromatin reprogramming in the zygote after fertilization. Specifically, it plays a role in DNA demethylation of the paternal pronucleus before implantation.<ref name='Rahul M. Kohli & Yi Zhang' />

== Disease Relation ==
=== TET1 Isoform ===

Point mutations within the TET1 isoform can lead to a loss of enzyme function which causes a lack of DNA demethylation; two occur at the 1672 and 1674 amino acid residues, the first being a H1672Y mutation and the second being a D1674A mutation. A severe mutation in the 1608-1609 codons can lead to TET1 becoming an oncogene in acute leukemias. This mutation fuses TET1 and KMT2A/MLL1 to form an oncogene.<ref>PMID:12124344</ref><ref>PMID:12646957</ref>

=== TET2 Isoform ===

TET2 has been identified as a tumor-suppressor gene that is linked to various myeloid cancers. Acquired mutations are predicted to truncate the protein, resulting in alterations of the function of the TET2 protein. TET2 defects have been identified in the CD34+ cells of patients with myelodysplastic syndrome, which include hematopoietic stem cells and hematopoietic progenitors. This suggests that TET2 mutations or defects, paired with mutations in other genes, such as Janus kinase 2 (JAK2) V617F gene or myeloproliferative leukemia virus oncogene (MPL) W515L/K can contribute to the progression of myeloid cancers. Due to the involvement of TET2 in hematopoietic stem cell development, mutations in this gene may also be associated with the amplification of the mutation in the early stages of hematopoietic differentiation.<ref name='Delhommeau et al.' />

== Structural highlights ==

The following highlights are of the Human TET2 enzyme in complex with DNA.

<scene name='72/728166/5d9y_helices_red/1'>Alpha helices</scene> are colored red.

<scene name='72/728166/5d9y_sheets_green/1'>Beta sheets</scene> are colored green.

Both <scene name='72/728166/5d9y_alpha_beta/1'>Alpha helices and beta sheets</scene> are displayed in this scene.

Here the <scene name='72/728166/5d9y_zinc_ions/1'>zinc ions</scene> are colored light blue, but since they are so small they may be slightly difficult to see.

Here some of the major residues of the <scene name='72/728166/5d9y_catalytic_site/1'>catalytic site</scene> are highlighted. The light green residues are 2-oxoglutarate binding residues, the orange residue binds the substrate, and the blue residue binds the catalytic iron ion. For the rest of the protein, only the backbone is shown in light gray.

== References ==
<references/>

User:Madelyn Kasprzak/Sandbox 6

2016-04-28T04:59:23Z

Madelyn Kasprzak:

== TET Enzymes==

TET enzymes are a family of [[Dioxygenase|dioxygenases]] that are involved in the process of oxidizing methylated cytosine. Members of this family include ten-eleven translocation methylcytosine dioxygenase 1 (<scene name='72/728164/Naegleria_gruberi_tet1/1'>TET1</scene>), methylcytosine dioxygenase <scene name='72/728164/Human_tet2_5fc/1'>TET2</scene>, and methylcytosine dioxygenase <scene name='72/728164/Xenopus_tropicalis_tet3_dna/1'>TET3</scene>. The gene for the first of these proteins, TET1, was identified when it was determined to be fused to the ''Mixed Lineage Leukemia'' (MLL) gene as a result of a translocation event that occurred between chromosomes ten and eleven (hence the name). <ref>DOI 10.1038/sj.leu.2402834</ref>

<div style="width:auto;clear:both;">
== Structure ==
<div style="width:66%;float:left;">

The TET enzymes have a cysteine-rich region closely followed by a double stranded beta-helix (DSBH) domain near their C-terminus.<ref name='Kinney et al.'>DOI 10.1007/978-1-4419-9967-2_3</ref> The DSBH domain contains three <scene name='72/728164/Two_iron_binding_residues/1'>Fe(II) binding sites</scene> and an <scene name='72/728164/2-oxoglutarate_binding_site/2'>α-ketoglutarate binding site</scene>.<ref name='Kinney et al.' /> For all α-ketoglutarate oxygenases, including TET enzymes, the DSBH domain and the preceding cysteine-rich region perform the main catalytic activity for these enzymes.

In addition, TET1 has a CXXC-type zinc finger domain near the N-terminus. However, the TET1 CXXC domain lacks the conserved lysine-phenylalanine-glycine-glycine (KFGG) motif commonly seen within the CXXC domains of other DNA binding proteins, such as DNA methyltransferase-1 (DNMT1). A study conducted by Frauer et al. in 2011 showed that the isolated CXXC domain of TET1 has no DNA binding activity, which agrees with the evidence suggesting that the KFGG motif increases affinity for unmethylated DNA.<ref name='Frauer et al.'>DOI 10.1371/journal.pone.0016627</ref> Frauer et al. also speculated that the CXXC domain of TET1 may be involved with protein-protein interactions instead of DNA binding.<ref name='Frauer et al.' />
</div>
<div style="width:33%;float:right;clear:right;border:1px solid black;">
<StructureSection load='5d9y' size='335' side='right' caption='Human TET2 in complex with DNA containing 5fC.' scene=''></StructureSection>
</div>

</div>

== Function ==
===Common Function===

All three TET enzymes and their isoforms are involved in the biochemical pathway that converts 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC). They also regulate the further conversions of 5hmC to 5-formylcytosine (5fC) and then 5fC to 5-carboxylcytosine (5caC).<ref name='He et al.'>DOI: 10.1126/science.1210944</ref> Although experimental data shows that TET3 does so to a lesser extent than TET1 and TET2.<ref name='He et al.' />

While the oxidation performed by TET enzymes was originally thought to be a source of DNA damage, new research has implied that this catalytic activity may actually be the initial steps of a process of DNA demethylation. This hypothesized DNA demethylation pathway starts with the conversion of 5mC to 5caC after several rounds of oxidation by TET enzymes. The next step is the removal of the modified cytosine base by thymine DNA glycosylase (TDG) which leaves an abasic site on the DNA. The last step is then the process of base excision repair in which a new unmodified cytosine is regenerated at the site, thus completing the process of DNA demethylation.<ref name='He et al.' /><ref name='Rahul M. Kohli & Yi Zhang'>DOI 10.1038/nature12750</ref>

[[Image:nsmb.2437-F1.jpg|395px|left|thumb|Cycle of DNA methylation and demethylation by DNA methyltransferases (DNMTs) and TET proteins.<ref>DOI 10.1038/nsmb.2437</ref>]]

===Specific Functions===
Experimental data shows that the TET genes have different expression patterns and at different levels, which indicates that each of the TET enzymes do not fully overlap in their functionality.

TET1 is usually expressed in fetal heart, lung, and brain tissue and in adult skeletal muscle, thymus, and ovary. It is not generally expressed in adult heart, lung, and brain tissue. Moreover, studies have shown that TET1 expression in adult brain tissue is correlated with brain cancer. This occurs through TET1’s indirect activation of brain cancer-related genes such as EGFR, AKT3, CDK6, CCND2, and BRAF through creation of 5hmC which recruits the CHTOP-methylosome complex that activates these genes.<ref>DOI 10.1016/j.celrep.2014.08.071</ref>

TET2 is broadly expressed, but it is especially highly expressed in hematopoietic cells, which develop into blood cells. Regarding this, it is suggested that TET2 plays a role in hematopoiesis due to the presence of TET2 mutations in many myelodysplastic syndromes.<ref name='Delhommeau et al.'>DOI 10.1056/NEJMoa0810069</ref><ref>DOI 10.1038/ng.391</ref>

TET3 is highly expressed in zygotes and is involved with epigenetic chromatin reprogramming in the zygote after fertilization. Specifically, it plays a role in DNA demethylation of the paternal pronucleus before implantation.<ref name='Rahul M. Kohli & Yi Zhang' />

== Disease Relation ==
=== TET1 Isoform ===

Point mutations within the TET1 isoform can lead to a loss of enzyme function which causes a lack of DNA demethylation; two occur at the 1672 and 1674 amino acid residues, the first being a H1672Y mutation and the second being a D1674A mutation. A severe mutation in the 1608-1609 codons can lead to TET1 becoming an oncogene in acute leukemias. This mutation fuses TET1 and KMT2A/MLL1 to form an oncogene.<ref>PMID:12124344</ref><ref>PMID:12646957</ref>

=== TET2 Isoform ===

TET2 has been identified as a tumor-suppressor gene that is linked to various myeloid cancers. Acquired mutations are predicted to truncate the protein, resulting in alterations of the function of the TET2 protein. TET2 defects have been identified in the CD34+ cells of patients with myelodysplastic syndrome, which include hematopoietic stem cells and hematopoietic progenitors. This suggests that TET2 mutations or defects, paired with mutations in other genes, such as Janus kinase 2 (JAK2) V617F gene or myeloproliferative leukemia virus oncogene (MPL) W515L/K can contribute to the progression of myeloid cancers. Due to the involvement of TET2 in hematopoietic stem cell development, mutations in this gene may also be associated with the amplification of the mutation in the early stages of hematopoietic differentiation.<ref name='Delhommeau et al.' />

== Structural highlights ==

The following highlights are of the Human TET2 enzyme in complex with DNA.

<scene name='72/728166/5d9y_helices_red/1'>Alpha helices</scene> are colored red.

<scene name='72/728166/5d9y_sheets_green/1'>Beta sheets</scene> are colored green.

Both <scene name='72/728166/5d9y_alpha_beta/1'>Alpha helices and beta sheets</scene> are displayed in this scene.

Here the <scene name='72/728166/5d9y_zinc_ions/1'>zinc ions</scene> are colored light blue, but since they are so small they may be slightly difficult to see.

Here some of the major residues of the <scene name='72/728166/5d9y_catalytic_site/1'>catalytic site</scene> are highlighted. The light green residues are 2-oxoglutarate binding residues, the orange residue binds the substrate, and the blue residue binds the catalytic iron ion. For the rest of the protein, only the backbone is shown in light gray.

== References ==
<references/>

TET Enzymes

2016-04-28T04:52:46Z

Madelyn Kasprzak: New page: == TET Enzymes== TET enzymes are a family of dioxygenases that are involved in the process of oxidizing methylated cytosine. Members of this family include ten-eleven tran...

== TET Enzymes==

TET enzymes are a family of [[Dioxygenase|dioxygenases]] that are involved in the process of oxidizing methylated cytosine. Members of this family include ten-eleven translocation methylcytosine dioxygenase 1 (<scene name='72/728164/Naegleria_gruberi_tet1/1'>TET1</scene>), methylcytosine dioxygenase <scene name='72/728164/Human_tet2_5fc/1'>TET2</scene>, and methylcytosine dioxygenase <scene name='72/728164/Xenopus_tropicalis_tet3_dna/1'>TET3</scene>. The gene for the first of these proteins, TET1, was identified when it was determined to be fused to the ''Mixed Lineage Leukemia'' (MLL) gene as a result of a translocation event that occurred between chromosomes ten and eleven (hence the name). <ref>DOI 10.1038/sj.leu.2402834</ref>

<div style="width:auto;clear:both;">
== Structure ==
<div style="width:66%;float:left;">

The TET enzymes have a cysteine-rich region closely followed by a double stranded beta-helix (DSBH) domain near their C-terminus.<ref name='Kinney et al.'>DOI 10.1007/978-1-4419-9967-2_3</ref> The DSBH domain contains three <scene name='72/728164/Two_iron_binding_residues/1'>Fe<sup>2+</sup> binding sites</scene> and an <scene name='72/728164/2-oxoglutarate_binding_site/1'>α-ketoglutarate binding site</scene>.<ref name='Kinney et al.' /> For all α-ketoglutarate oxygenases, including TET enzymes, the DSBH domain and the preceding cysteine-rich region perform the main catalytic activity for these enzymes.

In addition, TET1 has a CXXC-type zinc finger domain near the N-terminus. However, the TET1 CXXC domain lacks the conserved lysine-phenylalanine-glycine-glycine (KFGG) motif commonly seen within the CXXC domains of other DNA binding proteins, such as DNA methyltransferase-1 (DNMT1). A study conducted by Frauer et al. in 2011 showed that the isolated CXXC domain of TET1 has no DNA binding activity, which agrees with the evidence suggesting that the KFGG motif increases affinity for unmethylated DNA.<ref name='Frauer et al.'>DOI 10.1371/journal.pone.0016627</ref> Frauer et al. also speculated that the CXXC domain of TET1 may be involved with protein-protein interactions instead of DNA binding.<ref name='Frauer et al.' />
</div>
<div style="width:33%;float:right;clear:right;border:1px solid black;">
<StructureSection load='5d9y' size='335' side='right' caption='Human TET2 in complex with DNA containing 5fC.' scene=''></StructureSection>
</div>

</div>

== Function ==
===Common Function===

All three TET enzymes and their isoforms are involved in the biochemical pathway that converts 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC). They also regulate the further conversions of 5hmC to 5-formylcytosine (5fC) and then 5fC to 5-carboxylcytosine (5caC).<ref name='He et al.'>DOI: 10.1126/science.1210944</ref> Although experimental data shows that TET3 does so to a lesser extent than TET1 and TET2.<ref name='He et al.' />

While the oxidation performed by TET enzymes was originally thought to be a source of DNA damage, new research has implied that this catalytic activity may actually be the initial steps of a process of DNA demethylation. This hypothesized DNA demethylation pathway starts with the conversion of 5mC to 5caC after several rounds of oxidation by TET enzymes. The next step is the removal of the modified cytosine base by thymine DNA glycosylase (TDG) which leaves an abasic site on the DNA. The last step is then the process of base excision repair in which a new unmodified cytosine is regenerated at the site, thus completing the process of DNA demethylation.<ref name='He et al.' /><ref name='Rahul M. Kohli & Yi Zhang'>DOI 10.1038/nature12750</ref>

[[Image:nsmb.2437-F1.jpg|395px|left|thumb|Cycle of DNA methylation and demethylation by DNA methyltransferases (DNMTs) and TET proteins.<ref>DOI 10.1038/nsmb.2437</ref>]]

===Specific Functions===
Experimental data shows that the TET genes have different expression patterns and at different levels, which indicates that each of the TET enzymes do not fully overlap in their functionality.

TET1 is usually expressed in fetal heart, lung, and brain tissue and in adult skeletal muscle, thymus, and ovary. It is not generally expressed in adult heart, lung, and brain tissue. Moreover, studies have shown that TET1 expression in adult brain tissue is correlated with brain cancer. This occurs through TET1’s indirect activation of brain cancer-related genes such as EGFR, AKT3, CDK6, CCND2, and BRAF through creation of 5hmC which recruits the CHTOP-methylosome complex that activates these genes.<ref>DOI 10.1016/j.celrep.2014.08.071</ref>

TET2 is broadly expressed, but it is especially highly expressed in hematopoietic cells, which develop into blood cells. Regarding this, it is suggested that TET2 plays a role in hematopoiesis due to the presence of TET2 mutations in many myelodysplastic syndromes.<ref name='Delhommeau et al.'>DOI 10.1056/NEJMoa0810069</ref><ref>DOI 10.1038/ng.391</ref>

TET3 is highly expressed in zygotes and is involved with epigenetic chromatin reprogramming in the zygote after fertilization. Specifically, it plays a role in DNA demethylation of the paternal pronucleus before implantation.<ref name='Rahul M. Kohli & Yi Zhang' />

== Disease Relation ==
=== TET1 Isoform ===

Point mutations within the TET1 isoform can lead to a loss of enzyme function which causes a lack of DNA demethylation; two occur at the 1672 and 1674 amino acid residues, the first being a H1672Y mutation and the second being a D1674A mutation. A severe mutation in the 1608-1609 codons can lead to TET1 becoming an oncogene in acute leukemias. This mutation fuses TET1 and KMT2A/MLL1 to form an oncogene.<ref>PMID:12124344</ref><ref>PMID:12646957</ref>

=== TET2 Isoform ===

TET2 has been identified as a tumor-suppressor gene that is linked to various myeloid cancers. Acquired mutations are predicted to truncate the protein, resulting in alterations of the function of the TET2 protein. TET2 defects have been identified in the CD34+ cells of patients with myelodysplastic syndrome, which include hematopoietic stem cells and hematopoietic progenitors. This suggests that TET2 mutations or defects, paired with mutations in other genes, such as Janus kinase 2 (JAK2) V617F gene or myeloproliferative leukemia virus oncogene (MPL) W515L/K can contribute to the progression of myeloid cancers. Due to the involvement of TET2 in hematopoietic stem cell development, mutations in this gene may also be associated with the amplification of the mutation in the early stages of hematopoietic differentiation.<ref name='Delhommeau et al.' />

== Structural highlights ==

The following highlights are of the Human TET2 enzyme in complex with DNA.

<scene name='72/728166/5d9y_helices_red/1'>Alpha helices</scene> are colored red.

<scene name='72/728166/5d9y_sheets_green/1'>Beta sheets</scene> are colored green.

Both <scene name='72/728166/5d9y_alpha_beta/1'>Alpha helices and beta sheets</scene> are displayed in this scene.

Here the <scene name='72/728166/5d9y_zinc_ions/1'>zinc ions</scene> are colored light blue, but since they are so small they may be slightly difficult to see.

Here some of the major residues of the <scene name='72/728166/5d9y_catalytic_site/1'>catalytic site</scene> are highlighted. The light green residues are 2-oxoglutarate binding residues, the orange residue binds the substrate, and the blue residue binds the catalytic iron ion. For the rest of the protein, only the backbone is shown in light gray.

== References ==
<references/>

User:Madelyn Kasprzak/Sandbox 6

2016-04-28T04:47:52Z

Madelyn Kasprzak: added two green links for iron binding and 2-oxoglutarate binding residues

== TET Enzymes==

TET enzymes are a family of [[Dioxygenase|dioxygenases]] that are involved in the process of oxidizing methylated cytosine. Members of this family include ten-eleven translocation methylcytosine dioxygenase 1 (<scene name='72/728164/Naegleria_gruberi_tet1/1'>TET1</scene>), methylcytosine dioxygenase <scene name='72/728164/Human_tet2_5fc/1'>TET2</scene>, and methylcytosine dioxygenase <scene name='72/728164/Xenopus_tropicalis_tet3_dna/1'>TET3</scene>. The gene for the first of these proteins, TET1, was identified when it was determined to be fused to the ''Mixed Lineage Leukemia'' (MLL) gene as a result of a translocation event that occurred between chromosomes ten and eleven (hence the name). <ref>DOI 10.1038/sj.leu.2402834</ref>

<div style="width:auto;clear:both;">
== Structure ==
<div style="width:66%;float:left;">

The TET enzymes have a cysteine-rich region closely followed by a double stranded beta-helix (DSBH) domain near their C-terminus.<ref name='Kinney et al.'>DOI 10.1007/978-1-4419-9967-2_3</ref> The DSBH domain contains three <scene name='72/728164/Two_iron_binding_residues/1'>Fe<sup>2+</sup> binding sites</scene> and an <scene name='72/728164/2-oxoglutarate_binding_site/1'>α-ketoglutarate binding site</scene>.<ref name='Kinney et al.' /> For all α-ketoglutarate oxygenases, including TET enzymes, the DSBH domain and the preceding cysteine-rich region perform the main catalytic activity for these enzymes.

In addition, TET1 has a CXXC-type zinc finger domain near the N-terminus. However, the TET1 CXXC domain lacks the conserved lysine-phenylalanine-glycine-glycine (KFGG) motif commonly seen within the CXXC domains of other DNA binding proteins, such as DNA methyltransferase-1 (DNMT1). A study conducted by Frauer et al. in 2011 showed that the isolated CXXC domain of TET1 has no DNA binding activity, which agrees with the evidence suggesting that the KFGG motif increases affinity for unmethylated DNA.<ref name='Frauer et al.'>DOI 10.1371/journal.pone.0016627</ref> Frauer et al. also speculated that the CXXC domain of TET1 may be involved with protein-protein interactions instead of DNA binding.<ref name='Frauer et al.' />
</div>
<div style="width:33%;float:right;clear:right;border:1px solid black;">
<StructureSection load='5d9y' size='335' side='right' caption='Human TET2 in complex with DNA containing 5fC.' scene=''></StructureSection>
</div>

</div>

== Function ==
===Common Function===

All three TET enzymes and their isoforms are involved in the biochemical pathway that converts 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC). They also regulate the further conversions of 5hmC to 5-formylcytosine (5fC) and then 5fC to 5-carboxylcytosine (5caC).<ref name='He et al.'>DOI: 10.1126/science.1210944</ref> Although experimental data shows that TET3 does so to a lesser extent than TET1 and TET2.<ref name='He et al.' />

While the oxidation performed by TET enzymes was originally thought to be a source of DNA damage, new research has implied that this catalytic activity may actually be the initial steps of a process of DNA demethylation. This hypothesized DNA demethylation pathway starts with the conversion of 5mC to 5caC after several rounds of oxidation by TET enzymes. The next step is the removal of the modified cytosine base by thymine DNA glycosylase (TDG) which leaves an abasic site on the DNA. The last step is then the process of base excision repair in which a new unmodified cytosine is regenerated at the site, thus completing the process of DNA demethylation.<ref name='He et al.' /><ref name='Rahul M. Kohli & Yi Zhang'>DOI 10.1038/nature12750</ref>

[[Image:nsmb.2437-F1.jpg|395px|left|thumb|Cycle of DNA methylation and demethylation by DNA methyltransferases (DNMTs) and TET proteins.<ref>DOI 10.1038/nsmb.2437</ref>]]

===Specific Functions===
Experimental data shows that the TET genes have different expression patterns and at different levels, which indicates that each of the TET enzymes do not fully overlap in their functionality.

TET1 is usually expressed in fetal heart, lung, and brain tissue and in adult skeletal muscle, thymus, and ovary. It is not generally expressed in adult heart, lung, and brain tissue. Moreover, studies have shown that TET1 expression in adult brain tissue is correlated with brain cancer. This occurs through TET1’s indirect activation of brain cancer-related genes such as EGFR, AKT3, CDK6, CCND2, and BRAF through creation of 5hmC which recruits the CHTOP-methylosome complex that activates these genes.<ref>DOI 10.1016/j.celrep.2014.08.071</ref>

TET2 is broadly expressed, but it is especially highly expressed in hematopoietic cells, which develop into blood cells. Regarding this, it is suggested that TET2 plays a role in hematopoiesis due to the presence of TET2 mutations in many myelodysplastic syndromes.<ref name='Delhommeau et al.'>DOI 10.1056/NEJMoa0810069</ref><ref>DOI 10.1038/ng.391</ref>

TET3 is highly expressed in zygotes and is involved with epigenetic chromatin reprogramming in the zygote after fertilization. Specifically, it plays a role in DNA demethylation of the paternal pronucleus before implantation.<ref name='Rahul M. Kohli & Yi Zhang' />

== Disease Relation ==
=== TET1 Isoform ===

Point mutations within the TET1 isoform can lead to a loss of enzyme function which causes a lack of DNA demethylation; two occur at the 1672 and 1674 amino acid residues, the first being a H1672Y mutation and the second being a D1674A mutation. A severe mutation in the 1608-1609 codons can lead to TET1 becoming an oncogene in acute leukemias. This mutation fuses TET1 and KMT2A/MLL1 to form an oncogene.<ref>PMID:12124344</ref><ref>PMID:12646957</ref>

=== TET2 Isoform ===

TET2 has been identified as a tumor-suppressor gene that is linked to various myeloid cancers. Acquired mutations are predicted to truncate the protein, resulting in alterations of the function of the TET2 protein. TET2 defects have been identified in the CD34+ cells of patients with myelodysplastic syndrome, which include hematopoietic stem cells and hematopoietic progenitors. This suggests that TET2 mutations or defects, paired with mutations in other genes, such as Janus kinase 2 (JAK2) V617F gene or myeloproliferative leukemia virus oncogene (MPL) W515L/K can contribute to the progression of myeloid cancers. Due to the involvement of TET2 in hematopoietic stem cell development, mutations in this gene may also be associated with the amplification of the mutation in the early stages of hematopoietic differentiation.<ref name='Delhommeau et al.' />

== Structural highlights ==

The following highlights are of the Human TET2 enzyme in complex with DNA.

<scene name='72/728166/5d9y_helices_red/1'>Alpha helices</scene> are colored red.

<scene name='72/728166/5d9y_sheets_green/1'>Beta sheets</scene> are colored green.

Both <scene name='72/728166/5d9y_alpha_beta/1'>Alpha helices and beta sheets</scene> are displayed in this scene.

Here the <scene name='72/728166/5d9y_zinc_ions/1'>zinc ions</scene> are colored light blue, but since they are so small they may be slightly difficult to see.

Here some of the major residues of the <scene name='72/728166/5d9y_catalytic_site/1'>catalytic site</scene> are highlighted. The light green residues are 2-oxoglutarate binding residues, the orange residue binds the substrate, and the blue residue binds the catalytic iron ion. For the rest of the protein, only the backbone is shown in light gray.

== References ==
<references/>

User:Madelyn Kasprzak/Sandbox 6

2016-04-27T18:23:11Z

Madelyn Kasprzak:

== TET Enzymes==

TET enzymes are a family of [[Dioxygenase|dioxygenases]] that are involved in the process of oxidizing methylated cytosine. Members of this family include ten-eleven translocation methylcytosine dioxygenase 1 (<scene name='72/728164/Naegleria_gruberi_tet1/1'>TET1</scene>), methylcytosine dioxygenase <scene name='72/728164/Human_tet2_5fc/1'>TET2</scene>, and methylcytosine dioxygenase <scene name='72/728164/Xenopus_tropicalis_tet3_dna/1'>TET3</scene>. The gene for the first of these proteins, TET1, was identified when it was determined to be fused to the ''Mixed Lineage Leukemia'' (MLL) gene as a result of a translocation event that occurred between chromosomes ten and eleven (hence the name). <ref>DOI 10.1038/sj.leu.2402834</ref>

<div style="width:auto;clear:both;">
== Structure ==
<div style="width:66%;float:left;">

The TET enzymes have a cysteine-rich region closely followed by a double stranded beta-helix (DSBH) domain near their C-terminus.<ref name='Kinney et al.'>DOI 10.1007/978-1-4419-9967-2_3</ref> The DSBH domain contains three Fe<sup>2+</sup> binding sites and an α-ketoglutarate binding site.<ref name='Kinney et al.' /> For all α-ketoglutarate oxygenases, including TET enzymes, the DSBH domain and the preceding cysteine-rich region perform the main catalytic activity for these enzymes.

In addition, TET1 has a CXXC-type zinc finger domain near the N-terminus. However, the TET1 CXXC domain lacks the conserved lysine-phenylalanine-glycine-glycine (KFGG) motif commonly seen within the CXXC domains of other DNA binding proteins, such as DNA methyltransferase-1 (DNMT1). A study conducted by Frauer et al. in 2011 showed that the isolated CXXC domain of TET1 has no DNA binding activity, which agrees with the evidence suggesting that the KFGG motif increases affinity for unmethylated DNA.<ref name='Frauer et al.'>DOI 10.1371/journal.pone.0016627</ref> Frauer et al. also speculated that the CXXC domain of TET1 may be involved with protein-protein interactions instead of DNA binding.<ref name='Frauer et al.' />
</div>
<div style="width:33%;float:right;clear:right;border:1px solid black;">
<StructureSection load='5d9y' size='335' side='right' caption='Human TET2 in complex with DNA containing 5fC.' scene=''></StructureSection>
</div>

</div>

== Function ==
===Common Function===

All three TET enzymes and their isoforms are involved in the biochemical pathway that converts 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC). They also regulate the further conversions of 5hmC to 5-formylcytosine (5fC) and then 5fC to 5-carboxylcytosine (5caC).<ref name='He et al.'>DOI: 10.1126/science.1210944</ref> Although experimental data shows that TET3 does so to a lesser extent than TET1 and TET2.<ref name='He et al.' />

While the oxidation performed by TET enzymes was originally thought to be a source of DNA damage, new research has implied that this catalytic activity may actually be the initial steps of a process of DNA demethylation. This hypothesized DNA demethylation pathway starts with the conversion of 5mC to 5caC after several rounds of oxidation by TET enzymes. The next step is the removal of the modified cytosine base by thymine DNA glycosylase (TDG) which leaves an abasic site on the DNA. The last step is then the process of base excision repair in which a new unmodified cytosine is regenerated at the site, thus completing the process of DNA demethylation.<ref name='He et al.' /><ref name='Rahul M. Kohli & Yi Zhang'>DOI 10.1038/nature12750</ref>

[[Image:nsmb.2437-F1.jpg|395px|left|thumb|Cycle of DNA methylation and demethylation by DNA methyltransferases (DNMTs) and TET proteins.<ref>DOI 10.1038/nsmb.2437</ref>]]

===Specific Functions===
Experimental data shows that the TET genes have different expression patterns and at different levels, which indicates that each of the TET enzymes do not fully overlap in their functionality.

TET1 is usually expressed in fetal heart, lung, and brain tissue and in adult skeletal muscle, thymus, and ovary. It is not generally expressed in adult heart, lung, and brain tissue. Moreover, studies have shown that TET1 expression in adult brain tissue is correlated with brain cancer. This occurs through TET1’s indirect activation of brain cancer-related genes such as EGFR, AKT3, CDK6, CCND2, and BRAF through creation of 5hmC which recruits the CHTOP-methylosome complex that activates these genes.<ref>DOI 10.1016/j.celrep.2014.08.071</ref>

TET2 is broadly expressed, but it is especially highly expressed in hematopoietic cells, which develop into blood cells. Regarding this, it is suggested that TET2 plays a role in hematopoiesis due to the presence of TET2 mutations in many myelodysplastic syndromes.<ref name='Delhommeau et al.'>DOI 10.1056/NEJMoa0810069</ref><ref>DOI 10.1038/ng.391</ref>

TET3 is highly expressed in zygotes and is involved with epigenetic chromatin reprogramming in the zygote after fertilization. Specifically, it plays a role in DNA demethylation of the paternal pronucleus before implantation.<ref name='Rahul M. Kohli & Yi Zhang' />

== Disease Relation ==
=== TET1 Isoform ===

Point mutations within the TET1 isoform can lead to a loss of enzyme function which causes a lack of DNA demethylation; two occur at the 1672 and 1674 amino acid residues, the first being a H1672Y mutation and the second being a D1674A mutation. A severe mutation in the 1608-1609 codons can lead to TET1 becoming an oncogene in acute leukemias. This mutation fuses TET1 and KMT2A/MLL1 to form an oncogene.<ref>PMID:12124344</ref><ref>PMID:12646957</ref>

=== TET2 Isoform ===

TET2 has been identified as a tumor-suppressor gene that is linked to various myeloid cancers. Acquired mutations are predicted to truncate the protein, resulting in alterations of the function of the TET2 protein. TET2 defects have been identified in the CD34+ cells of patients with myelodysplastic syndrome, which include hematopoietic stem cells and hematopoietic progenitors. This suggests that TET2 mutations or defects, paired with mutations in other genes, such as Janus kinase 2 (JAK2) V617F gene or myeloproliferative leukemia virus oncogene (MPL) W515L/K can contribute to the progression of myeloid cancers. Due to the involvement of TET2 in hematopoietic stem cell development, mutations in this gene may also be associated with the amplification of the mutation in the early stages of hematopoietic differentiation.<ref name='Delhommeau et al.' />

== Structural highlights ==

The following highlights are of the Human TET2 enzyme in complex with DNA.

<scene name='72/728166/5d9y_helices_red/1'>Alpha helices</scene> are colored red.

<scene name='72/728166/5d9y_sheets_green/1'>Beta sheets</scene> are colored green.

Both <scene name='72/728166/5d9y_alpha_beta/1'>Alpha helices and beta sheets</scene> are displayed in this scene.

Here the <scene name='72/728166/5d9y_zinc_ions/1'>zinc ions</scene> are colored light blue, but since they are so small they may be slightly difficult to see.

Here some of the major residues of the <scene name='72/728166/5d9y_catalytic_site/1'>catalytic site</scene> are highlighted. The light green residues are 2-oxoglutarate binding residues, the orange residue binds the substrate, and the blue residue binds the catalytic iron ion. For the rest of the protein, only the backbone is shown in light gray.

== References ==
<references/>

User:Madelyn Kasprzak/Sandbox 6

2016-04-27T18:11:46Z

Madelyn Kasprzak:

== TET Enzymes==

TET enzymes are a family of [[Dioxygenase|dioxygenases]] that are involved in the process of oxidizing methylated cytosine. Members of this family include ten-eleven translocation methylcytosine dioxygenase 1 (<scene name='72/728164/Naegleria_gruberi_tet1/1'>TET1</scene>), methylcytosine dioxygenase <scene name='72/728164/Human_tet2_5fc/1'>TET2</scene>, and methylcytosine dioxygenase <scene name='72/728164/Xenopus_tropicalis_tet3_dna/1'>TET3</scene>. The gene for the first of these proteins, TET1, was identified when it was determined to be fused to the ''Mixed Lineage Leukemia'' (MLL) gene as a result of a translocation event that occurred between chromosomes ten and eleven (hence the name). <ref>DOI 10.1038/sj.leu.2402834</ref>

<div style="width:auto;clear:both;">
== Structure ==
<div style="width:66%;float:left;">

The TET enzymes have a cysteine-rich region closely followed by a double stranded beta-helix (DSBH) domain near their C-terminus.<ref name='Kinney et al.'>DOI 10.1007/978-1-4419-9967-2_3</ref> The DSBH domain contains three Fe<sup>2+</sup> binding sites and an α-ketoglutarate binding site.<ref name='Kinney et al.' /> For all α-ketoglutarate oxygenases, including TET enzymes, the DSBH domain and the preceding cysteine-rich region, perform the main catalytic activity for these enzymes.

In addition, TET1 has a CXXC-type zinc finger domain near the N-terminus. However, the TET1 CXXC domain lacks the conserved lysine-phenylalanine-glycine-glycine (KFGG) motif commonly seen within the CXXC domains of other DNA binding proteins, such as DNA methyltransferase-1 (DNMT1). A study conducted by Frauer et al. in 2011 showed that the isolated CXXC domain of TET1 has no DNA binding activity, which agrees with the evidence suggesting that the KFGG motif increases affinity for unmethylated DNA.<ref name='Frauer et al.'>DOI 10.1371/journal.pone.0016627</ref> Frauer et al. also speculated that the CXXC domain of TET1 may be involved with protein-protein interactions instead of DNA binding.<ref name='Frauer et al.' />
</div>
<div style="width:33%;float:right;clear:right;border:1px solid black;">
<StructureSection load='5d9y' size='335' side='right' caption='Human TET2 in complex with DNA containing 5fC.' scene=''></StructureSection>
</div>

</div>

== Function ==
===Common Function===

All three TET enzymes and their isoforms are involved in the biochemical pathway that converts 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC). They also regulate the further conversions of 5hmC to 5-formylcytosine (5fC) and then 5fC to 5-carboxylcytosine (5caC).<ref name='He et al.'>DOI: 10.1126/science.1210944</ref> Although experimental data shows that TET3 does so to a lesser extent than TET1 and TET2.<ref name='He et al.' />

While the oxidation performed by TET enzymes was originally thought to be a source of DNA damage, new research has implied that this catalytic activity may actually be the initial steps of a process of DNA demethylation. This hypothesized DNA demethylation pathway starts with the conversion of 5mC to 5caC after several rounds of oxidation by TET enzymes. The next step is the removal of the modified cytosine base by thymine DNA glycosylase (TDG) which leaves an abasic site on the DNA. The last step is then the process of base excision repair in which a new unmodified cytosine is regenerated at the site, thus completing the process of DNA demethylation.<ref name='He et al.' /><ref name='Rahul M. Kohli & Yi Zhang'>DOI 10.1038/nature12750</ref>

[[Image:nsmb.2437-F1.jpg|400px|left|thumb|Cycle of DNA methylation and demethylation by DNA methyltransferases (DNMTs) and TET proteins.<ref>DOI 10.1038/nsmb.2437</ref>]]

===Specific Functions===
Experimental data shows that the TET genes have different expression patterns and at different levels, which indicates that each of the TET enzymes do not fully overlap in their functionality.

TET1 is usually expressed in fetal heart, lung, and brain tissue and in adult skeletal muscle, thymus, and ovary. It is not generally expressed in adult heart, lung, and brain tissue. Moreover, studies have shown that TET1 expression in adult brain tissue is correlated with brain cancer. This occurs through TET1’s indirect activation of brain cancer-related genes such as EGFR, AKT3, CDK6, CCND2, and BRAF through creation of 5hmC which recruits the CHTOP-methylosome complex that activates these genes.<ref>DOI 10.1016/j.celrep.2014.08.071</ref>

TET2 is broadly expressed, but it is especially highly expressed in hematopoietic cells, which develop into blood cells. Regarding this, it is suggested that TET2 plays a role in hematopoiesis due to the presence of TET2 mutations in many myelodysplastic syndromes.<ref name='Delhommeau et al.'>DOI 10.1056/NEJMoa0810069</ref><ref>DOI 10.1038/ng.391</ref>

TET3 is highly expressed in zygotes and is involved with epigenetic chromatin reprogramming in the zygote after fertilization. Specifically, it plays a role in DNA demethylation of the paternal pronucleus before implantation.<ref name='Rahul M. Kohli & Yi Zhang' />

== Disease Relation ==
=== TET1 Isoform ===

Point mutations within the TET1 isoform can lead to a loss of enzyme function which causes a lack of DNA demethylation; two occur at the 1672 and 1674 amino acid residues, the first being a H1672Y mutation and the second being a D1674A mutation. A severe mutation in the 1608-1609 codons can lead to TET1 becoming an oncogene in acute leukemias. This mutation fuses TET1 and KMT2A/MLL1 to form an oncogene.<ref>PMID:12124344</ref><ref>PMID:12646957</ref>

=== TET2 Isoform ===

TET2 has been identified as a tumor-suppressor gene that is linked to various myeloid cancers. Acquired mutations are predicted to truncate the protein, resulting in alterations of the function of the TET2 protein. TET2 defects have been identified in the CD34+ cells of patients with myelodysplastic syndrome, which include hematopoietic stem cells and hematopoietic progenitors. This suggests that TET2 mutations or defects, paired with mutations in other genes, such as Janus kinase 2 (JAK2) V617F gene or myeloproliferative leukemia virus oncogene (MPL) W515L/K can contribute to the progression of myeloid cancers. Due to the involvement of TET2 in hematopoietic stem cell development, mutations in this gene may also be associated with the amplification of the mutation in the early stages of hematopoietic differentiation.<ref name='Delhommeau et al.' />

== Structural highlights ==

The following highlights are of the Human TET2 enzyme in complex with DNA.

<scene name='72/728166/5d9y_helices_red/1'>Alpha helices</scene> are colored red.

<scene name='72/728166/5d9y_sheets_green/1'>Beta sheets</scene> are colored green.

Both <scene name='72/728166/5d9y_alpha_beta/1'>Alpha helices and beta sheets</scene> are displayed in this scene.

Here the <scene name='72/728166/5d9y_zinc_ions/1'>zinc ions</scene> are colored light blue, but since they are so small they may be slightly difficult to see.

Here some of the major residues of the <scene name='72/728166/5d9y_catalytic_site/1'>catalytic site</scene> are highlighted. The light green residues are 2-oxoglutarate binding residues, the orange residue binds the substrate, and the blue residue binds the catalytic iron ion. For the rest of the protein, only the backbone is shown in light gray.

== References ==
<references/>

User:Madelyn Kasprzak/Sandbox 6

2016-04-27T18:10:00Z

Madelyn Kasprzak:

== TET Enzymes==

TET enzymes are a family of [[Dioxygenase|dioxygenases]] that are involved in the process of oxidizing methylated cytosine. Members of this family include ten-eleven translocation methylcytosine dioxygenase 1 (<scene name='72/728164/Naegleria_gruberi_tet1/1'>TET1</scene>), methylcytosine dioxygenase <scene name='72/728164/Human_tet2_5fc/1'>TET2</scene>, and methylcytosine dioxygenase <scene name='72/728164/Xenopus_tropicalis_tet3_dna/1'>TET3</scene>. The gene for the first of these proteins, TET1, was identified when it was determined to be fused to the ''Mixed Lineage Leukemia'' (MLL) gene as a result of a translocation event that occurred between chromosomes ten and eleven (hence the name). <ref>DOI 10.1038/sj.leu.2402834</ref>

<div style="width:auto;clear:both;">
== Structure ==
<div style="width:66%;float:left;">

The TET enzymes have a cysteine-rich region closely followed by a double stranded beta-helix (DSBH) domain near their C-terminus.<ref name='Kinney et al.'>DOI 10.1007/978-1-4419-9967-2_3</ref> The DSBH domain contains three Fe<sup>2+</sup> binding sites and an α-ketoglutarate binding site.<ref name='Kinney et al.' /> For all α-ketoglutarate oxygenases, including TET enzymes, the DSBH domain and the preceding cysteine-rich region, perform the main catalytic activity for these enzymes.

In addition, TET1 has a CXXC-type zinc finger domain near the N-terminus. However, the TET1 CXXC domain lacks the conserved lysine-phenylalanine-glycine-glycine (KFGG) motif commonly seen within the CXXC domains of other DNA binding proteins, such as DNA methyltransferase-1 (DNMT1). A study conducted by Frauer et al. in 2011 showed that the isolated CXXC domain of TET1 has no DNA binding activity, which agrees with the evidence suggesting that the KFGG motif increases affinity for unmethylated DNA.<ref name='Frauer et al.'>DOI 10.1371/journal.pone.0016627</ref> Frauer et al. also speculated that the CXXC domain of TET1 may be involved with protein-protein interactions instead of DNA binding.<ref name='Frauer et al.' />
</div>
<div style="width:33%;float:right;clear:right;border:1px solid black;">
<StructureSection load='5d9y' size='333' side='right' caption='Human TET2 in complex with DNA containing 5fC.' scene=''></StructureSection>
</div>

</div>

== Function ==
===Common Function===

All three TET enzymes and their isoforms are involved in the biochemical pathway that converts 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC). They also regulate the further conversions of 5hmC to 5-formylcytosine (5fC) and then 5fC to 5-carboxylcytosine (5caC).<ref name='He et al.'>DOI: 10.1126/science.1210944</ref> Although experimental data shows that TET3 does so to a lesser extent than TET1 and TET2.<ref name='He et al.' />

While the oxidation performed by TET enzymes was originally thought to be a source of DNA damage, new research has implied that this catalytic activity may actually be the initial steps of a process of DNA demethylation. This hypothesized DNA demethylation pathway starts with the conversion of 5mC to 5caC after several rounds of oxidation by TET enzymes. The next step is the removal of the modified cytosine base by thymine DNA glycosylase (TDG) which leaves an abasic site on the DNA. The last step is then the process of base excision repair in which a new unmodified cytosine is regenerated at the site, thus completing the process of DNA demethylation.<ref name='He et al.' /><ref name='Rahul M. Kohli & Yi Zhang'>DOI 10.1038/nature12750</ref>

[[Image:nsmb.2437-F1.jpg|400px|left|thumb|Cycle of DNA methylation and demethylation by DNA methyltransferases (DNMTs) and TET proteins.<ref>DOI 10.1038/nsmb.2437</ref>]]

===Specific Functions===
Experimental data shows that the TET genes have different expression patterns and at different levels, which indicates that each of the TET enzymes do not fully overlap in their functionality.

TET1 is usually expressed in fetal heart, lung, and brain tissue and in adult skeletal muscle, thymus, and ovary. It is not generally expressed in adult heart, lung, and brain tissue. Moreover, studies have shown that TET1 expression in adult brain tissue is correlated with brain cancer. This occurs through TET1’s indirect activation of brain cancer-related genes such as EGFR, AKT3, CDK6, CCND2, and BRAF through creation of 5hmC which recruits the CHTOP-methylosome complex that activates these genes.<ref>DOI 10.1016/j.celrep.2014.08.071</ref>

TET2 is broadly expressed, but it is especially highly expressed in hematopoietic cells, which develop into blood cells. Regarding this, it is suggested that TET2 plays a role in hematopoiesis due to the presence of TET2 mutations in many myelodysplastic syndromes.<ref name='Delhommeau et al.'>DOI 10.1056/NEJMoa0810069</ref><ref>DOI 10.1038/ng.391</ref>

TET3 is highly expressed in zygotes and is involved with epigenetic chromatin reprogramming in the zygote after fertilization. Specifically, it plays a role in DNA demethylation of the paternal pronucleus before implantation.<ref name='Rahul M. Kohli & Yi Zhang' />

== Disease Relation ==
=== TET1 Isoform ===

Point mutations within the TET1 isoform can lead to a loss of enzyme function which causes a lack of DNA demethylation; two occur at the 1672 and 1674 amino acid residues, the first being a H1672Y mutation and the second being a D1674A mutation. A severe mutation in the 1608-1609 codons can lead to TET1 becoming an oncogene in acute leukemias. This mutation fuses TET1 and KMT2A/MLL1 to form an oncogene.<ref>PMID:12124344</ref><ref>PMID:12646957</ref>

=== TET2 Isoform ===

TET2 has been identified as a tumor-suppressor gene that is linked to various myeloid cancers. Acquired mutations are predicted to truncate the protein, resulting in alterations of the function of the TET2 protein. TET2 defects have been identified in the CD34+ cells of patients with myelodysplastic syndrome, which include hematopoietic stem cells and hematopoietic progenitors. This suggests that TET2 mutations or defects, paired with mutations in other genes, such as Janus kinase 2 (JAK2) V617F gene or myeloproliferative leukemia virus oncogene (MPL) W515L/K can contribute to the progression of myeloid cancers. Due to the involvement of TET2 in hematopoietic stem cell development, mutations in this gene may also be associated with the amplification of the mutation in the early stages of hematopoietic differentiation.<ref name='Delhommeau et al.' />

== Structural highlights ==

The following highlights are of the Human TET2 enzyme in complex with DNA.

<scene name='72/728166/5d9y_helices_red/1'>Alpha helices</scene> are colored red.

<scene name='72/728166/5d9y_sheets_green/1'>Beta sheets</scene> are colored green.

Both <scene name='72/728166/5d9y_alpha_beta/1'>Alpha helices and beta sheets</scene> are displayed in this scene.

Here the <scene name='72/728166/5d9y_zinc_ions/1'>zinc ions</scene> are colored light blue, but since they are so small they may be slightly difficult to see.

Here some of the major residues of the <scene name='72/728166/5d9y_catalytic_site/1'>catalytic site</scene> are highlighted. The light green residues are 2-oxoglutarate binding residues, the orange residue binds the substrate, and the blue residue binds the catalytic iron ion. For the rest of the protein, only the backbone is shown in light gray.

== References ==
<references/>

User:Madelyn Kasprzak/Sandbox 6

2016-04-27T18:01:36Z

Madelyn Kasprzak:

== TET Enzymes==

TET enzymes are a family of [[Dioxygenase|dioxygenases]] that are involved in the process of oxidizing methylated cytosine. Members of this family include ten-eleven translocation methylcytosine dioxygenase 1 (<scene name='72/728164/Naegleria_gruberi_tet1/1'>TET1</scene>), methylcytosine dioxygenase <scene name='72/728164/Human_tet2_5fc/1'>TET2</scene>, and methylcytosine dioxygenase <scene name='72/728164/Xenopus_tropicalis_tet3_dna/1'>TET3</scene>. The gene for the first of these proteins, TET1, was identified when it was determined to be fused to the ''Mixed Lineage Leukemia'' (MLL) gene as a result of a translocation event that occurred between chromosomes ten and eleven (hence the name). <ref>DOI 10.1038/sj.leu.2402834</ref>

<div style="width:auto;clear:both;">
== Structure ==
<div style="width:50%;float:left;">

The TET enzymes have a cysteine-rich region closely followed by a double stranded beta-helix (DSBH) domain near their C-terminus.<ref name='Kinney et al.'>DOI 10.1007/978-1-4419-9967-2_3</ref> The DSBH domain contains three Fe<sup>2+</sup> binding sites and an α-ketoglutarate binding site.<ref name='Kinney et al.' /> For all α-ketoglutarate oxygenases, including TET enzymes, the DSBH domain and the preceding cysteine-rich region, perform the main catalytic activity for these enzymes.

In addition, TET1 has a CXXC-type zinc finger domain near the N-terminus. However, the TET1 CXXC domain lacks the conserved lysine-phenylalanine-glycine-glycine (KFGG) motif commonly seen within the CXXC domains of other DNA binding proteins, such as DNA methyltransferase-1 (DNMT1). A study conducted by Frauer et al. in 2011 showed that the isolated CXXC domain of TET1 has no DNA binding activity, which agrees with the evidence suggesting that the KFGG motif increases affinity for unmethylated DNA.<ref name='Frauer et al.'>DOI 10.1371/journal.pone.0016627</ref> Frauer et al. also speculated that the CXXC domain of TET1 may be involved with protein-protein interactions instead of DNA binding.<ref name='Frauer et al.' />
</div>
<div style="width:45%;float:right;clear:right;border:1px solid black;">
<StructureSection load='5d9y' size='360' side='right' caption='Human TET2 in complex with DNA containing 5fC.' scene=''></StructureSection>
</div>
</div>

== Function ==
===Common Function===

All three TET enzymes and their isoforms are involved in the biochemical pathway that converts 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC). They also regulate the further conversions of 5hmC to 5-formylcytosine (5fC) and then 5fC to 5-carboxylcytosine (5caC).<ref name='He et al.'>DOI: 10.1126/science.1210944</ref> Although experimental data shows that TET3 does so to a lesser extent than TET1 and TET2.<ref name='He et al.' />

While the oxidation performed by TET enzymes was originally thought to be a source of DNA damage, new research has implied that this catalytic activity may actually be the initial steps of a process of DNA demethylation. This hypothesized DNA demethylation pathway starts with the conversion of 5mC to 5caC after several rounds of oxidation by TET enzymes. The next step is the removal of the modified cytosine base by thymine DNA glycosylase (TDG) which leaves an abasic site on the DNA. The last step is then the process of base excision repair in which a new unmodified cytosine is regenerated at the site, thus completing the process of DNA demethylation.<ref name='He et al.' /><ref name='Rahul M. Kohli & Yi Zhang'>DOI 10.1038/nature12750</ref>

[[Image:nsmb.2437-F1.jpg|400px|left|thumb|Cycle of DNA methylation and demethylation by DNA methyltransferases (DNMTs) and TET proteins.<ref>DOI 10.1038/nsmb.2437</ref>]]

===Specific Functions===
Experimental data shows that the TET genes have different expression patterns and at different levels, which indicates that each of the TET enzymes do not fully overlap in their functionality.

TET1 is usually expressed in fetal heart, lung, and brain tissue and in adult skeletal muscle, thymus, and ovary. It is not generally expressed in adult heart, lung, and brain tissue. Moreover, studies have shown that TET1 expression in adult brain tissue is correlated with brain cancer. This occurs through TET1’s indirect activation of brain cancer-related genes such as EGFR, AKT3, CDK6, CCND2, and BRAF through creation of 5hmC which recruits the CHTOP-methylosome complex that activates these genes.<ref>DOI 10.1016/j.celrep.2014.08.071</ref>

TET2 is broadly expressed, but it is especially highly expressed in hematopoietic cells, which develop into blood cells. Regarding this, it is suggested that TET2 plays a role in hematopoiesis due to the presence of TET2 mutations in many myelodysplastic syndromes.<ref name='Delhommeau et al.'>DOI 10.1056/NEJMoa0810069</ref><ref>DOI 10.1038/ng.391</ref>

TET3 is highly expressed in zygotes and is involved with epigenetic chromatin reprogramming in the zygote after fertilization. Specifically, it plays a role in DNA demethylation of the paternal pronucleus before implantation.<ref name='Rahul M. Kohli & Yi Zhang' />

== Disease Relation ==
=== TET1 Isoform ===

Point mutations within the TET1 isoform can lead to a loss of enzyme function which causes a lack of DNA demethylation; two occur at the 1672 and 1674 amino acid residues, the first being a H1672Y mutation and the second being a D1674A mutation. A severe mutation in the 1608-1609 codons can lead to TET1 becoming an oncogene in acute leukemias. This mutation fuses TET1 and KMT2A/MLL1 to form an oncogene.<ref>PMID:12124344</ref><ref>PMID:12646957</ref>

=== TET2 Isoform ===

TET2 has been identified as a tumor-suppressor gene that is linked to various myeloid cancers. Acquired mutations are predicted to truncate the protein, resulting in alterations of the function of the TET2 protein. TET2 defects have been identified in the CD34+ cells of patients with myelodysplastic syndrome, which include hematopoietic stem cells and hematopoietic progenitors. This suggests that TET2 mutations or defects, paired with mutations in other genes, such as Janus kinase 2 (JAK2) V617F gene or myeloproliferative leukemia virus oncogene (MPL) W515L/K can contribute to the progression of myeloid cancers. Due to the involvement of TET2 in hematopoietic stem cell development, mutations in this gene may also be associated with the amplification of the mutation in the early stages of hematopoietic differentiation.<ref name='Delhommeau et al.' />

== Structural highlights ==

The following highlights are of the Human TET2 enzyme in complex with DNA.

<scene name='72/728166/5d9y_helices_red/1'>Alpha helices</scene> are colored red.

<scene name='72/728166/5d9y_sheets_green/1'>Beta sheets</scene> are colored green.

Both <scene name='72/728166/5d9y_alpha_beta/1'>Alpha helices and beta sheets</scene> are displayed in this scene.

Here the <scene name='72/728166/5d9y_zinc_ions/1'>zinc ions</scene> are colored light blue, but since they are so small they may be slightly difficult to see.

Here some of the major residues of the <scene name='72/728166/5d9y_catalytic_site/1'>catalytic site</scene> are highlighted. The light green residues are 2-oxoglutarate binding residues, the orange residue binds the substrate, and the blue residue binds the catalytic iron ion. For the rest of the protein, only the backbone is shown in light gray.

== References ==
<references/>

User:Madelyn Kasprzak/Sandbox 6

2016-04-27T17:38:28Z

Madelyn Kasprzak: changed viewer size

== TET Enzymes==

TET enzymes are a family of [[Dioxygenase|dioxygenases]] that are involved in the process of oxidizing methylated cytosine. Members of this family include ten-eleven translocation methylcytosine dioxygenase 1 (<scene name='72/728164/Naegleria_gruberi_tet1/1'>TET1</scene>), methylcytosine dioxygenase <scene name='72/728164/Human_tet2_5fc/1'>TET2</scene>, and methylcytosine dioxygenase <scene name='72/728164/Xenopus_tropicalis_tet3_dna/1'>TET3</scene>. The gene for the first of these proteins, TET1, was identified when it was determined to be fused to the ''Mixed Lineage Leukemia'' (MLL) gene as a result of a translocation event that occurred between chromosomes ten and eleven (hence the name). <ref>DOI 10.1038/sj.leu.2402834</ref>

<StructureSection load='5d9y' size='400' side='right' caption='Human TET2 in complex with DNA containing 5fC.' scene=''>

== Structure ==
The TET enzymes have a cysteine-rich region closely followed by a double stranded beta-helix (DSBH) domain near their C-terminus.<ref name='Kinney et al.'>DOI 10.1007/978-1-4419-9967-2_3</ref> The DSBH domain contains three Fe<sup>2+</sup> binding sites and an α-ketoglutarate binding site.<ref name='Kinney et al.' /> For all α-ketoglutarate oxygenases, including TET enzymes, the DSBH domain and the preceding cysteine-rich region, perform the main catalytic activity for these enzymes.

In addition, TET1 has a CXXC-type zinc finger domain near the N-terminus. However, the TET1 CXXC domain lacks the conserved lysine-phenylalanine-glycine-glycine (KFGG) motif commonly seen within the CXXC domains of other DNA binding proteins, such as DNA methyltransferase-1 (DNMT1). A study conducted by Frauer et al. in 2011 showed that the isolated CXXC domain of TET1 has no DNA binding activity, which agrees with the evidence suggesting that the KFGG motif increases affinity for unmethylated DNA.<ref name='Frauer et al.'>DOI 10.1371/journal.pone.0016627</ref> Frauer et al. also speculated that the CXXC domain of TET1 may be involved with protein-protein interactions instead of DNA binding.<ref name='Frauer et al.' />

</StructureSection>

== Function ==
===Common Function===

All three TET enzymes and their isoforms are involved in the biochemical pathway that converts 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC). They also regulate the further conversions of 5hmC to 5-formylcytosine (5fC) and then 5fC to 5-carboxylcytosine (5caC).<ref name='He et al.'>DOI: 10.1126/science.1210944</ref> Although experimental data shows that TET3 does so to a lesser extent than TET1 and TET2.<ref name='He et al.' />

While the oxidation performed by TET enzymes was originally thought to be a source of DNA damage, new research has implied that this catalytic activity may actually be the initial steps of a process of DNA demethylation. This hypothesized DNA demethylation pathway starts with the conversion of 5mC to 5caC after several rounds of oxidation by TET enzymes. The next step is the removal of the modified cytosine base by thymine DNA glycosylase (TDG) which leaves an abasic site on the DNA. The last step is then the process of base excision repair in which a new unmodified cytosine is regenerated at the site, thus completing the process of DNA demethylation.<ref name='He et al.' /><ref name='Rahul M. Kohli & Yi Zhang'>DOI 10.1038/nature12750</ref>

[[Image:nsmb.2437-F1.jpg|400px|left|thumb|Cycle of DNA methylation and demethylation by DNA methyltransferases (DNMTs) and TET proteins.<ref>DOI 10.1038/nsmb.2437</ref>]]

===Specific Functions===
Experimental data shows that the TET genes have different expression patterns and at different levels, which indicates that each of the TET enzymes do not fully overlap in their functionality.

TET1 is usually expressed in fetal heart, lung, and brain tissue and in adult skeletal muscle, thymus, and ovary. It is not generally expressed in adult heart, lung, and brain tissue. Moreover, studies have shown that TET1 expression in adult brain tissue is correlated with brain cancer. This occurs through TET1’s indirect activation of brain cancer-related genes such as EGFR, AKT3, CDK6, CCND2, and BRAF through creation of 5hmC which recruits the CHTOP-methylosome complex that activates these genes.<ref>DOI 10.1016/j.celrep.2014.08.071</ref>

TET2 is broadly expressed, but it is especially highly expressed in hematopoietic cells, which develop into blood cells. Regarding this, it is suggested that TET2 plays a role in hematopoiesis due to the presence of TET2 mutations in many myelodysplastic syndromes.<ref name='Delhommeau et al.'>DOI 10.1056/NEJMoa0810069</ref><ref>DOI 10.1038/ng.391</ref>

TET3 is highly expressed in zygotes and is involved with epigenetic chromatin reprogramming in the zygote after fertilization. Specifically, it plays a role in DNA demethylation of the paternal pronucleus before implantation.<ref name='Rahul M. Kohli & Yi Zhang' />

== Disease Relation ==
=== TET1 Isoform ===

Point mutations within the TET1 isoform can lead to a loss of enzyme function which causes a lack of DNA demethylation; two occur at the 1672 and 1674 amino acid residues, the first being a H1672Y mutation and the second being a D1674A mutation. A severe mutation in the 1608-1609 codons can lead to TET1 becoming an oncogene in acute leukemias. This mutation fuses TET1 and KMT2A/MLL1 to form an oncogene.<ref>PMID:12124344</ref><ref>PMID:12646957</ref>

=== TET2 Isoform ===

TET2 has been identified as a tumor-suppressor gene that is linked to various myeloid cancers. Acquired mutations are predicted to truncate the protein, resulting in alterations of the function of the TET2 protein. TET2 defects have been identified in the CD34+ cells of patients with myelodysplastic syndrome, which include hematopoietic stem cells and hematopoietic progenitors. This suggests that TET2 mutations or defects, paired with mutations in other genes, such as Janus kinase 2 (JAK2) V617F gene or myeloproliferative leukemia virus oncogene (MPL) W515L/K can contribute to the progression of myeloid cancers. Due to the involvement of TET2 in hematopoietic stem cell development, mutations in this gene may also be associated with the amplification of the mutation in the early stages of hematopoietic differentiation.<ref name='Delhommeau et al.' />

== Structural highlights ==

The following highlights are of the Human TET2 enzyme in complex with DNA.

<scene name='72/728166/5d9y_helices_red/1'>Alpha helices</scene> are colored red.

<scene name='72/728166/5d9y_sheets_green/1'>Beta sheets</scene> are colored green.

Both <scene name='72/728166/5d9y_alpha_beta/1'>Alpha helices and beta sheets</scene> are displayed in this scene.

Here the <scene name='72/728166/5d9y_zinc_ions/1'>zinc ions</scene> are colored light blue, but since they are so small they may be slightly difficult to see.

Here some of the major residues of the <scene name='72/728166/5d9y_catalytic_site/1'>catalytic site</scene> are highlighted. The light green residues are 2-oxoglutarate binding residues, the orange residue binds the substrate, and the blue residue binds the catalytic iron ion. For the rest of the protein, only the backbone is shown in light gray.

== References ==
<references/>

User:Madelyn Kasprzak/Sandbox 6

2016-04-27T17:35:29Z

Madelyn Kasprzak: altered page layout

== TET Enzymes==

TET enzymes are a family of [[Dioxygenase|dioxygenases]] that are involved in the process of oxidizing methylated cytosine. Members of this family include ten-eleven translocation methylcytosine dioxygenase 1 (<scene name='72/728164/Naegleria_gruberi_tet1/1'>TET1</scene>), methylcytosine dioxygenase <scene name='72/728164/Human_tet2_5fc/1'>TET2</scene>, and methylcytosine dioxygenase <scene name='72/728164/Xenopus_tropicalis_tet3_dna/1'>TET3</scene>. The gene for the first of these proteins, TET1, was identified when it was determined to be fused to the ''Mixed Lineage Leukemia'' (MLL) gene as a result of a translocation event that occurred between chromosomes ten and eleven (hence the name). <ref>DOI 10.1038/sj.leu.2402834</ref>

<StructureSection load='5d9y' size='320' side='right' caption='Human TET2 in complex with DNA containing 5fC.' scene=''>

== Structure ==
The TET enzymes have a cysteine-rich region closely followed by a double stranded beta-helix (DSBH) domain near their C-terminus.<ref name='Kinney et al.'>DOI 10.1007/978-1-4419-9967-2_3</ref> The DSBH domain contains three Fe<sup>2+</sup> binding sites and an α-ketoglutarate binding site.<ref name='Kinney et al.' /> For all α-ketoglutarate oxygenases, including TET enzymes, the DSBH domain and the preceding cysteine-rich region, perform the main catalytic activity for these enzymes.

In addition, TET1 has a CXXC-type zinc finger domain near the N-terminus. However, the TET1 CXXC domain lacks the conserved lysine-phenylalanine-glycine-glycine (KFGG) motif commonly seen within the CXXC domains of other DNA binding proteins, such as DNA methyltransferase-1 (DNMT1). A study conducted by Frauer et al. in 2011 showed that the isolated CXXC domain of TET1 has no DNA binding activity, which agrees with the evidence suggesting that the KFGG motif increases affinity for unmethylated DNA.<ref name='Frauer et al.'>DOI 10.1371/journal.pone.0016627</ref> Frauer et al. also speculated that the CXXC domain of TET1 may be involved with protein-protein interactions instead of DNA binding.<ref name='Frauer et al.' />

</StructureSection>

== Function ==
===Common Function===

All three TET enzymes and their isoforms are involved in the biochemical pathway that converts 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC). They also regulate the further conversions of 5hmC to 5-formylcytosine (5fC) and then 5fC to 5-carboxylcytosine (5caC).<ref name='He et al.'>DOI: 10.1126/science.1210944</ref> Although experimental data shows that TET3 does so to a lesser extent than TET1 and TET2.<ref name='He et al.' />

While the oxidation performed by TET enzymes was originally thought to be a source of DNA damage, new research has implied that this catalytic activity may actually be the initial steps of a process of DNA demethylation. This hypothesized DNA demethylation pathway starts with the conversion of 5mC to 5caC after several rounds of oxidation by TET enzymes. The next step is the removal of the modified cytosine base by thymine DNA glycosylase (TDG) which leaves an abasic site on the DNA. The last step is then the process of base excision repair in which a new unmodified cytosine is regenerated at the site, thus completing the process of DNA demethylation.<ref name='He et al.' /><ref name='Rahul M. Kohli & Yi Zhang'>DOI 10.1038/nature12750</ref>

[[Image:nsmb.2437-F1.jpg|400px|left|thumb|Cycle of DNA methylation and demethylation by DNA methyltransferases (DNMTs) and TET proteins.<ref>DOI 10.1038/nsmb.2437</ref>]]

===Specific Functions===
Experimental data shows that the TET genes have different expression patterns and at different levels, which indicates that each of the TET enzymes do not fully overlap in their functionality.

TET1 is usually expressed in fetal heart, lung, and brain tissue and in adult skeletal muscle, thymus, and ovary. It is not generally expressed in adult heart, lung, and brain tissue. Moreover, studies have shown that TET1 expression in adult brain tissue is correlated with brain cancer. This occurs through TET1’s indirect activation of brain cancer-related genes such as EGFR, AKT3, CDK6, CCND2, and BRAF through creation of 5hmC which recruits the CHTOP-methylosome complex that activates these genes.<ref>DOI 10.1016/j.celrep.2014.08.071</ref>

TET2 is broadly expressed, but it is especially highly expressed in hematopoietic cells, which develop into blood cells. Regarding this, it is suggested that TET2 plays a role in hematopoiesis due to the presence of TET2 mutations in many myelodysplastic syndromes.<ref name='Delhommeau et al.'>DOI 10.1056/NEJMoa0810069</ref><ref>DOI 10.1038/ng.391</ref>

TET3 is highly expressed in zygotes and is involved with epigenetic chromatin reprogramming in the zygote after fertilization. Specifically, it plays a role in DNA demethylation of the paternal pronucleus before implantation.<ref name='Rahul M. Kohli & Yi Zhang' />

== Disease Relation ==
=== TET1 Isoform ===

Point mutations within the TET1 isoform can lead to a loss of enzyme function which causes a lack of DNA demethylation; two occur at the 1672 and 1674 amino acid residues, the first being a H1672Y mutation and the second being a D1674A mutation. A severe mutation in the 1608-1609 codons can lead to TET1 becoming an oncogene in acute leukemias. This mutation fuses TET1 and KMT2A/MLL1 to form an oncogene.<ref>PMID:12124344</ref><ref>PMID:12646957</ref>

=== TET2 Isoform ===

TET2 has been identified as a tumor-suppressor gene that is linked to various myeloid cancers. Acquired mutations are predicted to truncate the protein, resulting in alterations of the function of the TET2 protein. TET2 defects have been identified in the CD34+ cells of patients with myelodysplastic syndrome, which include hematopoietic stem cells and hematopoietic progenitors. This suggests that TET2 mutations or defects, paired with mutations in other genes, such as Janus kinase 2 (JAK2) V617F gene or myeloproliferative leukemia virus oncogene (MPL) W515L/K can contribute to the progression of myeloid cancers. Due to the involvement of TET2 in hematopoietic stem cell development, mutations in this gene may also be associated with the amplification of the mutation in the early stages of hematopoietic differentiation.<ref name='Delhommeau et al.' />

== Structural highlights ==

The following highlights are of the Human TET2 enzyme in complex with DNA.

<scene name='72/728166/5d9y_helices_red/1'>Alpha helices</scene> are colored red.

<scene name='72/728166/5d9y_sheets_green/1'>Beta sheets</scene> are colored green.

Both <scene name='72/728166/5d9y_alpha_beta/1'>Alpha helices and beta sheets</scene> are displayed in this scene.

Here the <scene name='72/728166/5d9y_zinc_ions/1'>zinc ions</scene> are colored light blue, but since they are so small they may be slightly difficult to see.

Here some of the major residues of the <scene name='72/728166/5d9y_catalytic_site/1'>catalytic site</scene> are highlighted. The light green residues are 2-oxoglutarate binding residues, the orange residue binds the substrate, and the blue residue binds the catalytic iron ion. For the rest of the protein, only the backbone is shown in light gray.

== References ==
<references/>

User:Madelyn Kasprzak/Sandbox 6

2016-04-27T17:17:27Z

Madelyn Kasprzak:

== TET Enzymes==

TET enzymes are a family of [[Dioxygenase|dioxygenases]] that are involved in the process of oxidizing methylated cytosine. Members of this family include ten-eleven translocation methylcytosine dioxygenase 1 (<scene name='72/728164/Naegleria_gruberi_tet1/1'>TET1</scene>), methylcytosine dioxygenase <scene name='72/728164/Human_tet2_5fc/1'>TET2</scene>, and methylcytosine dioxygenase <scene name='72/728164/Xenopus_tropicalis_tet3_dna/1'>TET3</scene>. The gene for the first of these proteins, TET1, was identified when it was determined to be fused to the ''Mixed Lineage Leukemia'' (MLL) gene as a result of a translocation event that occurred between chromosomes ten and eleven (hence the name). <ref>DOI 10.1038/sj.leu.2402834</ref>

<StructureSection load='5d9y' size='320' side='right' caption='Human TET2 in complex with DNA containing 5fC.' scene=''>

== Structure ==
The TET enzymes have a cysteine-rich region closely followed by a double stranded beta-helix (DSBH) domain near their C-terminus.<ref name='Kinney et al.'>DOI 10.1007/978-1-4419-9967-2_3</ref> The DSBH domain contains three Fe<sup>2+</sup> binding sites and an α-ketoglutarate binding site.<ref name='Kinney et al.' /> For all α-ketoglutarate oxygenases, including TET enzymes, the DSBH domain and the preceding cysteine-rich region, perform the main catalytic activity for these enzymes.

In addition, TET1 has a CXXC-type zinc finger domain near the N-terminus. However, the TET1 CXXC domain lacks the conserved lysine-phenylalanine-glycine-glycine (KFGG) motif commonly seen within the CXXC domains of other DNA binding proteins, such as DNA methyltransferase-1 (DNMT1). A study conducted by Frauer et al. in 2011 showed that the isolated CXXC domain of TET1 has no DNA binding activity, which agrees with the evidence suggesting that the KFGG motif increases affinity for unmethylated DNA.<ref name='Frauer et al.'>DOI 10.1371/journal.pone.0016627</ref> Frauer et al. also speculated that the CXXC domain of TET1 may be involved with protein-protein interactions instead of DNA binding.<ref name='Frauer et al.' />

== Function ==
===Common Function===

All three TET enzymes and their isoforms are involved in the biochemical pathway that converts 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC). They also regulate the further conversions of 5hmC to 5-formylcytosine (5fC) and then 5fC to 5-carboxylcytosine (5caC).<ref name='He et al.'>DOI: 10.1126/science.1210944</ref> Although experimental data shows that TET3 does so to a lesser extent than TET1 and TET2.<ref name='He et al.' />

While the oxidation performed by TET enzymes was originally thought to be a source of DNA damage, new research has implied that this catalytic activity may actually be the initial steps of a process of DNA demethylation. This hypothesized DNA demethylation pathway starts with the conversion of 5mC to 5caC after several rounds of oxidation by TET enzymes. The next step is the removal of the modified cytosine base by thymine DNA glycosylase (TDG) which leaves an abasic site on the DNA. The last step is then the process of base excision repair in which a new unmodified cytosine is regenerated at the site, thus completing the process of DNA demethylation.<ref name='He et al.' /><ref name='Rahul M. Kohli & Yi Zhang'>DOI 10.1038/nature12750</ref>

[[Image:nsmb.2437-F1.jpg|400px|left|thumb|Cycle of DNA methylation and demethylation by DNA methyltransferases (DNMTs) and TET proteins.<ref>DOI 10.1038/nsmb.2437</ref>]]

===Specific Functions===
Experimental data shows that the TET genes have different expression patterns and at different levels, which indicates that each of the TET enzymes do not fully overlap in their functionality.

TET1 is usually expressed in fetal heart, lung, and brain tissue and in adult skeletal muscle, thymus, and ovary. It is not generally expressed in adult heart, lung, and brain tissue. Moreover, studies have shown that TET1 expression in adult brain tissue is correlated with brain cancer. This occurs through TET1’s indirect activation of brain cancer-related genes such as EGFR, AKT3, CDK6, CCND2, and BRAF through creation of 5hmC which recruits the CHTOP-methylosome complex that activates these genes.<ref>DOI 10.1016/j.celrep.2014.08.071</ref>

TET2 is broadly expressed, but it is especially highly expressed in hematopoietic cells, which develop into blood cells. Regarding this, it is suggested that TET2 plays a role in hematopoiesis due to the presence of TET2 mutations in many myelodysplastic syndromes.<ref name='Delhommeau et al.'>DOI 10.1056/NEJMoa0810069</ref><ref>DOI 10.1038/ng.391</ref>

TET3 is highly expressed in zygotes and is involved with epigenetic chromatin reprogramming in the zygote after fertilization. Specifically, it plays a role in DNA demethylation of the paternal pronucleus before implantation.<ref name='Rahul M. Kohli & Yi Zhang' />

== Disease Relation ==
=== TET1 Isoform ===

Point mutations within the TET1 isoform can lead to a loss of enzyme function which causes a lack of DNA demethylation; two occur at the 1672 and 1674 amino acid residues, the first being a H1672Y mutation and the second being a D1674A mutation. A severe mutation in the 1608-1609 codons can lead to TET1 becoming an oncogene in acute leukemias. This mutation fuses TET1 and KMT2A/MLL1 to form an oncogene.<ref>PMID:12124344</ref><ref>PMID:12646957</ref>

=== TET2 Isoform ===

TET2 has been identified as a tumor-suppressor gene that is linked to various myeloid cancers. Acquired mutations are predicted to truncate the protein, resulting in alterations of the function of the TET2 protein. TET2 defects have been identified in the CD34+ cells of patients with myelodysplastic syndrome, which include hematopoietic stem cells and hematopoietic progenitors. This suggests that TET2 mutations or defects, paired with mutations in other genes, such as Janus kinase 2 (JAK2) V617F gene or myeloproliferative leukemia virus oncogene (MPL) W515L/K can contribute to the progression of myeloid cancers. Due to the involvement of TET2 in hematopoietic stem cell development, mutations in this gene may also be associated with the amplification of the mutation in the early stages of hematopoietic differentiation.<ref name='Delhommeau et al.' />

== Structural highlights ==

The following highlights are of the Human TET2 enzyme in complex with DNA.

<scene name='72/728166/5d9y_helices_red/1'>Alpha helices</scene> are colored red.

<scene name='72/728166/5d9y_sheets_green/1'>Beta sheets</scene> are colored green.

Both <scene name='72/728166/5d9y_alpha_beta/1'>Alpha helices and beta sheets</scene> are displayed in this scene.

Here the <scene name='72/728166/5d9y_zinc_ions/1'>zinc ions</scene> are colored light blue, but since they are so small they may be slightly difficult to see.

Here some of the major residues of the <scene name='72/728166/5d9y_catalytic_site/1'>catalytic site</scene> are highlighted. The light green residues are 2-oxoglutarate binding residues, the orange residue binds the substrate, and the blue residue binds the catalytic iron ion. For the rest of the protein, only the backbone is shown in light gray.

</StructureSection>
== References ==
<references/>

User:Madelyn Kasprzak/Sandbox 6

2016-04-14T08:05:18Z

Madelyn Kasprzak: Added short description to structural highlights section

== TET Enzymes==

TET enzymes are a family of [[Dioxygenase|dioxygenases]] that are involved in the process of oxidizing methylated cytosine. Members of this family include ten-eleven translocation methylcytosine dioxygenase 1 (<scene name='72/728164/Naegleria_gruberi_tet1/1'>TET1</scene>), methylcytosine dioxygenase <scene name='72/728164/Human_tet2_5fc/1'>TET2</scene>, and methylcytosine dioxygenase <scene name='72/728164/Xenopus_tropicalis_tet3_dna/1'>TET3</scene>. The gene for the first of these proteins, TET1, was identified when it was determined to be fused to the ''Mixed Lineage Leukemia'' (MLL) gene as a result of a translocation event that occurred between chromosomes ten and eleven (hence the name). <ref>DOI 10.1038/sj.leu.2402834</ref>

<StructureSection load='5d9y' size='320' side='right' caption='Human TET2 in complex with DNA containing 5fC.' scene=''>

== Structure ==
The TET enzymes have a cysteine-rich region closely followed by a double stranded beta-helix (DSBH) domain near their C-terminus.<ref name='Kinney et al.'>DOI 10.1007/978-1-4419-9967-2_3</ref> The DSBH domain contains three Fe<sup>2+</sup> binding sites and an α-ketoglutarate binding site.<ref name='Kinney et al.' /> This DSBH domain, along with the preceding cysteine-rich region, performs the main catalytic activity of these enzymes and more generally, for all α-ketoglutarate oxygenases.

In addition, TET1 has a CXXC-type zinc finger domain near the N-terminus. However, the TET1 CXXC domain lacks the conserved lysine-phenylalanine-glycine-glycine (KFGG) motif commonly seen within the CXXC domains of other DNA binding proteins, such as DNA methyltransferase-1 (DNMT1). A study conducted by Frauer et al. in 2011 showed that the isolated CXXC domain of TET1 has no DNA binding activity, which agrees with the evidence suggesting that the KFGG motif increases affinity for unmethylated DNA.<ref name='Frauer et al.'>DOI 10.1371/journal.pone.0016627</ref> Frauer et al. also speculated that the CXXC domain of TET1 may be involved with protein-protein interactions instead of DNA binding.<ref name='Frauer et al.' />

== Function ==
===Common Function===

All three TET enzymes and their isoforms are involved in the biochemical pathway that converts 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC). They also regulate the further conversions of 5hmC to 5-formylcytosine (5fC) and then 5fC to 5-carboxylcytosine (5caC).<ref name='He et al.'>DOI: 10.1126/science.1210944</ref> Although experimental data shows that TET3 does so to a lesser extent than TET1 and TET2.<ref name='He et al.' />

While the oxidation performed by TET enzymes was originally thought to be a source of DNA damage, new research has implied that this catalytic activity may actually be the initial steps of a process of DNA demethylation. This hypothesized DNA demethylation pathway starts with the conversion of 5mC to 5caC after several rounds of oxidation by TET enzymes. The next step is the removal of the modified cytosine base by thymine DNA glycosylase (TDG) which leaves an abasic site on the DNA. The last step is then the process of base excision repair in which a new unmodified cytosine is regenerated at the site, thus completing the process of DNA demethylation.<ref name='He et al.' /><ref name='Rahul M. Kohli & Yi Zhang'>DOI 10.1038/nature12750</ref>

[[Image:nsmb.2437-F1.jpg|400px|left|thumb|Cycle of DNA methylation and demethylation by DNA methyltransferases (DNMTs) and TET proteins.<ref>DOI 10.1038/nsmb.2437</ref>]]

===Specific Functions===
Experimental data shows that the TET genes have different expression patterns and at different levels, which indicates that each of the TET enzymes do not fully overlap in their functionality.

TET1 is usually expressed in fetal heart, lung, and brain tissue and in adult skeletal muscle, thymus, and ovary. It is not generally expressed in adult heart, lung, and brain tissue. Moreover, studies have shown that TET1 expression in adult brain tissue is correlated with brain cancer. This occurs through TET1’s indirect activation of brain cancer-related genes such as EGFR, AKT3, CDK6, CCND2, and BRAF through creation of 5hmC which recruits the CHTOP-methylosome complex that activates these genes.<ref>DOI 10.1016/j.celrep.2014.08.071</ref>

TET2 is broadly expressed, but it is especially highly expressed in hematopoietic cells, which develop into blood cells. Regarding this, it is suggested that TET2 plays a role in hematopoiesis due to the presence of TET2 mutations in many myelodysplastic syndromes.<ref name='Delhommeau et al.'>DOI 10.1056/NEJMoa0810069</ref><ref>DOI 10.1038/ng.391</ref>

TET3 is highly expressed in zygotes and is involved with epigenetic chromatin reprogramming in the zygote after fertilization. Specifically, it plays a role in DNA demethylation of the paternal pronucleus before implantation.<ref name='Rahul M. Kohli & Yi Zhang' />

== Disease Relation ==
=== TET1 Isoform ===

Point mutations within the TET1 isoform can lead to a loss of enzyme function which causes a lack of DNA demethylation; two occur at the 1672 and 1674 amino acid residues, the first being a H1672Y mutation and the second being a D1674A mutation. A severe mutation in the 1608-1609 codons can lead to TET1 becoming an oncogene in acute leukemias. This mutation fuses TET1 and KMT2A/MLL1 to form an oncogene.<ref>PMID:12124344</ref><ref>PMID:12646957</ref>

=== TET2 Isoform ===

TET2 has been identified as a tumor-suppressor gene that is linked to various myeloid cancers. Acquired mutations are predicted to truncate the protein, resulting in alterations of the function of the TET2 protein. TET2 defects have been identified in the CD34+ cells of patients with myelodysplastic syndrome, which include hematopoietic stem cells and hematopoietic progenitors. This suggests that TET2 mutations or defects, paired with mutations in other genes, such as Janus kinase 2 (JAK2) V617F gene or myeloproliferative leukemia virus oncogene (MPL) W515L/K can contribute to the progression of myeloid cancers. Due to the involvement of TET2 in hematopoietic stem cell development, mutations in this gene may also be associated with the amplification of the mutation in the early stages of hematopoietic differentiation.<ref name='Delhommeau et al.' />

== Structural highlights ==

The following highlights are of the Human TET2 enzyme in complex with DNA.

<scene name='72/728166/5d9y_helices_red/1'>Alpha helices</scene> are colored red.

<scene name='72/728166/5d9y_sheets_green/1'>Beta sheets</scene> are colored green.

Both <scene name='72/728166/5d9y_alpha_beta/1'>Alpha helices and beta sheets</scene> are displayed in this scene.

Here the <scene name='72/728166/5d9y_zinc_ions/1'>zinc ions</scene> are colored light blue, but since they are so small they may be slightly difficult to see.

Here some of the major residues of the <scene name='72/728166/5d9y_catalytic_site/1'>catalytic site</scene> are highlighted. The light green residues are 2-oxoglutarate binding residues, the orange residue binds the substrate, and the blue residue binds the catalytic iron ion. For the rest of the protein, only the backbone is shown in light gray.

</StructureSection>
== References ==
<references/>

User:Madelyn Kasprzak/Sandbox 6

2016-04-14T08:01:25Z

Madelyn Kasprzak: Added 3 Different TET pdbs, one for each TET enzyme.

== TET Enzymes==

TET enzymes are a family of [[Dioxygenase|dioxygenases]] that are involved in the process of oxidizing methylated cytosine. Members of this family include ten-eleven translocation methylcytosine dioxygenase 1 (<scene name='72/728164/Naegleria_gruberi_tet1/1'>TET1</scene>), methylcytosine dioxygenase <scene name='72/728164/Human_tet2_5fc/1'>TET2</scene>, and methylcytosine dioxygenase <scene name='72/728164/Xenopus_tropicalis_tet3_dna/1'>TET3</scene>. The gene for the first of these proteins, TET1, was identified when it was determined to be fused to the ''Mixed Lineage Leukemia'' (MLL) gene as a result of a translocation event that occurred between chromosomes ten and eleven (hence the name). <ref>DOI 10.1038/sj.leu.2402834</ref>

<StructureSection load='5d9y' size='320' side='right' caption='Human TET2 in complex with DNA containing 5fC.' scene=''>

== Structure ==
The TET enzymes have a cysteine-rich region closely followed by a double stranded beta-helix (DSBH) domain near their C-terminus.<ref name='Kinney et al.'>DOI 10.1007/978-1-4419-9967-2_3</ref> The DSBH domain contains three Fe<sup>2+</sup> binding sites and an α-ketoglutarate binding site.<ref name='Kinney et al.' /> This DSBH domain, along with the preceding cysteine-rich region, performs the main catalytic activity of these enzymes and more generally, for all α-ketoglutarate oxygenases.

In addition, TET1 has a CXXC-type zinc finger domain near the N-terminus. However, the TET1 CXXC domain lacks the conserved lysine-phenylalanine-glycine-glycine (KFGG) motif commonly seen within the CXXC domains of other DNA binding proteins, such as DNA methyltransferase-1 (DNMT1). A study conducted by Frauer et al. in 2011 showed that the isolated CXXC domain of TET1 has no DNA binding activity, which agrees with the evidence suggesting that the KFGG motif increases affinity for unmethylated DNA.<ref name='Frauer et al.'>DOI 10.1371/journal.pone.0016627</ref> Frauer et al. also speculated that the CXXC domain of TET1 may be involved with protein-protein interactions instead of DNA binding.<ref name='Frauer et al.' />

== Function ==
===Common Function===

All three TET enzymes and their isoforms are involved in the biochemical pathway that converts 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC). They also regulate the further conversions of 5hmC to 5-formylcytosine (5fC) and then 5fC to 5-carboxylcytosine (5caC).<ref name='He et al.'>DOI: 10.1126/science.1210944</ref> Although experimental data shows that TET3 does so to a lesser extent than TET1 and TET2.<ref name='He et al.' />

While the oxidation performed by TET enzymes was originally thought to be a source of DNA damage, new research has implied that this catalytic activity may actually be the initial steps of a process of DNA demethylation. This hypothesized DNA demethylation pathway starts with the conversion of 5mC to 5caC after several rounds of oxidation by TET enzymes. The next step is the removal of the modified cytosine base by thymine DNA glycosylase (TDG) which leaves an abasic site on the DNA. The last step is then the process of base excision repair in which a new unmodified cytosine is regenerated at the site, thus completing the process of DNA demethylation.<ref name='He et al.' /><ref name='Rahul M. Kohli & Yi Zhang'>DOI 10.1038/nature12750</ref>

[[Image:nsmb.2437-F1.jpg|400px|left|thumb|Cycle of DNA methylation and demethylation by DNA methyltransferases (DNMTs) and TET proteins.<ref>DOI 10.1038/nsmb.2437</ref>]]

===Specific Functions===
Experimental data shows that the TET genes have different expression patterns and at different levels, which indicates that each of the TET enzymes do not fully overlap in their functionality.

TET1 is usually expressed in fetal heart, lung, and brain tissue and in adult skeletal muscle, thymus, and ovary. It is not generally expressed in adult heart, lung, and brain tissue. Moreover, studies have shown that TET1 expression in adult brain tissue is correlated with brain cancer. This occurs through TET1’s indirect activation of brain cancer-related genes such as EGFR, AKT3, CDK6, CCND2, and BRAF through creation of 5hmC which recruits the CHTOP-methylosome complex that activates these genes.<ref>DOI 10.1016/j.celrep.2014.08.071</ref>

TET2 is broadly expressed, but it is especially highly expressed in hematopoietic cells, which develop into blood cells. Regarding this, it is suggested that TET2 plays a role in hematopoiesis due to the presence of TET2 mutations in many myelodysplastic syndromes.<ref name='Delhommeau et al.'>DOI 10.1056/NEJMoa0810069</ref><ref>DOI 10.1038/ng.391</ref>

TET3 is highly expressed in zygotes and is involved with epigenetic chromatin reprogramming in the zygote after fertilization. Specifically, it plays a role in DNA demethylation of the paternal pronucleus before implantation.<ref name='Rahul M. Kohli & Yi Zhang' />

== Disease Relation ==
=== TET1 Isoform ===

Point mutations within the TET1 isoform can lead to a loss of enzyme function which causes a lack of DNA demethylation; two occur at the 1672 and 1674 amino acid residues, the first being a H1672Y mutation and the second being a D1674A mutation. A severe mutation in the 1608-1609 codons can lead to TET1 becoming an oncogene in acute leukemias. This mutation fuses TET1 and KMT2A/MLL1 to form an oncogene.<ref>PMID:12124344</ref><ref>PMID:12646957</ref>

=== TET2 Isoform ===

TET2 has been identified as a tumor-suppressor gene that is linked to various myeloid cancers. Acquired mutations are predicted to truncate the protein, resulting in alterations of the function of the TET2 protein. TET2 defects have been identified in the CD34+ cells of patients with myelodysplastic syndrome, which include hematopoietic stem cells and hematopoietic progenitors. This suggests that TET2 mutations or defects, paired with mutations in other genes, such as Janus kinase 2 (JAK2) V617F gene or myeloproliferative leukemia virus oncogene (MPL) W515L/K can contribute to the progression of myeloid cancers. Due to the involvement of TET2 in hematopoietic stem cell development, mutations in this gene may also be associated with the amplification of the mutation in the early stages of hematopoietic differentiation.<ref name='Delhommeau et al.' />

== Structural highlights ==

<scene name='72/728166/5d9y_helices_red/1'>Alpha helices</scene> are colored red.

<scene name='72/728166/5d9y_sheets_green/1'>Beta sheets</scene> are colored green.

Both <scene name='72/728166/5d9y_alpha_beta/1'>Alpha helices and beta sheets</scene> are displayed in this scene.

Here the <scene name='72/728166/5d9y_zinc_ions/1'>zinc ions</scene> are colored light blue, but since they are so small they may be slightly difficult to see.

Here some of the major residues of the <scene name='72/728166/5d9y_catalytic_site/1'>catalytic site</scene> are highlighted. The light green residues are 2-oxoglutarate binding residues, the orange residue binds the substrate, and the blue residue binds the catalytic iron ion. For the rest of the protein, only the backbone is shown in light gray.

</StructureSection>
== References ==
<references/>

User:Madelyn Kasprzak/Sandbox 6

2016-04-14T07:41:58Z

Madelyn Kasprzak:

== TET Enzymes==

TET enzymes are a family of [[Dioxygenase|dioxygenases]] that are involved in the process of oxidizing methylated cytosine. Members of this family include ten-eleven translocation methylcytosine dioxygenase 1 (TET1), methylcytosine dioxygenase TET2, and methylcytosine dioxygenase TET3. The gene for the first of these proteins, TET1, was identified when it was determined to be fused to the ''Mixed Lineage Leukemia'' (MLL) gene as a result of a translocation event that occurred between chromosomes ten and eleven (hence the name). <ref>DOI 10.1038/sj.leu.2402834</ref>

<StructureSection load='5d9y' size='320' side='right' caption='Human TET2 in complex with DNA containing 5fC.' scene=''>

== Structure ==
The TET enzymes have a cysteine-rich region closely followed by a double stranded beta-helix (DSBH) domain near their C-terminus.<ref name='Kinney et al.'>DOI 10.1007/978-1-4419-9967-2_3</ref> The DSBH domain contains three Fe<sup>2+</sup> binding sites and an α-ketoglutarate binding site.<ref name='Kinney et al.' /> This DSBH domain, along with the preceding cysteine-rich region, performs the main catalytic activity of these enzymes and more generally, for all α-ketoglutarate oxygenases.

In addition, TET1 has a CXXC-type zinc finger domain near the N-terminus. However, the TET1 CXXC domain lacks the conserved lysine-phenylalanine-glycine-glycine (KFGG) motif commonly seen within the CXXC domains of other DNA binding proteins, such as DNA methyltransferase-1 (DNMT1). A study conducted by Frauer et al. in 2011 showed that the isolated CXXC domain of TET1 has no DNA binding activity, which agrees with the evidence suggesting that the KFGG motif increases affinity for unmethylated DNA.<ref name='Frauer et al.'>DOI 10.1371/journal.pone.0016627</ref> Frauer et al. also speculated that the CXXC domain of TET1 may be involved with protein-protein interactions instead of DNA binding.<ref name='Frauer et al.' />

== Function ==
===Common Function===

All three TET enzymes and their isoforms are involved in the biochemical pathway that converts 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC). They also regulate the further conversions of 5hmC to 5-formylcytosine (5fC) and then 5fC to 5-carboxylcytosine (5caC).<ref name='He et al.'>DOI: 10.1126/science.1210944</ref> Although experimental data shows that TET3 does so to a lesser extent than TET1 and TET2.<ref name='He et al.' />

While the oxidation performed by TET enzymes was originally thought to be a source of DNA damage, new research has implied that this catalytic activity may actually be the initial steps of a process of DNA demethylation. This hypothesized DNA demethylation pathway starts with the conversion of 5mC to 5caC after several rounds of oxidation by TET enzymes. The next step is the removal of the modified cytosine base by thymine DNA glycosylase (TDG) which leaves an abasic site on the DNA. The last step is then the process of base excision repair in which a new unmodified cytosine is regenerated at the site, thus completing the process of DNA demethylation.<ref name='He et al.' /><ref name='Rahul M. Kohli & Yi Zhang'>DOI 10.1038/nature12750</ref>

[[Image:nsmb.2437-F1.jpg|400px|left|thumb|Cycle of DNA methylation and demethylation by DNA methyltransferases (DNMTs) and TET proteins.<ref>DOI 10.1038/nsmb.2437</ref>]]

===Specific Functions===
Experimental data shows that the TET genes have different expression patterns and at different levels, which indicates that each of the TET enzymes do not fully overlap in their functionality.

TET1 is usually expressed in fetal heart, lung, and brain tissue and in adult skeletal muscle, thymus, and ovary. It is not generally expressed in adult heart, lung, and brain tissue. Moreover, studies have shown that TET1 expression in adult brain tissue is correlated with brain cancer. This occurs through TET1’s indirect activation of brain cancer-related genes such as EGFR, AKT3, CDK6, CCND2, and BRAF through creation of 5hmC which recruits the CHTOP-methylosome complex that activates these genes.<ref>DOI 10.1016/j.celrep.2014.08.071</ref>

TET2 is broadly expressed, but it is especially highly expressed in hematopoietic cells, which develop into blood cells. Regarding this, it is suggested that TET2 plays a role in hematopoiesis due to the presence of TET2 mutations in many myelodysplastic syndromes.<ref name='Delhommeau et al.'>DOI 10.1056/NEJMoa0810069</ref><ref>DOI 10.1038/ng.391</ref>

TET3 is highly expressed in zygotes and is involved with epigenetic chromatin reprogramming in the zygote after fertilization. Specifically, it plays a role in DNA demethylation of the paternal pronucleus before implantation.<ref name='Rahul M. Kohli & Yi Zhang' />

== Disease Relation ==
=== TET1 Isoform ===

Point mutations within the TET1 isoform can lead to a loss of enzyme function which causes a lack of DNA demethylation; two occur at the 1672 and 1674 amino acid residues, the first being a H1672Y mutation and the second being a D1674A mutation. A severe mutation in the 1608-1609 codons can lead to TET1 becoming an oncogene in acute leukemias. This mutation fuses TET1 and KMT2A/MLL1 to form an oncogene.<ref>PMID:12124344</ref><ref>PMID:12646957</ref>

=== TET2 Isoform ===

TET2 has been identified as a tumor-suppressor gene that is linked to various myeloid cancers. Acquired mutations are predicted to truncate the protein, resulting in alterations of the function of the TET2 protein. TET2 defects have been identified in the CD34+ cells of patients with myelodysplastic syndrome, which include hematopoietic stem cells and hematopoietic progenitors. This suggests that TET2 mutations or defects, paired with mutations in other genes, such as Janus kinase 2 (JAK2) V617F gene or myeloproliferative leukemia virus oncogene (MPL) W515L/K can contribute to the progression of myeloid cancers. Due to the involvement of TET2 in hematopoietic stem cell development, mutations in this gene may also be associated with the amplification of the mutation in the early stages of hematopoietic differentiation.<ref name='Delhommeau et al.' />

== Structural highlights ==

<scene name='72/728166/5d9y_helices_red/1'>Alpha helices</scene> are colored red.

<scene name='72/728166/5d9y_sheets_green/1'>Beta sheets</scene> are colored green.

Both <scene name='72/728166/5d9y_alpha_beta/1'>Alpha helices and beta sheets</scene> are displayed in this scene.

Here the <scene name='72/728166/5d9y_zinc_ions/1'>zinc ions</scene> are colored light blue, but since they are so small they may be slightly difficult to see.

Here some of the major residues of the <scene name='72/728166/5d9y_catalytic_site/1'>catalytic site</scene> are highlighted. The light green residues are 2-oxoglutarate binding residues, the orange residue binds the substrate, and the blue residue binds the catalytic iron ion. For the rest of the protein, only the backbone is shown in light gray.

</StructureSection>
== References ==
<references/>

User:Madelyn Kasprzak/Sandbox 6

2016-04-14T07:33:14Z

Madelyn Kasprzak:

== TET Enzymes==

TET enzymes are a family of [[Dioxygenase|dioxygenases]] that are involved in the process of oxidizing methylated cytosine. Members of this family include ten-eleven translocation methylcytosine dioxygenase 1 (TET1), methylcytosine dioxygenase TET2, and methylcytosine dioxygenase TET3. The gene for the first of these proteins, TET1, was identified when it was determined to be fused to the ''Mixed Lineage Leukemia'' (MLL) gene as a result of a translocation event that occurred between chromosomes ten and eleven (hence the name). <ref>DOI 10.1038/sj.leu.2402834</ref>

<StructureSection load='5cg9' size='320' side='right' caption='TET-like protein in Naegleria gruberi in complex with DNA containing 5hmC.' scene=''>

== Structure ==
The TET enzymes have a cysteine-rich region closely followed by a double stranded beta-helix (DSBH) domain near their C-terminus.<ref name='Kinney et al.'>DOI 10.1007/978-1-4419-9967-2_3</ref> The DSBH domain contains three Fe<sup>2+</sup> binding sites and an α-ketoglutarate binding site.<ref name='Kinney et al.' /> This DSBH domain, along with the preceding cysteine-rich region, performs the main catalytic activity of these enzymes and more generally, for all α-ketoglutarate oxygenases.

In addition, TET1 has a CXXC-type zinc finger domain near the N-terminus. However, the TET1 CXXC domain lacks the conserved lysine-phenylalanine-glycine-glycine (KFGG) motif commonly seen within the CXXC domains of other DNA binding proteins, such as DNA methyltransferase-1 (DNMT1). A study conducted by Frauer et al. in 2011 showed that the isolated CXXC domain of TET1 has no DNA binding activity, which agrees with the evidence suggesting that the KFGG motif increases affinity for unmethylated DNA.<ref name='Frauer et al.'>DOI 10.1371/journal.pone.0016627</ref> Frauer et al. also speculated that the CXXC domain of TET1 may be involved with protein-protein interactions instead of DNA binding.<ref name='Frauer et al.' />

== Function ==
===Common Function===

All three TET enzymes and their isoforms are involved in the biochemical pathway that converts 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC). They also regulate the further conversions of 5hmC to 5-formylcytosine (5fC) and then 5fC to 5-carboxylcytosine (5caC).<ref name='He et al.'>DOI: 10.1126/science.1210944</ref> Although experimental data shows that TET3 does so to a lesser extent than TET1 and TET2.<ref name='He et al.' />

While the oxidation performed by TET enzymes was originally thought to be a source of DNA damage, new research has implied that this catalytic activity may actually be the initial steps of a process of DNA demethylation. This hypothesized DNA demethylation pathway starts with the conversion of 5mC to 5caC after several rounds of oxidation by TET enzymes. The next step is the removal of the modified cytosine base by thymine DNA glycosylase (TDG) which leaves an abasic site on the DNA. The last step is then the process of base excision repair in which a new unmodified cytosine is regenerated at the site, thus completing the process of DNA demethylation.<ref name='He et al.' /><ref name='Rahul M. Kohli & Yi Zhang'>DOI 10.1038/nature12750</ref>

[[Image:nsmb.2437-F1.jpg|400px|left|thumb|Cycle of DNA methylation and demethylation by DNA methyltransferases (DNMTs) and TET proteins.<ref>DOI 10.1038/nsmb.2437</ref>]]

===Specific Functions===
Experimental data shows that the TET genes have different expression patterns and at different levels, which indicates that each of the TET enzymes do not fully overlap in their functionality.

TET1 is usually expressed in fetal heart, lung, and brain tissue and in adult skeletal muscle, thymus, and ovary. It is not generally expressed in adult heart, lung, and brain tissue. Moreover, studies have shown that TET1 expression in adult brain tissue is correlated with brain cancer. This occurs through TET1’s indirect activation of brain cancer-related genes such as EGFR, AKT3, CDK6, CCND2, and BRAF through creation of 5hmC which recruits the CHTOP-methylosome complex that activates these genes.<ref>DOI 10.1016/j.celrep.2014.08.071</ref>

TET2 is broadly expressed, but it is especially highly expressed in hematopoietic cells, which develop into blood cells. Regarding this, it is suggested that TET2 plays a role in hematopoiesis due to the presence of TET2 mutations in many myelodysplastic syndromes.<ref name='Delhommeau et al.'>DOI 10.1056/NEJMoa0810069</ref><ref>DOI 10.1038/ng.391</ref>

TET3 is highly expressed in zygotes and is involved with epigenetic chromatin reprogramming in the zygote after fertilization. Specifically, it plays a role in DNA demethylation of the paternal pronucleus before implantation.<ref name='Rahul M. Kohli & Yi Zhang' />

== Disease Relation ==
=== TET1 Isoform ===

Point mutations within the TET1 isoform can lead to a loss of enzyme function which causes a lack of DNA demethylation; two occur at the 1672 and 1674 amino acid residues, the first being a H1672Y mutation and the second being a D1674A mutation. A severe mutation in the 1608-1609 codons can lead to TET1 becoming an oncogene in acute leukemias. This mutation fuses TET1 and KMT2A/MLL1 to form an oncogene.<ref>PMID:12124344</ref><ref>PMID:12646957</ref>

=== TET2 Isoform ===

TET2 has been identified as a tumor-suppressor gene that is linked to various myeloid cancers. Acquired mutations are predicted to truncate the protein, resulting in alterations of the function of the TET2 protein. TET2 defects have been identified in the CD34+ cells of patients with myelodysplastic syndrome, which include hematopoietic stem cells and hematopoietic progenitors. This suggests that TET2 mutations or defects, paired with mutations in other genes, such as Janus kinase 2 (JAK2) V617F gene or myeloproliferative leukemia virus oncogene (MPL) W515L/K can contribute to the progression of myeloid cancers. Due to the involvement of TET2 in hematopoietic stem cell development, mutations in this gene may also be associated with the amplification of the mutation in the early stages of hematopoietic differentiation.<ref name='Delhommeau et al.' />

== Structural highlights ==

<scene name='72/728166/5d9y_helices_red/1'>Alpha Helices</scene>
<scene name='72/728166/5d9y_sheets_green/1'>Beta Sheets</scene>
<scene name='72/728166/5d9y_alpha_beta/1'>Alpha & Beta</scene>
<scene name='72/728166/5d9y_zinc_ions/1'>Zinc Ions</scene>
<scene name='72/728166/5d9y_catalytic_site/1'>Catalytic Site</scene>

</StructureSection>
== References ==
<references/>

User:Madelyn Kasprzak/Sandbox 6

2016-04-14T05:35:44Z

Madelyn Kasprzak:

== TET Enzymes==

TET enzymes are a family of [[Dioxygenase|dioxygenases]] that are involved in the process of oxidizing methylated cytosine. Members of this family include ten-eleven translocation methylcytosine dioxygenase 1 (TET1), methylcytosine dioxygenase TET2, and methylcytosine dioxygenase TET3. The gene for the first of these proteins, TET1, was identified when it was determined to be fused to the ''Mixed Lineage Leukemia'' (MLL) gene as a result of a translocation event that occurred between chromosomes ten and eleven (hence the name). <ref>DOI 10.1038/sj.leu.2402834</ref>

<StructureSection load='5cg9' size='320' side='right' caption='TET-like protein in Naegleria gruberi in complex with DNA containing 5hmC.' scene=''>

== Structure ==
The TET enzymes have a cysteine-rich region closely followed by a double stranded beta-helix (DSBH) domain near their C-terminus.<ref name='Kinney et al.'>DOI 10.1007/978-1-4419-9967-2_3</ref> The DSBH domain contains three Fe<sup>2+</sup> binding sites and an α-ketoglutarate binding site.<ref name='Kinney et al.' /> This DSBH domain, along with the preceding cysteine-rich region, performs the main catalytic activity of these enzymes and more generally, for all α-ketoglutarate oxygenases.

In addition, TET1 has a CXXC-type zinc finger domain near the N-terminus. However, the TET1 CXXC domain lacks the conserved lysine-phenylalanine-glycine-glycine (KFGG) motif commonly seen within the CXXC domains of other DNA binding proteins, such as DNA methyltransferase-1 (DNMT1). A study conducted by Frauer et al. in 2011 showed that the isolated CXXC domain of TET1 has no DNA binding activity, which agrees with the evidence suggesting that the KFGG motif increases affinity for unmethylated DNA.<ref name='Frauer et al.'>DOI 10.1371/journal.pone.0016627</ref> Frauer et al. also speculated that the CXXC domain of TET1 may be involved with protein-protein interactions instead of DNA binding.<ref name='Frauer et al.' />

== Function ==
===Common Function===

All three TET enzymes and their isoforms are involved in the biochemical pathway that converts 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC). They also regulate the further conversions of 5hmC to 5-formylcytosine (5fC) and then 5fC to 5-carboxylcytosine (5caC).<ref name='He et al.'>DOI: 10.1126/science.1210944</ref> Although experimental data shows that TET3 does so to a lesser extent than TET1 and TET2.<ref name='He et al.' />

While the oxidation performed by TET enzymes was originally thought to be a source of DNA damage, new research has implied that this catalytic activity may actually be the initial steps of a process of DNA demethylation. This hypothesized DNA demethylation pathway starts with the conversion of 5mC to 5caC after several rounds of oxidation by TET enzymes. The next step is the removal of the modified cytosine base by thymine DNA glycosylase (TDG) which leaves an abasic site on the DNA. The last step is then the process of base excision repair in which a new unmodified cytosine is regenerated at the site, thus completing the process of DNA demethylation.<ref name='He et al.' /><ref name='Rahul M. Kohli & Yi Zhang'>DOI 10.1038/nature12750</ref>

[[Image:nsmb.2437-F1.jpg|400px|left|thumb|Cycle of DNA methylation and demethylation by DNA methyltransferases (DNMTs) and TET proteins.<ref>DOI 10.1038/nsmb.2437</ref>]]

===Specific Functions===
Experimental data shows that the TET genes have different expression patterns and at different levels, which indicates that each of the TET enzymes do not fully overlap in their functionality.

TET1 is usually expressed in fetal heart, lung, and brain tissue and in adult skeletal muscle, thymus, and ovary. It is not generally expressed in adult heart, lung, and brain tissue. Moreover, studies have shown that TET1 expression in adult brain tissue is correlated with brain cancer. This occurs through TET1’s indirect activation of brain cancer-related genes such as EGFR, AKT3, CDK6, CCND2, and BRAF through creation of 5hmC which recruits the CHTOP-methylosome complex that activates these genes.<ref>DOI 10.1016/j.celrep.2014.08.071</ref>

TET2 is broadly expressed, but it is especially highly expressed in hematopoietic cells, which develop into blood cells. Regarding this, it is suggested that TET2 plays a role in hematopoiesis due to the presence of TET2 mutations in many myelodysplastic syndromes.<ref name='Delhommeau et al.'>DOI 10.1056/NEJMoa0810069</ref><ref>DOI 10.1038/ng.391</ref>

TET3 is highly expressed in zygotes and is involved with epigenetic chromatin reprogramming in the zygote after fertilization. Specifically, it plays a role in DNA demethylation of the paternal pronucleus before implantation.<ref name='Rahul M. Kohli & Yi Zhang' />

== Disease Relation ==
=== TET1 Isoform ===

Point mutations within the TET1 isoform can lead to a loss of enzyme function which causes a lack of DNA demethylation; two occur at the 1672 and 1674 amino acid residues, the first being a H1672Y mutation and the second being a D1674A mutation. A severe mutation in the 1608-1609 codons can lead to TET1 becoming an oncogene in acute leukemias. This mutation fuses TET1 and KMT2A/MLL1 to form an oncogene.<ref>PMID:12124344</ref><ref>PMID:12646957</ref>

=== TET2 Isoform ===

TET2 has been identified as a tumor-suppressor gene that is linked to various myeloid cancers. Acquired mutations are predicted to truncate the protein, resulting in alterations of the function of the TET2 protein. TET2 defects have been identified in the CD34+ cells of patients with myelodysplastic syndrome, which include hematopoietic stem cells and hematopoietic progenitors. This suggests that TET2 mutations or defects, paired with mutations in other genes, such as Janus kinase 2 (JAK2) V617F gene or myeloproliferative leukemia virus oncogene (MPL) W515L/K can contribute to the progression of myeloid cancers. Due to the involvement of TET2 in hematopoietic stem cell development, mutations in this gene may also be associated with the amplification of the mutation in the early stages of hematopoietic differentiation.<ref name='Delhommeau et al.' />

== Structural highlights ==

This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.

</StructureSection>
== References ==
<references/>

User:Madelyn Kasprzak/Sandbox 6

2016-04-14T05:32:39Z

Madelyn Kasprzak:

== TET Enzymes==

TET enzymes are a family of [[Dioxygenase|dioxygenases]] that are involved in the process of oxidizing methylated cytosine. Members of this family include ten-eleven translocation methylcytosine dioxygenase 1 (TET1), methylcytosine dioxygenase TET2, and methylcytosine dioxygenase TET3. The gene for the first of these proteins, TET1, was identified when it was determined to be fused to the ''Mixed Lineage Leukemia'' (MLL) gene as a result of a translocation event that occurred between chromosomes ten and eleven (hence the name). <ref>DOI 10.1038/sj.leu.2402834</ref>

<StructureSection load='5cg9' size='320' side='right' caption='TET-like protein in Naegleria gruberi in complex with DNA containing 5hmC.' scene=''>

== Structure ==
The TET enzymes have a cysteine-rich region closely followed by a double stranded beta-helix (DSBH) domain near their C-terminus.<ref name='Kinney et al.'>DOI 10.1007/978-1-4419-9967-2_3</ref> The DSBH domain contains three Fe<sup>2+</sup> binding sites and an α-ketoglutarate binding site.<ref name='Kinney et al.' /> This DSBH domain, along with the preceding cysteine-rich region, performs the main catalytic activity of these enzymes and more generally, for all α-ketoglutarate oxygenases.

In addition, TET1 has a CXXC-type zinc finger domain near the N-terminus. However, the TET1 CXXC domain lacks the conserved lysine-phenylalanine-glycine-glycine (KFGG) motif commonly seen within the CXXC domains of other DNA binding proteins, such as DNA methyltransferase-1 (DNMT1). A study conducted by Frauer et al. in 2011 showed that the isolated CXXC domain of TET1 has no DNA binding activity, which agrees with the evidence suggesting that the KFGG motif increases affinity for unmethylated DNA.<ref name='Frauer et al.'>DOI 10.1371/journal.pone.0016627</ref> Frauer et al. also speculated that the CXXC domain of TET1 may be involved with protein-protein interactions instead of DNA binding.<ref name='Frauer et al.' />

== Function ==
===Common Function===

All three TET enzymes and their isoforms are involved in the biochemical pathway that converts 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC). They also regulate the further conversions of 5hmC to 5-formylcytosine (5fC) and then 5fC to 5-carboxylcytosine (5caC).<ref name='He et al.'>DOI: 10.1126/science.1210944</ref> Although experimental data shows that TET3 does so to a lesser extent than TET1 and TET2.<ref name='He et al.' />

While the oxidation performed by TET enzymes was originally thought to be a source of DNA damage, new research has implied that this catalytic activity may actually be the initial steps of a process of DNA demethylation. This hypothesized DNA demethylation pathway starts with the conversion of 5mC to 5caC after several rounds of oxidation by TET enzymes. The next step is the removal of the modified cytosine base by thymine DNA glycosylase (TDG) which leaves an abasic site on the DNA. The last step is then the process of base excision repair in which a new unmodified cytosine is regenerated at the site, thus completing the process of DNA demethylation.<ref name='He et al.' /><ref name='Rahul M. Kohli & Yi Zhang'>DOI 10.1038/nature12750</ref>

[[Image:nsmb.2437-F1.jpg|frame|Cycle of DNA methylation and demethylation by DNA methyltransferases (DNMTs) and TET proteins.<ref name="Huang"/>]]

===Specific Functions===
Experimental data shows that the TET genes have different expression patterns and at different levels, which indicates that each of the TET enzymes do not fully overlap in their functionality.

TET1 is usually expressed in fetal heart, lung, and brain tissue and in adult skeletal muscle, thymus, and ovary. It is not generally expressed in adult heart, lung, and brain tissue. Moreover, studies have shown that TET1 expression in adult brain tissue is correlated with brain cancer. This occurs through TET1’s indirect activation of brain cancer-related genes such as EGFR, AKT3, CDK6, CCND2, and BRAF through creation of 5hmC which recruits the CHTOP-methylosome complex that activates these genes.<ref>DOI 10.1016/j.celrep.2014.08.071</ref>

TET2 is broadly expressed, but it is especially highly expressed in hematopoietic cells, which develop into blood cells. Regarding this, it is suggested that TET2 plays a role in hematopoiesis due to the presence of TET2 mutations in many myelodysplastic syndromes.<ref name='Delhommeau et al.'>DOI 10.1056/NEJMoa0810069</ref><ref>DOI 10.1038/ng.391</ref>

TET3 is highly expressed in zygotes and is involved with epigenetic chromatin reprogramming in the zygote after fertilization. Specifically, it plays a role in DNA demethylation of the paternal pronucleus before implantation.<ref name='Rahul M. Kohli & Yi Zhang' />

== Disease Relation ==
=== TET1 Isoform ===

Point mutations within the TET1 isoform can lead to a loss of enzyme function which causes a lack of DNA demethylation; two occur at the 1672 and 1674 amino acid residues, the first being a H1672Y mutation and the second being a D1674A mutation. A severe mutation in the 1608-1609 codons can lead to TET1 becoming an oncogene in acute leukemias. This mutation fuses TET1 and KMT2A/MLL1 to form an oncogene.<ref>PMID:12124344</ref><ref>PMID:12646957</ref>

=== TET2 Isoform ===

TET2 has been identified as a tumor-suppressor gene that is linked to various myeloid cancers. Acquired mutations are predicted to truncate the protein, resulting in alterations of the function of the TET2 protein. TET2 defects have been identified in the CD34+ cells of patients with myelodysplastic syndrome, which include hematopoietic stem cells and hematopoietic progenitors. This suggests that TET2 mutations or defects, paired with mutations in other genes, such as Janus kinase 2 (JAK2) V617F gene or myeloproliferative leukemia virus oncogene (MPL) W515L/K can contribute to the progression of myeloid cancers. Due to the involvement of TET2 in hematopoietic stem cell development, mutations in this gene may also be associated with the amplification of the mutation in the early stages of hematopoietic differentiation.<ref name='Delhommeau et al.' />

== Structural highlights ==

This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.

</StructureSection>
== References ==
<references/>

File:Nsmb.2437-F1.jpg

2016-04-14T05:25:33Z

Madelyn Kasprzak:

User:Madelyn Kasprzak/Sandbox 6

2016-04-14T05:25:10Z

Madelyn Kasprzak:

== TET Enzymes==

TET enzymes are a family of [[Dioxygenase|dioxygenases]] that are involved in the process of oxidizing methylated cytosine. Members of this family include ten-eleven translocation methylcytosine dioxygenase 1 (TET1), methylcytosine dioxygenase TET2, and methylcytosine dioxygenase TET3. The gene for the first of these proteins, TET1, was identified when it was determined to be fused to the ''Mixed Lineage Leukemia'' (MLL) gene as a result of a translocation event that occurred between chromosomes ten and eleven (hence the name). <ref>DOI 10.1038/sj.leu.2402834</ref>

<StructureSection load='5cg9' size='320' side='right' caption='TET-like protein in Naegleria gruberi in complex with DNA containing 5hmC.' scene=''>

== Structure ==
The TET enzymes have a cysteine-rich region closely followed by a double stranded beta-helix (DSBH) domain near their C-terminus.<ref name='Kinney et al.'>DOI 10.1007/978-1-4419-9967-2_3</ref> The DSBH domain contains three Fe<sup>2+</sup> binding sites and an α-ketoglutarate binding site.<ref name='Kinney et al.' /> This DSBH domain, along with the preceding cysteine-rich region, performs the main catalytic activity of these enzymes and more generally, for all α-ketoglutarate oxygenases.

In addition, TET1 has a CXXC-type zinc finger domain near the N-terminus. However, the TET1 CXXC domain lacks the conserved lysine-phenylalanine-glycine-glycine (KFGG) motif commonly seen within the CXXC domains of other DNA binding proteins, such as DNA methyltransferase-1 (DNMT1). A study conducted by Frauer et al. in 2011 showed that the isolated CXXC domain of TET1 has no DNA binding activity, which agrees with the evidence suggesting that the KFGG motif increases affinity for unmethylated DNA.<ref name='Frauer et al.'>DOI 10.1371/journal.pone.0016627</ref> Frauer et al. also speculated that the CXXC domain of TET1 may be involved with protein-protein interactions instead of DNA binding.<ref name='Frauer et al.' />

== Function ==
===Common Function===

All three TET enzymes and their isoforms are involved in the biochemical pathway that converts 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC). They also regulate the further conversions of 5hmC to 5-formylcytosine (5fC) and then 5fC to 5-carboxylcytosine (5caC).<ref name='He et al.'>DOI: 10.1126/science.1210944</ref> Although experimental data shows that TET3 does so to a lesser extent than TET1 and TET2.<ref name='He et al.' />

While the oxidation performed by TET enzymes was originally thought to be a source of DNA damage, new research has implied that this catalytic activity may actually be the initial steps of a process of DNA demethylation. This hypothesized DNA demethylation pathway starts with the conversion of 5mC to 5caC after several rounds of oxidation by TET enzymes. The next step is the removal of the modified cytosine base by thymine DNA glycosylase (TDG) which leaves an abasic site on the DNA. The last step is then the process of base excision repair in which a new unmodified cytosine is regenerated at the site, thus completing the process of DNA demethylation.<ref name='He et al.' /><ref name='Rahul M. Kohli & Yi Zhang'>DOI 10.1038/nature12750</ref>

[[Image:nsmb.2437-F1.jpg|frame|Cycle of DNA methylation and demethylation by DNA methyltransferases (DNMTs) and TET proteins.<ref name="Huang"/>]]

===Specific Functions===
Experimental data shows that the TET genes have different expression patterns and at different levels, which indicates that each of the TET enzymes do not fully overlap in their functionality.

TET1 is usually expressed in fetal heart, lung, and brain tissue and in adult skeletal muscle, thymus, and ovary. It is not generally expressed in adult heart, lung, and brain tissue. Moreover, studies have shown that TET1 expression in adult brain tissue is correlated with brain cancer. This occurs through TET1’s indirect activation of brain cancer-related genes such as EGFR, AKT3, CDK6, CCND2, and BRAF through creation of 5hmC which recruits the CHTOP-methylosome complex that activates these genes.<ref>DOI 10.1016/j.celrep.2014.08.071</ref>

TET2 is broadly expressed, but it is especially highly expressed in hematopoietic cells, which develop into blood cells. Regarding this, it is suggested that TET2 plays a role in hematopoiesis due to the presence of TET2 mutations in many myelodysplastic syndromes.<ref>DOI 10.1056/NEJMoa0810069</ref><ref>DOI 10.1038/ng.391</ref>

TET3 is highly expressed in zygotes and is involved with epigenetic chromatin reprogramming in the zygote after fertilization. Specifically, it plays a role in DNA demethylation of the paternal pronucleus before implantation.<ref name='Rahul M. Kohli & Yi Zhang' />

== Disease Relation ==
=== TET1 Isoform ===

Point mutations within the TET1 isoform can lead to a loss of enzyme function which causes a lack of DNA demethylation; two occur at the 1672 and 1674 amino acid residues, the first being a H1672Y mutation and the second being a D1674A mutation. A severe mutation in the 1608-1609 codons can lead to TET1 becoming an oncogene in acute leukemias. This mutation fuses TET1 and KMT2A/MLL1 to form an oncogene.<ref>PMID:12124344</ref><ref>PMID:12646957</ref>

=== TET2 Isoform ===

TET2 has been identified as a tumor-suppressor gene that is linked to various myeloid cancers. Acquired mutations are predicted to truncate the protein, resulting in alterations of the function of the TET2 protein. TET2 defects have been identified in the CD34+ cells of patients with myelodysplastic syndrome, which include hematopoietic stem cells and hematopoietic progenitors. This suggests that TET2 mutations or defects, paired with mutations in other genes, such as Janus kinase 2 (JAK2) V617F gene or myeloproliferative leukemia virus oncogene (MPL) W515L/K can contribute to the progression of myeloid cancers. Due to the involvement of TET2 in hematopoietic stem cell development, mutations in this gene may also be associated with the amplification of the mutation in the early stages of hematopoietic differentiation.*** ref

== Structural highlights ==

This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.

</StructureSection>
== References ==
<references/>

User:Madelyn Kasprzak/Sandbox 6

2016-04-14T05:22:24Z

Madelyn Kasprzak:

== TET Enzymes==

TET enzymes are a family of [[Dioxygenase|dioxygenases]] that are involved in the process of oxidizing methylated cytosine. Members of this family include ten-eleven translocation methylcytosine dioxygenase 1 (TET1), methylcytosine dioxygenase TET2, and methylcytosine dioxygenase TET3. The gene for the first of these proteins, TET1, was identified when it was determined to be fused to the ''Mixed Lineage Leukemia'' (MLL) gene as a result of a translocation event that occurred between chromosomes ten and eleven (hence the name). <ref>DOI 10.1038/sj.leu.2402834</ref>

<StructureSection load='5cg9' size='320' side='right' caption='TET-like protein in Naegleria gruberi in complex with DNA containing 5hmC.' scene=''>

== Structure ==
The TET enzymes have a cysteine-rich region closely followed by a double stranded beta-helix (DSBH) domain near their C-terminus.<ref name='Kinney et al.'>DOI 10.1007/978-1-4419-9967-2_3</ref> The DSBH domain contains three Fe<sup>2+</sup> binding sites and an α-ketoglutarate binding site.<ref name='Kinney et al.' /> This DSBH domain, along with the preceding cysteine-rich region, performs the main catalytic activity of these enzymes and more generally, for all α-ketoglutarate oxygenases.

In addition, TET1 has a CXXC-type zinc finger domain near the N-terminus. However, the TET1 CXXC domain lacks the conserved lysine-phenylalanine-glycine-glycine (KFGG) motif commonly seen within the CXXC domains of other DNA binding proteins, such as DNA methyltransferase-1 (DNMT1). A study conducted by Frauer et al. in 2011 showed that the isolated CXXC domain of TET1 has no DNA binding activity, which agrees with the evidence suggesting that the KFGG motif increases affinity for unmethylated DNA.<ref name='Frauer et al.'>DOI 10.1371/journal.pone.0016627</ref> Frauer et al. also speculated that the CXXC domain of TET1 may be involved with protein-protein interactions instead of DNA binding.<ref name='Frauer et al.' />

== Function ==
===Common Function===

All three TET enzymes and their isoforms are involved in the biochemical pathway that converts 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC). They also regulate the further conversions of 5hmC to 5-formylcytosine (5fC) and then 5fC to 5-carboxylcytosine (5caC).<ref name='He et al.'>DOI: 10.1126/science.1210944</ref> Although experimental data shows that TET3 does so to a lesser extent than TET1 and TET2.<ref name='He et al.' />

While the oxidation performed by TET enzymes was originally thought to be a source of DNA damage, new research has implied that this catalytic activity may actually be the initial steps of a process of DNA demethylation. This hypothesized DNA demethylation pathway starts with the conversion of 5mC to 5caC after several rounds of oxidation by TET enzymes. The next step is the removal of the modified cytosine base by thymine DNA glycosylase (TDG) which leaves an abasic site on the DNA. The last step is then the process of base excision repair in which a new unmodified cytosine is regenerated at the site, thus completing the process of DNA demethylation.<ref name='He et al.' /><ref name='Rahul M. Kohli & Yi Zhang'>DOI 10.1038/nature12750</ref>

[[Image:nsmb.2437-F1.jpg Cycle of DNA methylation and demethylation by DNA methyltransferases (DNMTs) and TET proteins.]]

===Specific Functions===
Experimental data shows that the TET genes have different expression patterns and at different levels, which indicates that each of the TET enzymes do not fully overlap in their functionality.

TET1 is usually expressed in fetal heart, lung, and brain tissue and in adult skeletal muscle, thymus, and ovary. It is not generally expressed in adult heart, lung, and brain tissue. Moreover, studies have shown that TET1 expression in adult brain tissue is correlated with brain cancer. This occurs through TET1’s indirect activation of brain cancer-related genes such as EGFR, AKT3, CDK6, CCND2, and BRAF through creation of 5hmC which recruits the CHTOP-methylosome complex that activates these genes.<ref>DOI 10.1016/j.celrep.2014.08.071</ref>

TET2 is broadly expressed, but it is especially highly expressed in hematopoietic cells, which develop into blood cells. Regarding this, it is suggested that TET2 plays a role in hematopoiesis due to the presence of TET2 mutations in many myelodysplastic syndromes.<ref>DOI 10.1056/NEJMoa0810069</ref><ref>DOI 10.1038/ng.391</ref>

TET3 is highly expressed in zygotes and is involved with epigenetic chromatin reprogramming in the zygote after fertilization. Specifically, it plays a role in DNA demethylation of the paternal pronucleus before implantation.<ref name='Rahul M. Kohli & Yi Zhang' />

== Disease Relation ==
=== TET1 Isoform ===

Point mutations within the TET1 isoform can lead to a loss of enzyme function which causes a lack of DNA demethylation; two occur at the 1672 and 1674 amino acid residues, the first being a H1672Y mutation and the second being a D1674A mutation. A severe mutation in the 1608-1609 codons can lead to TET1 becoming an oncogene in acute leukemias. This mutation fuses TET1 and KMT2A/MLL1 to form an oncogene.<ref>PMID:12124344</ref><ref>PMID:12646957</ref>

=== TET2 Isoform ===

TET2 has been identified as a tumor-suppressor gene that is linked to various myeloid cancers. Acquired mutations are predicted to truncate the protein, resulting in alterations of the function of the TET2 protein. TET2 defects have been identified in the CD34+ cells of patients with myelodysplastic syndrome, which include hematopoietic stem cells and hematopoietic progenitors. This suggests that TET2 mutations or defects, paired with mutations in other genes, such as Janus kinase 2 (JAK2) V617F gene or myeloproliferative leukemia virus oncogene (MPL) W515L/K can contribute to the progression of myeloid cancers. Due to the involvement of TET2 in hematopoietic stem cell development, mutations in this gene may also be associated with the amplification of the mutation in the early stages of hematopoietic differentiation.*** ref

== Structural highlights ==

This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.

</StructureSection>
== References ==
<references/>

User:Madelyn Kasprzak/Sandbox 6

2016-04-14T05:13:31Z

Madelyn Kasprzak:

== TET Enzymes==

TET enzymes are a family of [[Dioxygenase|dioxygenases]] that are involved in the process of oxidizing methylated cytosine. Members of this family include ten-eleven translocation methylcytosine dioxygenase 1 (TET1), methylcytosine dioxygenase TET2, and methylcytosine dioxygenase TET3. The gene for the first of these proteins, TET1, was identified when it was determined to be fused to the ''Mixed Lineage Leukemia'' (MLL) gene as a result of a translocation event that occurred between chromosomes ten and eleven (hence the name). <ref>DOI 10.1038/sj.leu.2402834</ref>

<StructureSection load='5cg9' size='320' side='right' caption='TET-like protein in Naegleria gruberi in complex with DNA containing 5hmC.' scene=''>

== Structure ==
The TET enzymes have a cysteine-rich region closely followed by a double stranded beta-helix (DSBH) domain near their C-terminus.<ref name='Kinney et al.'>DOI 10.1007/978-1-4419-9967-2_3</ref> The DSBH domain contains three Fe<sup>2+</sup> binding sites and an α-ketoglutarate binding site.<ref name='Kinney et al.' /> This DSBH domain, along with the preceding cysteine-rich region, performs the main catalytic activity of these enzymes and more generally, for all α-ketoglutarate oxygenases.

In addition, TET1 has a CXXC-type zinc finger domain near the N-terminus. However, the TET1 CXXC domain lacks the conserved lysine-phenylalanine-glycine-glycine (KFGG) motif commonly seen within the CXXC domains of other DNA binding proteins, such as DNA methyltransferase-1 (DNMT1). A study conducted by Frauer et al. in 2011 showed that the isolated CXXC domain of TET1 has no DNA binding activity, which agrees with the evidence suggesting that the KFGG motif increases affinity for unmethylated DNA.<ref name='Frauer et al.'>DOI 10.1371/journal.pone.0016627</ref> Frauer et al. also speculated that the CXXC domain of TET1 may be involved with protein-protein interactions instead of DNA binding.<ref name='Frauer et al.' />

== Function ==
===Common Function===

All three TET enzymes and their isoforms are involved in the biochemical pathway that converts 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC). They also regulate the further conversions of 5hmC to 5-formylcytosine (5fC) and then 5fC to 5-carboxylcytosine (5caC).<ref name='He et al.'>DOI: 10.1126/science.1210944</ref> Although experimental data shows that TET3 does so to a lesser extent than TET1 and TET2.<ref name='He et al.' />

While the oxidation performed by TET enzymes was originally thought to be a source of DNA damage, new research has implied that this catalytic activity may actually be the initial steps of a process of DNA demethylation. This hypothesized DNA demethylation pathway starts with the conversion of 5mC to 5caC after several rounds of oxidation by TET enzymes. The next step is the removal of the modified cytosine base by thymine DNA glycosylase (TDG) which leaves an abasic site on the DNA. The last step is then the process of base excision repair in which a new unmodified cytosine is regenerated at the site, thus completing the process of DNA demethylation.<ref name='He et al.' /><ref name='Rahul M. Kohli & Yi Zhang'>DOI 10.1038/nature12750</ref>

===Specific Functions===
Experimental data shows that the TET genes have different expression patterns and at different levels, which indicates that each of the TET enzymes do not fully overlap in their functionality.

TET1 is usually expressed in fetal heart, lung, and brain tissue and in adult skeletal muscle, thymus, and ovary. It is not generally expressed in adult heart, lung, and brain tissue. Moreover, studies have shown that TET1 expression in adult brain tissue is correlated with brain cancer. This occurs through TET1’s indirect activation of brain cancer-related genes such as EGFR, AKT3, CDK6, CCND2, and BRAF through creation of 5hmC which recruits the CHTOP-methylosome complex that activates these genes.<ref>DOI 10.1016/j.celrep.2014.08.071</ref>

TET2 is broadly expressed, but it is especially highly expressed in hematopoietic cells, which develop into blood cells. Regarding this, it is suggested that TET2 plays a role in hematopoiesis due to the presence of TET2 mutations in many myelodysplastic syndromes.<ref>DOI 10.1056/NEJMoa0810069</ref><ref>DOI 10.1038/ng.391</ref>

TET3 is highly expressed in zygotes and is involved with epigenetic chromatin reprogramming in the zygote after fertilization. Specifically, it plays a role in DNA demethylation of the paternal pronucleus before implantation.<ref name='Rahul M. Kohli & Yi Zhang' />

== Disease Relation ==
=== TET1 Isoform ===

Point mutations within the TET1 isoform can lead to a loss of enzyme function which causes a lack of DNA demethylation; two occur at the 1672 and 1674 amino acid residues, the first being a H1672Y mutation and the second being a D1674A mutation. A severe mutation in the 1608-1609 codons can lead to TET1 becoming an oncogene in acute leukemias. This mutation fuses TET1 and KMT2A/MLL1 to form an oncogene.<ref>PMID:12124344</ref><ref>PMID:12646957</ref>

=== TET2 Isoform ===

TET2 has been identified as a tumor-suppressor gene that is linked to various myeloid cancers. Acquired mutations are predicted to truncate the protein, resulting in alterations of the function of the TET2 protein. TET2 defects have been identified in the CD34+ cells of patients with myelodysplastic syndrome, which include hematopoietic stem cells and hematopoietic progenitors. This suggests that TET2 mutations or defects, paired with mutations in other genes, such as Janus kinase 2 (JAK2) V617F gene or myeloproliferative leukemia virus oncogene (MPL) W515L/K can contribute to the progression of myeloid cancers. Due to the involvement of TET2 in hematopoietic stem cell development, mutations in this gene may also be associated with the amplification of the mutation in the early stages of hematopoietic differentiation.*** ref

== Structural highlights ==

This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.

</StructureSection>
== References ==
<references/>

User:Madelyn Kasprzak/Sandbox 6

2016-04-14T05:12:11Z

Madelyn Kasprzak:

== TET Enzymes==

TET enzymes are a family of [[Dioxygenase|dioxygenases]] that are involved in the process of oxidizing methylated cytosine. Members of this family include ten-eleven translocation methylcytosine dioxygenase 1 (TET1), methylcytosine dioxygenase TET2, and methylcytosine dioxygenase TET3. The gene for the first of these proteins, TET1, was identified when it was determined to be fused to the ''Mixed Lineage Leukemia'' (MLL) gene as a result of a translocation event that occurred between chromosomes ten and eleven (hence the name). <ref>DOI 10.1038/sj.leu.2402834</ref>

<StructureSection load='5cg9' size='320' side='right' caption='TET-like protein in Naegleria gruberi in complex with DNA containing 5hmC.' scene=''>

== Structure ==
The TET enzymes have a cysteine-rich region closely followed by a double stranded beta-helix (DSBH) domain near their C-terminus.<ref name='Kinney et al.'>DOI 10.1007/978-1-4419-9967-2_3</ref> The DSBH domain contains three Fe<sup>2+</sup> binding sites and an α-ketoglutarate binding site.<ref name='Kinney et al.' /> This DSBH domain, along with the preceding cysteine-rich region, performs the main catalytic activity of these enzymes and more generally, for all α-ketoglutarate oxygenases.

In addition, TET1 has a CXXC-type zinc finger domain near the N-terminus. However, the TET1 CXXC domain lacks the conserved lysine-phenylalanine-glycine-glycine (KFGG) motif commonly seen within the CXXC domains of other DNA binding proteins, such as DNA methyltransferase-1 (DNMT1). A study conducted by Frauer et al. in 2011 showed that the isolated CXXC domain of TET1 has no DNA binding activity, which agrees with the evidence suggesting that the KFGG motif increases affinity for unmethylated DNA.<ref name='Frauer et al.'>DOI 10.1371/journal.pone.0016627</ref> Frauer et al. also speculated that the CXXC domain of TET1 may be involved with protein-protein interactions instead of DNA binding.<ref name='Frauer et al.' />

== Function ==
===Common Function===

All three TET enzymes and their isoforms are involved in the biochemical pathway that converts 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC). They also regulate the further conversions of 5hmC to 5-formylcytosine (5fC) and then 5fC to 5-carboxylcytosine (5caC).<ref name='He et al.'>DOI: 10.1126/science.1210944</ref> Although experimental data shows that TET3 does so to a lesser extent than TET1 and TET2.<ref name='He et al.' />

While the oxidation performed by TET enzymes was originally thought to be a source of DNA damage, new research has implied that this catalytic activity may actually be the initial steps of a process of DNA demethylation. This hypothesized DNA demethylation pathway starts with the conversion of 5mC to 5caC after several rounds of oxidation by TET enzymes. The next step is the removal of the modified cytosine base by thymine DNA glycosylase (TDG) which leaves an abasic site on the DNA. The last step is then the process of base excision repair in which a new unmodified cytosine is regenerated at the site, thus completing the process of DNA demethylation.<ref name='He et al.' /><ref name='Rahul M. Kohli & Yi Zhang'>DOI 10.1038/nature12750</ref>

===Specific Functions===
Experimental data shows that the TET genes have different expression patterns and at different levels, which indicates that each of the TET enzymes do not fully overlap in their functionality.

TET1 is usually expressed in fetal heart, lung, and brain tissue and in adult skeletal muscle, thymus, and ovary. It is not generally expressed in adult heart, lung, and brain tissue. Moreover, studies have shown that TET1 expression in adult brain tissue is correlated with brain cancer. This occurs through TET1’s indirect activation of brain cancer-related genes such as EGFR, AKT3, CDK6, CCND2, and BRAF through creation of 5hmC which recruits the CHTOP-methylosome complex that activates these genes.<ref>DOI 10.1016/j.celrep.2014.08.071</ref>

TET2 is broadly expressed, but it is especially highly expressed in hematopoietic cells, which develop into blood cells. Regarding this, it is suggested that TET2 plays a role in hematopoiesis due to the presence of TET2 mutations in many myelodysplastic syndromes.<ref>DOI 10.1056/NEJMoa0810069</ref><ref>DOI 10.1038/ng.391</ref>

TET3 is highly expressed in zygotes and is involved with epigenetic chromatin reprogramming in the zygote after fertilization. Specifically, it plays a role in DNA demethylation of the paternal pronucleus before implantation.<ref name='Rahul M. Kohli & Yi Zhang' />

== Disease Relation ==
=== TET1 Isoform ===

Point mutations within the TET1 isoform can lead to a loss of enzyme function which causes a lack of DNA demethylation; two occur at the 1672 and 1674 amino acid residues, the first being a H1672Y mutation and the second being a D1674A mutation. A severe mutation in the 1608-1609 codons can lead to TET1 becoming an oncogene in acute leukemias. This mutation fuses TET1 and KMT2A/MLL1 to form an oncogene.<ref>PMID:12124344</ref><ref>PMID:12646957</ref>

=== TET2 Isoform ===

TET2 has been identified as a tumor-suppressor gene that is linked to various myeloid cancers. Acquired mutations are predicted to truncate the protein, resulting in alterations of the function of the TET2 protein. TET2 defects have been identified in the CD34+ cells of patients with myelodysplastic syndrome, which include hematopoietic stem cells and hematopoietic progenitors. This suggests that TET2 mutations or defects, paired with mutations in other genes, such as Janus kinase 2 (JAK2) V617F gene or myeloproliferative leukemia virus oncogene (MPL) W515L/K can contribute to the progression of myeloid cancers. Due to the involvement of TET2 in hematopoietic stem cell development, mutations in this gene may also be associated with the amplification of the mutation in the early stages of hematopoietic differentiation.*** ref

== Structural highlights ==

This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.

</StructureSection>
== References ==
<references/>

User:Madelyn Kasprzak/Sandbox 6

2016-04-14T05:09:26Z

Madelyn Kasprzak:

== TET Enzymes==

TET enzymes are a family of [[Dioxygenase|dioxygenases]] that are involved in the process of oxidizing methylated cytosine. Members of this family include ten-eleven translocation methylcytosine dioxygenase 1 (TET1), methylcytosine dioxygenase TET2, and methylcytosine dioxygenase TET3. The gene for the first of these proteins, TET1, was identified when it was determined to be fused to the ''Mixed Lineage Leukemia'' (MLL) gene as a result of a translocation event that occurred between chromosomes ten and eleven (hence the name). <ref>DOI 10.1038/sj.leu.2402834</ref>

<StructureSection load='5cg9' size='320' side='right' caption='TET-like protein in Naegleria gruberi in complex with DNA containing 5hmC.' scene=''>

== Structure ==
The TET enzymes have a cysteine-rich region closely followed by a double stranded beta-helix (DSBH) domain near their C-terminus.<ref name='Kinney et al.'>DOI 10.1007/978-1-4419-9967-2_3</ref> The DSBH domain contains three Fe<sup>2+</sup> binding sites and an α-ketoglutarate binding site.<ref name='Kinney et al.' /> This DSBH domain, along with the preceding cysteine-rich region, performs the main catalytic activity of these enzymes and more generally, for all α-ketoglutarate oxygenases.

In addition, TET1 has a CXXC-type zinc finger domain near the N-terminus. However, the TET1 CXXC domain lacks the conserved lysine-phenylalanine-glycine-glycine (KFGG) motif commonly seen within the CXXC domains of other DNA binding proteins, such as DNA methyltransferase-1 (DNMT1). A study conducted by Frauer et al. in 2011 showed that the isolated CXXC domain of TET1 has no DNA binding activity, which agrees with the evidence suggesting that the KFGG motif increases affinity for unmethylated DNA.<ref name='Frauer et al.'>DOI 10.1371/journal.pone.0016627</ref> Frauer et al. also speculated that the CXXC domain of TET1 may be involved with protein-protein interactions instead of DNA binding.<ref name='Frauer et al.' />

== Function ==
===Common Function===

All three TET enzymes and their isoforms are involved in the biochemical pathway that converts 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC). They also regulate the further conversions of 5hmC to 5-formylcytosine (5fC) and then 5fC to 5-carboxylcytosine (5caC).<ref name='He et al.'>DOI: 10.1126/science.1210944</ref> Although experimental data shows that TET3 does so to a lesser extent than TET1 and TET2.<ref name='He et al.' />

While the oxidation performed by TET enzymes was originally thought to be a source of DNA damage, new research has implied that this catalytic activity may actually be the initial steps of a process of DNA demethylation. This hypothesized DNA demethylation pathway starts with the conversion of 5mC to 5caC after several rounds of oxidation by TET enzymes. The next step is the removal of the modified cytosine base by thymine DNA glycosylase (TDG) which leaves an abasic site on the DNA. The last step is then the process of base excision repair in which a new unmodified cytosine is regenerated at the site, thus completing the process of DNA demethylation.<ref name='He et al.' /><ref name='Rahul M. Kohli & Yi Zhang'>DOI 10.1038/nature12750</ref>

===Specific Functions===
Experimental data shows that the TET genes have different expression patterns and at different levels, which indicates that each of the TET enzymes do not fully overlap in their functionality.

TET1 is usually expressed in fetal heart, lung, and brain tissue and in adult skeletal muscle, thymus, and ovary. It is not generally expressed in adult heart, lung, and brain tissue. Moreover, studies have shown that TET1 expression in adult brain tissue is correlated with brain cancer. This occurs through TET1’s indirect activation of brain cancer-related genes such as EGFR, AKT3, CDK6, CCND2, and BRAF through creation of 5hmC which recruits the CHTOP-methylosome complex that activates these genes.<ref>DOI 10.1016/j.celrep.2014.08.071</ref>

TET2 is broadly expressed, but it is especially highly expressed in hematopoietic cells, which develop into blood cells. Regarding this, it is suggested that TET2 plays a role in hematopoiesis due to the presence of TET2 mutations in many myelodysplastic syndromes.<ref>DOI 10.1056/NEJMoa0810069</ref><ref>DOI 10.1038/ng.391</ref>

TET3 is highly expressed in zygotes and is involved with epigenetic chromatin reprogramming in the zygote after fertilization. Specifically, it plays a role in DNA demethylation of the paternal pronucleus before implantation.<ref name='Rahul M. Kohli & Yi Zhang' />

== Disease Relation ==
=== TET1 Isoform ===

Point mutations within the TET1 isoform can lead to a loss of enzyme function which causes a lack of DNA demethylation; two occur at the 1672 and 1674 amino acid residues, the first being a H1672Y mutation and the second being a D1674A mutation. A severe mutation in the 1608-1609 codons can lead to TET1 becoming an oncogene in acute leukemias. This mutation fuses TET1 and KMT2A/MLL1 to form an oncogene.<ref>PMID:12124344</ref><ref>PMID:12646957</ref>

=== TET2 Isoform ===

TET2 has been identified as a tumor-suppressor gene that is linked to various myeloid cancers. Acquired mutations are predicted to truncate the protein, resulting in alterations of the function of the TET2 protein. TET2 defects have been identified in the CD34+ cells of patients with myelodysplastic syndrome, which include hematopoietic stem cells and hematopoietic progenitors. This suggests that TET2 mutations or defects, paired with mutations in other genes, such as Janus kinase 2 (JAK2) V617F gene or myeloproliferative leukemia virus oncogene (MPL) W515L/K can contribute to the progression of myeloid cancers. Due to the involvement of TET2 in hematopoietic stem cell development, mutations in this gene may also be associated with the amplification of the mutation in the early stages of hematopoietic differentiation.<ref name=’Delhommeau et al.’ />

== Structural highlights ==

This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.

</StructureSection>
== References ==
<references/>

User:Madelyn Kasprzak/Sandbox 6

2016-04-14T05:07:57Z

Madelyn Kasprzak:

== TET Enzymes==

TET enzymes are a family of [[Dioxygenase|dioxygenases]] that are involved in the process of oxidizing methylated cytosine. Members of this family include ten-eleven translocation methylcytosine dioxygenase 1 (TET1), methylcytosine dioxygenase TET2, and methylcytosine dioxygenase TET3. The gene for the first of these proteins, TET1, was identified when it was determined to be fused to the ''Mixed Lineage Leukemia'' (MLL) gene as a result of a translocation event that occurred between chromosomes ten and eleven (hence the name). <ref>DOI 10.1038/sj.leu.2402834</ref>

<StructureSection load='5cg9' size='320' side='right' caption='TET-like protein in Naegleria gruberi in complex with DNA containing 5hmC.' scene=''>

== Structure ==
The TET enzymes have a cysteine-rich region closely followed by a double stranded beta-helix (DSBH) domain near their C-terminus.<ref name='Kinney et al.'>DOI 10.1007/978-1-4419-9967-2_3</ref> The DSBH domain contains three Fe<sup>2+</sup> binding sites and an α-ketoglutarate binding site.<ref name='Kinney et al.' /> This DSBH domain, along with the preceding cysteine-rich region, performs the main catalytic activity of these enzymes and more generally, for all α-ketoglutarate oxygenases.

In addition, TET1 has a CXXC-type zinc finger domain near the N-terminus. However, the TET1 CXXC domain lacks the conserved lysine-phenylalanine-glycine-glycine (KFGG) motif commonly seen within the CXXC domains of other DNA binding proteins, such as DNA methyltransferase-1 (DNMT1). A study conducted by Frauer et al. in 2011 showed that the isolated CXXC domain of TET1 has no DNA binding activity, which agrees with the evidence suggesting that the KFGG motif increases affinity for unmethylated DNA.<ref name='Frauer et al.'>DOI 10.1371/journal.pone.0016627</ref> Frauer et al. also speculated that the CXXC domain of TET1 may be involved with protein-protein interactions instead of DNA binding.<ref name='Frauer et al.' />

== Function ==
===Common Function===

All three TET enzymes and their isoforms are involved in the biochemical pathway that converts 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC). They also regulate the further conversions of 5hmC to 5-formylcytosine (5fC) and then 5fC to 5-carboxylcytosine (5caC).<ref name='He et al.'>DOI: 10.1126/science.1210944</ref> Although experimental data shows that TET3 does so to a lesser extent than TET1 and TET2.<ref name='He et al.' />

While the oxidation performed by TET enzymes was originally thought to be a source of DNA damage, new research has implied that this catalytic activity may actually be the initial steps of a process of DNA demethylation. This hypothesized DNA demethylation pathway starts with the conversion of 5mC to 5caC after several rounds of oxidation by TET enzymes. The next step is the removal of the modified cytosine base by thymine DNA glycosylase (TDG) which leaves an abasic site on the DNA. The last step is then the process of base excision repair in which a new unmodified cytosine is regenerated at the site, thus completing the process of DNA demethylation.<ref name='He et al.' /><ref name='Rahul M. Kohli & Yi Zhang'>DOI 10.1038/nature12750</ref>

===Specific Functions===
Experimental data shows that the TET genes have different expression patterns and at different levels, which indicates that each of the TET enzymes do not fully overlap in their functionality.

TET1 is usually expressed in fetal heart, lung, and brain tissue and in adult skeletal muscle, thymus, and ovary. It is not generally expressed in adult heart, lung, and brain tissue. Moreover, studies have shown that TET1 expression in adult brain tissue is correlated with brain cancer. This occurs through TET1’s indirect activation of brain cancer-related genes such as EGFR, AKT3, CDK6, CCND2, and BRAF through creation of 5hmC which recruits the CHTOP-methylosome complex that activates these genes.<ref>DOI 10.1016/j.celrep.2014.08.071</ref>

TET2 is broadly expressed, but it is especially highly expressed in hematopoietic cells, which develop into blood cells. Regarding this, it is suggested that TET2 plays a role in hematopoiesis due to the presence of TET2 mutations in many myelodysplastic syndromes.<ref>DOI 10.1056/NEJMoa0810069</ref><ref>DOI 10.1038/ng.391</ref>

TET3 is highly expressed in zygotes and is involved with epigenetic chromatin reprogramming in the zygote after fertilization. Specifically, it plays a role in DNA demethylation of the paternal pronucleus before implantation.<ref name='Rahul M. Kohli & Yi Zhang' />

== Disease Relation ==
=== TET1 Isoform ===

Point mutations within the TET1 isoform can lead to a loss of enzyme function which causes a lack of DNA demethylation; two occur at the 1672 and 1674 amino acid residues, the first being a H1672Y mutation and the second being a D1674A mutation. A severe mutation in the 1608-1609 codons can lead to TET1 becoming an oncogene in acute leukemias. This mutation fuses TET1 and KMT2A/MLL1 to form an oncogene.<ref>PMID:12124344</ref><ref>PMID:12646957</ref>

=== TET2 Isoform ===

TET2 has been identified as a tumor-suppressor gene that is linked to various myeloid cancers. Acquired mutations are predicted to truncate the protein, resulting in alterations of the function of the TET2 protein. TET2 defects have been identified in the CD34+ cells of patients with myelodysplastic syndrome, which include hematopoietic stem cells and hematopoietic progenitors. This suggests that TET2 mutations or defects, paired with mutations in other genes, such as Janus kinase 2 (JAK2) V617F gene or myeloproliferative leukemia virus oncogene (MPL) W515L/K can contribute to the progression of myeloid cancers. Due to the involvement of TET2 in hematopoietic stem cell development, mutations in this gene may also be associated with the amplification of the mutation in the early stages of hematopoietic differentiation.<ref>DOI 10.1056/NEJMoa0810069</ref>

== Structural highlights ==

This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.

</StructureSection>
== References ==
<references/>

User:Madelyn Kasprzak/Sandbox 6

2016-04-14T05:07:24Z

Madelyn Kasprzak:

== TET Enzymes==

TET enzymes are a family of [[Dioxygenase|dioxygenases]] that are involved in the process of oxidizing methylated cytosine. Members of this family include ten-eleven translocation methylcytosine dioxygenase 1 (TET1), methylcytosine dioxygenase TET2, and methylcytosine dioxygenase TET3. The gene for the first of these proteins, TET1, was identified when it was determined to be fused to the ''Mixed Lineage Leukemia'' (MLL) gene as a result of a translocation event that occurred between chromosomes ten and eleven (hence the name). <ref>DOI 10.1038/sj.leu.2402834</ref>

<StructureSection load='5cg9' size='320' side='right' caption='TET-like protein in Naegleria gruberi in complex with DNA containing 5hmC.' scene=''>

== Structure ==
The TET enzymes have a cysteine-rich region closely followed by a double stranded beta-helix (DSBH) domain near their C-terminus.<ref name='Kinney et al.'>DOI 10.1007/978-1-4419-9967-2_3</ref> The DSBH domain contains three Fe<sup>2+</sup> binding sites and an α-ketoglutarate binding site.<ref name='Kinney et al.' /> This DSBH domain, along with the preceding cysteine-rich region, performs the main catalytic activity of these enzymes and more generally, for all α-ketoglutarate oxygenases.

In addition, TET1 has a CXXC-type zinc finger domain near the N-terminus. However, the TET1 CXXC domain lacks the conserved lysine-phenylalanine-glycine-glycine (KFGG) motif commonly seen within the CXXC domains of other DNA binding proteins, such as DNA methyltransferase-1 (DNMT1). A study conducted by Frauer et al. in 2011 showed that the isolated CXXC domain of TET1 has no DNA binding activity, which agrees with the evidence suggesting that the KFGG motif increases affinity for unmethylated DNA.<ref name='Frauer et al.'>DOI 10.1371/journal.pone.0016627</ref> Frauer et al. also speculated that the CXXC domain of TET1 may be involved with protein-protein interactions instead of DNA binding.<ref name='Frauer et al.' />

== Function ==
===Common Function===

All three TET enzymes and their isoforms are involved in the biochemical pathway that converts 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC). They also regulate the further conversions of 5hmC to 5-formylcytosine (5fC) and then 5fC to 5-carboxylcytosine (5caC).<ref name='He et al.'>DOI: 10.1126/science.1210944</ref> Although experimental data shows that TET3 does so to a lesser extent than TET1 and TET2.<ref name='He et al.' />

While the oxidation performed by TET enzymes was originally thought to be a source of DNA damage, new research has implied that this catalytic activity may actually be the initial steps of a process of DNA demethylation. This hypothesized DNA demethylation pathway starts with the conversion of 5mC to 5caC after several rounds of oxidation by TET enzymes. The next step is the removal of the modified cytosine base by thymine DNA glycosylase (TDG) which leaves an abasic site on the DNA. The last step is then the process of base excision repair in which a new unmodified cytosine is regenerated at the site, thus completing the process of DNA demethylation.<ref name='He et al.' /><ref name='Rahul M. Kohli & Yi Zhang'>DOI 10.1038/nature12750</ref>

===Specific Functions===
Experimental data shows that the TET genes have different expression patterns and at different levels, which indicates that each of the TET enzymes do not fully overlap in their functionality.

TET1 is usually expressed in fetal heart, lung, and brain tissue and in adult skeletal muscle, thymus, and ovary. It is not generally expressed in adult heart, lung, and brain tissue. Moreover, studies have shown that TET1 expression in adult brain tissue is correlated with brain cancer. This occurs through TET1’s indirect activation of brain cancer-related genes such as EGFR, AKT3, CDK6, CCND2, and BRAF through creation of 5hmC which recruits the CHTOP-methylosome complex that activates these genes.<ref>DOI 10.1016/j.celrep.2014.08.071</ref>

TET2 is broadly expressed, but it is especially highly expressed in hematopoietic cells, which develop into blood cells. Regarding this, it is suggested that TET2 plays a role in hematopoiesis due to the presence of TET2 mutations in many myelodysplastic syndromes.<ref>DOI 10.1056/NEJMoa0810069</ref><ref>DOI 10.1038/ng.391</ref>

TET3 is highly expressed in zygotes and is involved with epigenetic chromatin reprogramming in the zygote after fertilization. Specifically, it plays a role in DNA demethylation of the paternal pronucleus before implantation.<ref name='Rahul M. Kohli & Yi Zhang' />

== Disease Relation ==
=== TET1 Isoform ===

Point mutations within the TET1 isoform can lead to a loss of enzyme function which causes a lack of DNA demethylation; two occur at the 1672 and 1674 amino acid residues, the first being a H1672Y mutation and the second being a D1674A mutation. A severe mutation in the 1608-1609 codons can lead to TET1 becoming an oncogene in acute leukemias. This mutation fuses TET1 and KMT2A/MLL1 to form an oncogene.<ref>PMID:12124344</ref><ref>PMID:12646957</ref>

=== TET2 Isoform ===

TET2 has been identified as a tumor-suppressor gene that is linked to various myeloid cancers. Acquired mutations are predicted to truncate the protein, resulting in alterations of the function of the TET2 protein. TET2 defects have been identified in the CD34+ cells of patients with myelodysplastic syndrome, which include hematopoietic stem cells and hematopoietic progenitors. This suggests that TET2 mutations or defects, paired with mutations in other genes, such as Janus kinase 2 (JAK2) V617F gene or myeloproliferative leukemia virus oncogene (MPL) W515L/K can contribute to the progression of myeloid cancers. Due to the involvement of TET2 in hematopoietic stem cell development, mutations in this gene may also be associated with the amplification of the mutation in the early stages of hematopoietic differentiation.<ref>DOI 10.1056/NEJMoa0810069</ref><ref>DOI 10.1038/ng.391</ref>

== Structural highlights ==

This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.

</StructureSection>
== References ==
<references/>

User:Madelyn Kasprzak/Sandbox 6

2016-04-14T05:06:08Z

Madelyn Kasprzak:

== TET Enzymes==

TET enzymes are a family of [[Dioxygenase|dioxygenases]] that are involved in the process of oxidizing methylated cytosine. Members of this family include ten-eleven translocation methylcytosine dioxygenase 1 (TET1), methylcytosine dioxygenase TET2, and methylcytosine dioxygenase TET3. The gene for the first of these proteins, TET1, was identified when it was determined to be fused to the ''Mixed Lineage Leukemia'' (MLL) gene as a result of a translocation event that occurred between chromosomes ten and eleven (hence the name). <ref>DOI 10.1038/sj.leu.2402834</ref>

<StructureSection load='5cg9' size='320' side='right' caption='TET-like protein in Naegleria gruberi in complex with DNA containing 5hmC.' scene=''>

== Structure ==
The TET enzymes have a cysteine-rich region closely followed by a double stranded beta-helix (DSBH) domain near their C-terminus.<ref name='Kinney et al.'>DOI 10.1007/978-1-4419-9967-2_3</ref> The DSBH domain contains three Fe<sup>2+</sup> binding sites and an α-ketoglutarate binding site.<ref name='Kinney et al.' /> This DSBH domain, along with the preceding cysteine-rich region, performs the main catalytic activity of these enzymes and more generally, for all α-ketoglutarate oxygenases.

In addition, TET1 has a CXXC-type zinc finger domain near the N-terminus. However, the TET1 CXXC domain lacks the conserved lysine-phenylalanine-glycine-glycine (KFGG) motif commonly seen within the CXXC domains of other DNA binding proteins, such as DNA methyltransferase-1 (DNMT1). A study conducted by Frauer et al. in 2011 showed that the isolated CXXC domain of TET1 has no DNA binding activity, which agrees with the evidence suggesting that the KFGG motif increases affinity for unmethylated DNA.<ref name='Frauer et al.'>DOI 10.1371/journal.pone.0016627</ref> Frauer et al. also speculated that the CXXC domain of TET1 may be involved with protein-protein interactions instead of DNA binding.<ref name='Frauer et al.' />

== Function ==
===Common Function===

All three TET enzymes and their isoforms are involved in the biochemical pathway that converts 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC). They also regulate the further conversions of 5hmC to 5-formylcytosine (5fC) and then 5fC to 5-carboxylcytosine (5caC).<ref name='He et al.'>DOI: 10.1126/science.1210944</ref> Although experimental data shows that TET3 does so to a lesser extent than TET1 and TET2.<ref name='He et al.' />

While the oxidation performed by TET enzymes was originally thought to be a source of DNA damage, new research has implied that this catalytic activity may actually be the initial steps of a process of DNA demethylation. This hypothesized DNA demethylation pathway starts with the conversion of 5mC to 5caC after several rounds of oxidation by TET enzymes. The next step is the removal of the modified cytosine base by thymine DNA glycosylase (TDG) which leaves an abasic site on the DNA. The last step is then the process of base excision repair in which a new unmodified cytosine is regenerated at the site, thus completing the process of DNA demethylation.<ref name='He et al.' /><ref name='Rahul M. Kohli & Yi Zhang'>DOI 10.1038/nature12750</ref>

===Specific Functions===
Experimental data shows that the TET genes have different expression patterns and at different levels, which indicates that each of the TET enzymes do not fully overlap in their functionality.

TET1 is usually expressed in fetal heart, lung, and brain tissue and in adult skeletal muscle, thymus, and ovary. It is not generally expressed in adult heart, lung, and brain tissue. Moreover, studies have shown that TET1 expression in adult brain tissue is correlated with brain cancer. This occurs through TET1’s indirect activation of brain cancer-related genes such as EGFR, AKT3, CDK6, CCND2, and BRAF through creation of 5hmC which recruits the CHTOP-methylosome complex that activates these genes.<ref>DOI 10.1016/j.celrep.2014.08.071</ref>

TET2 is broadly expressed, but it is especially highly expressed in hematopoietic cells, which develop into blood cells. Regarding this, it is suggested that TET2 plays a role in hematopoiesis due to the presence of TET2 mutations in many myelodysplastic syndromes.<ref name=’Delhommeau et al.’>DOI: 10.1056/NEJMoa0810069</ref>

TET3 is highly expressed in zygotes and is involved with epigenetic chromatin reprogramming in the zygote after fertilization. Specifically, it plays a role in DNA demethylation of the paternal pronucleus before implantation.<ref name='Rahul M. Kohli & Yi Zhang' />

== Disease Relation ==
=== TET1 Isoform ===

Point mutations within the TET1 isoform can lead to a loss of enzyme function which causes a lack of DNA demethylation; two occur at the 1672 and 1674 amino acid residues, the first being a H1672Y mutation and the second being a D1674A mutation. A severe mutation in the 1608-1609 codons can lead to TET1 becoming an oncogene in acute leukemias. This mutation fuses TET1 and KMT2A/MLL1 to form an oncogene.<ref>PMID:12124344</ref><ref>PMID:12646957</ref>

=== TET2 Isoform ===

TET2 has been identified as a tumor-suppressor gene that is linked to various myeloid cancers. Acquired mutations are predicted to truncate the protein, resulting in alterations of the function of the TET2 protein. TET2 defects have been identified in the CD34+ cells of patients with myelodysplastic syndrome, which include hematopoietic stem cells and hematopoietic progenitors. This suggests that TET2 mutations or defects, paired with mutations in other genes, such as Janus kinase 2 (JAK2) V617F gene or myeloproliferative leukemia virus oncogene (MPL) W515L/K can contribute to the progression of myeloid cancers. Due to the involvement of TET2 in hematopoietic stem cell development, mutations in this gene may also be associated with the amplification of the mutation in the early stages of hematopoietic differentiation.<ref name=’Delhommeau et al.’</ref><ref name=’Delhommeau et al.’>DOI: 10.1056/NEJMoa0810069</ref>

== Structural highlights ==

This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.

</StructureSection>
== References ==
<references/>

User:Madelyn Kasprzak/Sandbox 6

2016-04-14T04:59:39Z

Madelyn Kasprzak:

== TET Enzymes==

TET enzymes are a family of [[Dioxygenase|dioxygenases]] that are involved in the process of oxidizing methylated cytosine. Members of this family include ten-eleven translocation methylcytosine dioxygenase 1 (TET1), methylcytosine dioxygenase TET2, and methylcytosine dioxygenase TET3. The gene for the first of these proteins, TET1, was identified when it was determined to be fused to the ''Mixed Lineage Leukemia'' (MLL) gene as a result of a translocation event that occurred between chromosomes ten and eleven (hence the name). <ref>DOI 10.1038/sj.leu.2402834</ref>

<StructureSection load='5cg9' size='320' side='right' caption='TET-like protein in Naegleria gruberi in complex with DNA containing 5hmC.' scene=''>

== Structure ==
The TET enzymes have a cysteine-rich region closely followed by a double stranded beta-helix (DSBH) domain near their C-terminus.<ref name='Kinney et al.'>DOI 10.1007/978-1-4419-9967-2_3</ref> The DSBH domain contains three Fe<sup>2+</sup> binding sites and an α-ketoglutarate binding site.<ref name='Kinney et al.' /> This DSBH domain, along with the preceding cysteine-rich region, performs the main catalytic activity of these enzymes and more generally, for all α-ketoglutarate oxygenases.

In addition, TET1 has a CXXC-type zinc finger domain near the N-terminus. However, the TET1 CXXC domain lacks the conserved lysine-phenylalanine-glycine-glycine (KFGG) motif commonly seen within the CXXC domains of other DNA binding proteins, such as DNA methyltransferase-1 (DNMT1). A study conducted by Frauer et al. in 2011 showed that the isolated CXXC domain of TET1 has no DNA binding activity, which agrees with the evidence suggesting that the KFGG motif increases affinity for unmethylated DNA.<ref name='Frauer et al.'>DOI 10.1371/journal.pone.0016627</ref> Frauer et al. also speculated that the CXXC domain of TET1 may be involved with protein-protein interactions instead of DNA binding.<ref name='Frauer et al.' />

== Function ==
===Common Function===

All three TET enzymes and their isoforms are involved in the biochemical pathway that converts 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC). They also regulate the further conversions of 5hmC to 5-formylcytosine (5fC) and then 5fC to 5-carboxylcytosine (5caC).<ref name='He et al.'>DOI: 10.1126/science.1210944</ref> Although experimental data shows that TET3 does so to a lesser extent than TET1 and TET2.<ref name='He et al.' />

While the oxidation performed by TET enzymes was originally thought to be a source of DNA damage, new research has implied that this catalytic activity may actually be the initial steps of a process of DNA demethylation. This hypothesized DNA demethylation pathway starts with the conversion of 5mC to 5caC after several rounds of oxidation by TET enzymes. The next step is the removal of the modified cytosine base by thymine DNA glycosylase (TDG) which leaves an abasic site on the DNA. The last step is then the process of base excision repair in which a new unmodified cytosine is regenerated at the site, thus completing the process of DNA demethylation.<ref name='He et al.' /><ref name='Rahul M. Kohli & Yi Zhang'>DOI 10.1038/nature12750</ref>

===Specific Functions===
Experimental data shows that the TET genes have different expression patterns and at different levels, which indicates that each of the TET enzymes do not fully overlap in their functionality.

TET1 is usually expressed in fetal heart, lung, and brain tissue and in adult skeletal muscle, thymus, and ovary. It is not generally expressed in adult heart, lung, and brain tissue. Moreover, studies have shown that TET1 expression in adult brain tissue is correlated with brain cancer. This occurs through TET1’s indirect activation of brain cancer-related genes such as EGFR, AKT3, CDK6, CCND2, and BRAF through creation of 5hmC which recruits the CHTOP-methylosome complex that activates these genes.<ref>DOI 10.1016/j.celrep.2014.08.071</ref>

TET2 is broadly expressed, but it is especially highly expressed in hematopoietic cells, which develop into blood cells. Regarding this, it is suggested that TET2 plays a role in hematopoiesis due to the presence of TET2 mutations in many myelodysplastic syndromes.<ref>DOI 10.1056/NEJMoa0810069</ref><ref>DOI 10.1038/ng.391</ref>

TET3 is highly expressed in zygotes and is involved with epigenetic chromatin reprogramming in the zygote after fertilization. Specifically, it plays a role in DNA demethylation of the paternal pronucleus before implantation.<ref name='Rahul M. Kohli & Yi Zhang' />

== Disease Relation ==
=== TET1 Isoform ===

Point mutations within the TET1 isoform can lead to a loss of enzyme function which causes a lack of DNA demethylation; two occur at the 1672 and 1674 amino acid residues, the first being a H1672Y mutation and the second being a D1674A mutation. A severe mutation in the 1608-1609 codons can lead to TET1 becoming an oncogene in acute leukemias. This mutation fuses TET1 and KMT2A/MLL1 to form an oncogene.<ref>PMID:12124344</ref><ref>PMID:12646957</ref>

=== TET2 Isoform ===

TET2 has been identified as a tumor-suppressor gene that is linked to various myeloid cancers. Acquired mutations are predicted to truncate the protein, resulting in alterations of the function of the TET2 protein. TET2 defects have been identified in the CD34+ cells of patients with myelodysplastic syndrome, which include hematopoietic stem cells and hematopoietic progenitors. This suggests that TET2 mutations or defects, paired with mutations in other genes, such as Janus kinase 2 (JAK2) V617F gene or myeloproliferative leukemia virus oncogene (MPL) W515L/K can contribute to the progression of myeloid cancers. Due to the involvement of TET2 in hematopoietic stem cell development, mutations in this gene may also be associated with the amplification of the mutation in the early stages of hematopoietic differentiation.<ref name=’Delhommeau et al.’>DOI: 10.1056/NEJMoa0810069</ref>

== Structural highlights ==

This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.

</StructureSection>
== References ==
<references/>

User:Madelyn Kasprzak/Sandbox 6

2016-04-14T04:51:25Z

Madelyn Kasprzak:

== TET Enzymes==

TET enzymes are a family of [[Dioxygenase|dioxygenases]] that are involved in the process of oxidizing methylated cytosine. Members of this family include ten-eleven translocation methylcytosine dioxygenase 1 (TET1), methylcytosine dioxygenase TET2, and methylcytosine dioxygenase TET3. The gene for the first of these proteins, TET1, was identified when it was determined to be fused to the ''Mixed Lineage Leukemia'' (MLL) gene as a result of a translocation event that occurred between chromosomes ten and eleven (hence the name). <ref>DOI 10.1038/sj.leu.2402834</ref>

<StructureSection load='5cg9' size='320' side='right' caption='TET-like protein in Naegleria gruberi in complex with DNA containing 5hmC.' scene=''>

== Structure ==
The TET enzymes have a cysteine-rich region closely followed by a double stranded beta-helix (DSBH) domain near their C-terminus.<ref name='Kinney et al.'>DOI 10.1007/978-1-4419-9967-2_3</ref> The DSBH domain contains three Fe<sup>2+</sup> binding sites and an α-ketoglutarate binding site.<ref name='Kinney et al.' /> This DSBH domain, along with the preceding cysteine-rich region, performs the main catalytic activity of these enzymes and more generally, for all α-ketoglutarate oxygenases.

In addition, TET1 has a CXXC-type zinc finger domain near the N-terminus. However, the TET1 CXXC domain lacks the conserved lysine-phenylalanine-glycine-glycine (KFGG) motif commonly seen within the CXXC domains of other DNA binding proteins, such as DNA methyltransferase-1 (DNMT1). A study conducted by Frauer et al. in 2011 showed that the isolated CXXC domain of TET1 has no DNA binding activity, which agrees with the evidence suggesting that the KFGG motif increases affinity for unmethylated DNA.<ref name='Frauer et al.'>DOI 10.1371/journal.pone.0016627</ref> Frauer et al. also speculated that the CXXC domain of TET1 may be involved with protein-protein interactions instead of DNA binding.<ref name='Frauer et al.' />

== Function ==
===Common Function===

All three TET enzymes and their isoforms are involved in the biochemical pathway that converts 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC). They also regulate the further conversions of 5hmC to 5-formylcytosine (5fC) and then 5fC to 5-carboxylcytosine (5caC).<ref name='He et al.'>DOI: 10.1126/science.1210944</ref> Although experimental data shows that TET3 does so to a lesser extent than TET1 and TET2.<ref name='He et al.' />

While the oxidation performed by TET enzymes was originally thought to be a source of DNA damage, new research has implied that this catalytic activity may actually be the initial steps of a process of DNA demethylation. This hypothesized DNA demethylation pathway starts with the conversion of 5mC to 5caC after several rounds of oxidation by TET enzymes. The next step is the removal of the modified cytosine base by thymine DNA glycosylase (TDG) which leaves an abasic site on the DNA. The last step is then the process of base excision repair in which a new unmodified cytosine is regenerated at the site, thus completing the process of DNA demethylation.<ref name='He et al.' /><ref name='Rahul M. Kohli & Yi Zhang'>DOI 10.1038/nature12750</ref>

===Specific Functions===
Experimental data shows that the TET genes have different expression patterns and at different levels, which indicates that each of the TET enzymes do not fully overlap in their functionality.

TET1 is usually expressed in fetal heart, lung, and brain tissue and in adult skeletal muscle, thymus, and ovary. It is not generally expressed in adult heart, lung, and brain tissue. Moreover, studies have shown that TET1 expression in adult brain tissue is correlated with brain cancer. This occurs through TET1’s indirect activation of brain cancer-related genes such as EGFR, AKT3, CDK6, CCND2, and BRAF through creation of 5hmC which recruits the CHTOP-methylosome complex that activates these genes.<ref>DOI 10.1016/j.celrep.2014.08.071</ref>

TET2 is broadly expressed, but it is especially highly expressed in hematopoietic cells, which develop into blood cells. Regarding this, it is suggested that TET2 plays a role in hematopoiesis due to the presence of TET2 mutations in many myelodysplastic syndromes.<ref>DOI 10.1056/NEJMoa0810069</ref><ref>DOI 10.1038/ng.391</ref>

TET3 is highly expressed in zygotes and is involved with epigenetic chromatin reprogramming in the zygote after fertilization. Specifically, it plays a role in DNA demethylation of the paternal pronucleus before implantation.<ref name='Rahul M. Kohli & Yi Zhang' />

== Disease Relation ==
=== TET1 Isoform ====

Point mutations within the TET1 isoform can lead to a loss of enzyme function which causes a lack of DNA demethylation; two occur at the 1672 and 1674 amino acid residues, the first being a H1672Y mutation and the second being a D1674A mutation. A severe mutation in the 1608-1609 codons can lead to TET1 becoming an oncogene in acute leukemias. This mutation fuses TET1 and KMT2A/MLL1 to form an oncogene.<ref>PMID:12124344</ref><ref>PMID:12646957</ref>

== Structural highlights ==

This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.

</StructureSection>
== References ==
<references/>

User:Madelyn Kasprzak/Sandbox 6

2016-04-14T04:25:27Z

Madelyn Kasprzak:

== TET Enzymes==

TET enzymes are a family of [[Dioxygenase|dioxygenases]] that are involved in the process of oxidizing methylated cytosine. Members of this family include ten-eleven translocation methylcytosine dioxygenase 1 (TET1), methylcytosine dioxygenase TET2, and methylcytosine dioxygenase TET3. The gene for the first of these proteins, TET1, was identified when it was determined to be fused to the ''Mixed Lineage Leukemia'' (MLL) gene as a result of a translocation event that occurred between chromosomes ten and eleven (hence the name). <ref>DOI 10.1038/sj.leu.2402834</ref>

<StructureSection load='5cg9' size='320' side='right' caption='TET-like protein in Naegleria gruberi in complex with DNA containing 5hmC.' scene=''>

== Structure ==
The TET enzymes have a cysteine-rich region closely followed by a double stranded beta-helix (DSBH) domain near their C-terminus.<ref name='Kinney et al.'>DOI 10.1007/978-1-4419-9967-2_3</ref> The DSBH domain contains three Fe<sup>2+</sup> binding sites and an α-ketoglutarate binding site.<ref name='Kinney et al.' /> This DSBH domain, along with the preceding cysteine-rich region, performs the main catalytic activity of these enzymes and more generally, for all α-ketoglutarate oxygenases.

In addition, TET1 has a CXXC-type zinc finger domain near the N-terminus. However, the TET1 CXXC domain lacks the conserved lysine-phenylalanine-glycine-glycine (KFGG) motif commonly seen within the CXXC domains of other DNA binding proteins, such as DNA methyltransferase-1 (DNMT1). A study conducted by Frauer et al. in 2011 showed that the isolated CXXC domain of TET1 has no DNA binding activity, which agrees with the evidence suggesting that the KFGG motif increases affinity for unmethylated DNA.<ref name='Frauer et al.'>DOI 10.1371/journal.pone.0016627</ref> Frauer et al. also speculated that the CXXC domain of TET1 may be involved with protein-protein interactions instead of DNA binding.<ref name='Frauer et al.' />

== Function ==
===Common Function===

All three TET enzymes and their isoforms are involved in the biochemical pathway that converts 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC). They also regulate the further conversions of 5hmC to 5-formylcytosine (5fC) and then 5fC to 5-carboxylcytosine (5caC).<ref name='He et al.'>DOI: 10.1126/science.1210944</ref> Although experimental data shows that TET3 does so to a lesser extent than TET1 and TET2.<ref name='He et al.' />

While the oxidation performed by TET enzymes was originally thought to be a source of DNA damage, new research has implied that this catalytic activity may actually be the initial steps of a process of DNA demethylation. This hypothesized DNA demethylation pathway starts with the conversion of 5mC to 5caC after several rounds of oxidation by TET enzymes. The next step is the removal of the modified cytosine base by thymine DNA glycosylase (TDG) which leaves an abasic site on the DNA. The last step is then the process of base excision repair in which a new unmodified cytosine is regenerated at the site, thus completing the process of DNA demethylation.<ref name='He et al.' /><ref name='Rahul M. Kohli & Yi Zhang'>DOI 10.1038/nature12750</ref>

===Specific Functions===
Experimental data shows that the TET genes have different expression patterns and at different levels, which indicates that each of the TET enzymes do not fully overlap in their functionality.

TET1 is usually expressed in fetal heart, lung, and brain tissue and in adult skeletal muscle, thymus, and ovary. It is not generally expressed in adult heart, lung, and brain tissue. Moreover, studies have shown that TET1 expression in adult brain tissue is correlated with brain cancer. This occurs through TET1’s indirect activation of brain cancer-related genes such as EGFR, AKT3, CDK6, CCND2, and BRAF through creation of 5hmC which recruits the CHTOP-methylosome complex that activates these genes.<ref>DOI 10.1016/j.celrep.2014.08.071</ref>

TET2 is broadly expressed, but it is especially highly expressed in hematopoietic cells, which develop into blood cells. Regarding this, it is suggested that TET2 plays a role in hematopoiesis due to the presence of TET2 mutations in many myelodysplastic syndromes.<ref>DOI 10.1056/NEJMoa0810069</ref><ref>DOI 10.1038/ng.391</ref>

TET3 is highly expressed in zygotes and is involved with epigenetic chromatin reprogramming in the zygote after fertilization. Specifically, it plays a role in DNA demethylation of the paternal pronucleus before implantation.<ref name='Rahul M. Kohli & Yi Zhang' />

== Disease Relation ==

== Relevance ==

== Structural highlights ==

This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.

</StructureSection>
== References ==
<references/>

User:Madelyn Kasprzak/Sandbox 6

2016-04-14T04:20:13Z

Madelyn Kasprzak:

== TET Enzymes==

TET enzymes are a family of [[Dioxygenase|dioxygenases]] that are involved in the process of oxidizing methylated cytosine. Members of this family include ten-eleven translocation methylcytosine dioxygenase 1 (TET1), methylcytosine dioxygenase TET2, and methylcytosine dioxygenase TET3. The gene for the first of these proteins, TET1, was identified when it was determined to be fused to the ''Mixed Lineage Leukemia'' (MLL) gene as a result of a translocation event that occurred between chromosomes ten and eleven (hence the name). <ref>DOI 10.1038/sj.leu.2402834</ref>

<StructureSection load='5cg9' size='320' side='right' caption='TET-like protein in Naegleria gruberi in complex with DNA containing 5hmC.' scene=''>

== Structure ==
The TET enzymes have a cysteine-rich region closely followed by a double stranded beta-helix (DSBH) domain near their C-terminus.<ref name='Kinney et al.'>DOI 10.1007/978-1-4419-9967-2_3</ref> The DSBH domain contains three Fe<sup>2+</sup> binding sites and an α-ketoglutarate binding site.<ref name='Kinney et al.' /> This DSBH domain, along with the preceding cysteine-rich region, performs the main catalytic activity of these enzymes and more generally, for all α-ketoglutarate oxygenases.

In addition, TET1 has a CXXC-type zinc finger domain near the N-terminus. However, the TET1 CXXC domain lacks the conserved lysine-phenylalanine-glycine-glycine (KFGG) motif commonly seen within the CXXC domains of other DNA binding proteins, such as DNA methyltransferase-1 (DNMT1). A study conducted by Frauer et al. in 2011 showed that the isolated CXXC domain of TET1 has no DNA binding activity, which agrees with the evidence suggesting that the KFGG motif increases affinity for unmethylated DNA.<ref name='Frauer et al.'>DOI 10.1371/journal.pone.0016627</ref> Frauer et al. also speculated that the CXXC domain of TET1 may be involved with protein-protein interactions instead of DNA binding.<ref name='Frauer et al.' />

== Function ==
===Common Function===

All three TET enzymes and their isoforms are involved in the biochemical pathway that converts 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC). They also regulate the further conversions of 5hmC to 5-formylcytosine (5fC) and then 5fC to 5-carboxylcytosine (5caC).<ref name='He et al.'>DOI: 10.1126/science.1210944</ref> Although experimental data shows that TET3 does so to a lesser extent than TET1 and TET2.<ref name='He et al.' />

While the oxidation performed by TET enzymes was originally thought to be a source of DNA damage, new research has implied that this catalytic activity may actually be the initial steps of a process of DNA demethylation. This hypothesized DNA demethylation pathway starts with the conversion of 5mC to 5caC after several rounds of oxidation by TET enzymes. The next step is the removal of the modified cytosine base by thymine DNA glycosylase (TDG) which leaves an abasic site on the DNA. The last step is then the process of base excision repair in which a new unmodified cytosine is regenerated at the site, thus completing the process of DNA demethylation.<ref name='He et al.' /><ref name='Rahul M. Kohli & Yi Zhang'>DOI 10.1038/nature12750</ref>

===Specific Functions===
Experimental data shows that the TET genes have different expression patterns and at different levels, which indicates that each of the TET enzymes do not fully overlap in their functionality.

TET1 is usually expressed in fetal heart, lung, and brain tissue and in adult skeletal muscle, thymus, and ovary. It is not generally expressed in adult heart, lung, and brain tissue. Moreover, studies have shown that TET1 expression in adult brain tissue is correlated with brain cancer. This occurs through TET1’s indirect activation of brain cancer-related genes such as EGFR, AKT3, CDK6, CCND2, and BRAF through creation of 5hmC which recruits the CHTOP-methylosome complex that activates these genes.<ref>DOI 10.1016/j.celrep.2014.08.071</ref>

TET2 is broadly expressed, but it is especially highly expressed in hematopoietic cells, which develop into blood cells. Regarding this, it is suggested that TET2 plays a role in hematopoiesis due to the presence of TET2 mutations in many myelodysplastic syndromes.

TET3 is highly expressed in zygotes and is involved with epigenetic chromatin reprogramming in the zygote after fertilization. Specifically, it plays a role in DNA demethylation of the paternal pronucleus before implantation.<ref name='Rahul M. Kohli & Yi Zhang' />

== Disease Relation ==

== Relevance ==

== Structural highlights ==

This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.

</StructureSection>
== References ==
<references/>

User:Madelyn Kasprzak/Sandbox 6

2016-04-14T04:17:57Z

Madelyn Kasprzak:

== TET Enzymes==

TET enzymes are a family of [[Dioxygenase|dioxygenases]] that are involved in the process of oxidizing methylated cytosine. Members of this family include ten-eleven translocation methylcytosine dioxygenase 1 (TET1), methylcytosine dioxygenase TET2, and methylcytosine dioxygenase TET3. The gene for the first of these proteins, TET1, was identified when it was determined to be fused to the ''Mixed Lineage Leukemia'' (MLL) gene as a result of a translocation event that occurred between chromosomes ten and eleven (hence the name). <ref>DOI 10.1038/sj.leu.2402834</ref>

<StructureSection load='5cg9' size='320' side='right' caption='TET-like protein in Naegleria gruberi in complex with DNA containing 5hmC.' scene=''>

== Structure ==
The TET enzymes have a cysteine-rich region closely followed by a double stranded beta-helix (DSBH) domain near their C-terminus.<ref name='Kinney et al.'>DOI 10.1007/978-1-4419-9967-2_3</ref> The DSBH domain contains three Fe<sup>2+</sup> binding sites and an α-ketoglutarate binding site.<ref name='Kinney et al.' /> This DSBH domain, along with the preceding cysteine-rich region, performs the main catalytic activity of these enzymes and more generally, for all α-ketoglutarate oxygenases.

In addition, TET1 has a CXXC-type zinc finger domain near the N-terminus. However, the TET1 CXXC domain lacks the conserved lysine-phenylalanine-glycine-glycine (KFGG) motif commonly seen within the CXXC domains of other DNA binding proteins, such as DNA methyltransferase-1 (DNMT1). A study conducted by Frauer et al. in 2011 showed that the isolated CXXC domain of TET1 has no DNA binding activity, which agrees with the evidence suggesting that the KFGG motif increases affinity for unmethylated DNA.<ref name='Frauer et al.'>DOI 10.1371/journal.pone.0016627</ref> Frauer et al. also speculated that the CXXC domain of TET1 may be involved with protein-protein interactions instead of DNA binding.<ref name='Frauer et al.' />

== Function ==
===Common Function===

All three TET enzymes and their isoforms are involved in the biochemical pathway that converts 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC). They also regulate the further conversions of 5hmC to 5-formylcytosine (5fC) and then 5fC to 5-carboxylcytosine (5caC).<ref name='He et al.'>DOI: 10.1126/science.1210944</ref> Although experimental data shows that TET3 does so to a lesser extent than TET1 and TET2.<ref name='He et al.' />

While the oxidation performed by TET enzymes was originally thought to be a source of DNA damage, new research has implied that this catalytic activity may actually be the initial steps of a process of DNA demethylation. This hypothesized DNA demethylation pathway starts with the conversion of 5mC to 5caC after several rounds of oxidation by TET enzymes. The next step is the removal of the modified cytosine base by thymine DNA glycosylase (TDG) which leaves an abasic site on the DNA. The last step is then the process of base excision repair in which a new unmodified cytosine is regenerated at the site, thus completing the process of DNA demethylation.<ref name='He et al.' /><ref name='Rahul M. Kohli & Yi Zhang'>DOI 10.1038/nature12750</ref>

===Specific Functions===
Experimental data shows that the TET genes have different expression patterns and at different levels, which indicates that each of the TET enzymes do not fully overlap in their functionality.

TET1 is usually expressed in fetal heart, lung, and brain tissue and in adult skeletal muscle, thymus, and ovary. It is not generally expressed in adult heart, lung, and brain tissue. Moreover, studies have shown that TET1 expression in adult brain tissue is correlated with brain cancer. This occurs through TET1’s indirect activation of brain cancer-related genes such as EGFR, AKT3, CDK6, CCND2, and BRAF through creation of 5hmC which recruits the CHTOP-methylosome complex that activates these genes.<ref>DOI 10.1016/j.celrep.2014.08.071</ref>

TET2

TET3 is highly expressed in zygotes and is involved with epigenetic chromatin reprogramming in the zygote after fertilization. Specifically, it plays a role in DNA demethylation of the paternal pronucleus before implantation.<ref name='Rahul M. Kohli & Yi Zhang' />

== Disease Relation ==

== Relevance ==

== Structural highlights ==

This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.

</StructureSection>
== References ==
<references/>

User:Madelyn Kasprzak/Sandbox 6

2016-04-14T04:16:15Z

Madelyn Kasprzak:

== TET Enzymes==

TET enzymes are a family of [[Dioxygenase|dioxygenases]] that are involved in the process of oxidizing methylated cytosine. Members of this family include ten-eleven translocation methylcytosine dioxygenase 1 (TET1), methylcytosine dioxygenase TET2, and methylcytosine dioxygenase TET3. The gene for the first of these proteins, TET1, was identified when it was determined to be fused to the ''Mixed Lineage Leukemia'' (MLL) gene as a result of a translocation event that occurred between chromosomes ten and eleven (hence the name). <ref>DOI 10.1038/sj.leu.2402834</ref>

<StructureSection load='5cg9' size='320' side='right' caption='TET-like protein in Naegleria gruberi in complex with DNA containing 5hmC.' scene=''>

== Structure ==
The TET enzymes have a cysteine-rich region closely followed by a double stranded beta-helix (DSBH) domain near their C-terminus.<ref name='Kinney et al.'>DOI 10.1007/978-1-4419-9967-2_3</ref> The DSBH domain contains three Fe<sup>2+</sup> binding sites and an α-ketoglutarate binding site.<ref name='Kinney et al.' /> This DSBH domain, along with the preceding cysteine-rich region, performs the main catalytic activity of these enzymes and more generally, for all α-ketoglutarate oxygenases.

In addition, TET1 has a CXXC-type zinc finger domain near the N-terminus. However, the TET1 CXXC domain lacks the conserved lysine-phenylalanine-glycine-glycine (KFGG) motif commonly seen within the CXXC domains of other DNA binding proteins, such as DNA methyltransferase-1 (DNMT1). A study conducted by Frauer et al. in 2011 showed that the isolated CXXC domain of TET1 has no DNA binding activity, which agrees with the evidence suggesting that the KFGG motif increases affinity for unmethylated DNA.<ref name='Frauer et al.'>DOI 10.1371/journal.pone.0016627</ref> Frauer et al. also speculated that the CXXC domain of TET1 may be involved with protein-protein interactions instead of DNA binding.<ref name='Frauer et al.' />

== Function ==
===Common Function===

All three TET enzymes and their isoforms are involved in the biochemical pathway that converts 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC). They also regulate the further conversions of 5hmC to 5-formylcytosine (5fC) and then 5fC to 5-carboxylcytosine (5caC).<ref name='He et al.'>DOI: 10.1126/science.1210944</ref> Although experimental data shows that TET3 does so to a lesser extent than TET1 and TET2.<ref name='He et al.' />

While the oxidation performed by TET enzymes was originally thought to be a source of DNA damage, new research has implied that this catalytic activity may actually be the initial steps of a process of DNA demethylation. This hypothesized DNA demethylation pathway starts with the conversion of 5mC to 5caC after several rounds of oxidation by TET enzymes. The next step is the removal of the modified cytosine base by thymine DNA glycosylase (TDG) which leaves an abasic site on the DNA. The last step is then the process of base excision repair in which a new unmodified cytosine is regenerated at the site, thus completing the process of DNA demethylation.<ref name='He et al.' /><ref name='Rahul M. Kohli & Yi Zhang'>DOI 10.1038/nature12750</ref>

===Specific Functions===
Experimental data shows that the TET genes have different expression patterns and at different levels, which indicates that each of the TET enzymes do not fully overlap in their functionality.

TET1 is usually expressed in fetal heart, lung, and brain tissue and in adult skeletal muscle, thymus, and ovary. It is not generally expressed in adult heart, lung, and brain tissue. Moreover, studies have shown that TET1 expression in adult brain tissue is correlated with brain cancer. This occurs through TET1’s indirect activation of brain cancer-related genes such as EGFR, AKT3, CDK6, CCND2, and BRAF through creation of 5hmC which recruits the CHTOP-methylosome complex that activates these genes.<ref>DOI 10.1016/j.celrep.2014.08.071</ref>

== Disease Relation ==

== Relevance ==

== Structural highlights ==

This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.

</StructureSection>
== References ==
<references/>

User:Madelyn Kasprzak/Sandbox 6

2016-04-14T04:15:14Z

Madelyn Kasprzak:

== TET Enzymes==

TET enzymes are a family of [[Dioxygenase|dioxygenases]] that are involved in the process of oxidizing methylated cytosine. Members of this family include ten-eleven translocation methylcytosine dioxygenase 1 (TET1), methylcytosine dioxygenase TET2, and methylcytosine dioxygenase TET3. The gene for the first of these proteins, TET1, was identified when it was determined to be fused to the ''Mixed Lineage Leukemia'' (MLL) gene as a result of a translocation event that occurred between chromosomes ten and eleven (hence the name). <ref>DOI 10.1038/sj.leu.2402834</ref>

<StructureSection load='5cg9' size='320' side='right' caption='TET-like protein in Naegleria gruberi in complex with DNA containing 5hmC.' scene=''>

== Structure ==
The TET enzymes have a cysteine-rich region closely followed by a double stranded beta-helix (DSBH) domain near their C-terminus.<ref name='Kinney et al.'>DOI 10.1007/978-1-4419-9967-2_3</ref> The DSBH domain contains three Fe<sup>2+</sup> binding sites and an α-ketoglutarate binding site.<ref name='Kinney et al.' /> This DSBH domain, along with the preceding cysteine-rich region, performs the main catalytic activity of these enzymes and more generally, for all α-ketoglutarate oxygenases.

In addition, TET1 has a CXXC-type zinc finger domain near the N-terminus. However, the TET1 CXXC domain lacks the conserved lysine-phenylalanine-glycine-glycine (KFGG) motif commonly seen within the CXXC domains of other DNA binding proteins, such as DNA methyltransferase-1 (DNMT1). A study conducted by Frauer et al. in 2011 showed that the isolated CXXC domain of TET1 has no DNA binding activity, which agrees with the evidence suggesting that the KFGG motif increases affinity for unmethylated DNA.<ref name='Frauer et al.'>DOI 10.1371/journal.pone.0016627</ref> Frauer et al. also speculated that the CXXC domain of TET1 may be involved with protein-protein interactions instead of DNA binding.<ref name='Frauer et al.' />

== Function ==
===Common Function===

All three TET enzymes and their isoforms are involved in the biochemical pathway that converts 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC). They also regulate the further conversions of 5hmC to 5-formylcytosine (5fC) and then 5fC to 5-carboxylcytosine (5caC).<ref name='He et al.'>DOI: 10.1126/science.1210944</ref> Although experimental data shows that TET3 does so to a lesser extent than TET1 and TET2.<ref name='He et al.' />

While the oxidation performed by TET enzymes was originally thought to be a source of DNA damage, new research has implied that this catalytic activity may actually be the initial steps of a process of DNA demethylation. This hypothesized DNA demethylation pathway starts with the conversion of 5mC to 5caC after several rounds of oxidation by TET enzymes. The next step is the removal of the modified cytosine base by thymine DNA glycosylase (TDG) which leaves an abasic site on the DNA. The last step is then the process of base excision repair in which a new unmodified cytosine is regenerated at the site, thus completing the process of DNA demethylation.<ref name='He et al.' /><ref name='Rahul M. Kohli & Yi Zhang'>DOI 10.1038/nature12750</ref>

===Specific Functions===
Experimental data shows that the TET genes have different expression patterns and at different levels, which indicates that each of the TET enzymes do not fully overlap in their functionality.

TET1 is usually expressed in fetal heart, lung, and brain tissue and in adult skeletal muscle, thymus, and ovary. It is not generally expressed in adult heart, lung, and brain tissue. Moreover, studies have shown that TET1 expression in adult brain tissue is correlated with brain cancer. This occurs through TET1’s indirect activation of brain cancer-related genes such as EGFR, AKT3, CDK6, CCND2, and BRAF through creation of 5hmC which recruits the CHTOP-methylosome complex that activates these genes.<ref>DOI 10.1016/j.celrep.2014.08.071</ref>

TET2 is broadly expressed, but it is especially highly expressed in hematopoietic cells, which develop into blood cells. Regarding this, it is suggested that TET2 plays a role in hematopoiesis due to the presence of TET2 mutations in many myelodysplastic syndromes.<ref>DOI 10.1182/blood-2009-03-210039</ref><ref>DOI 10.1056/NEJMoa0810069</ref><ref>DOI 10.1038/ng.391</ref>

== Disease ==

== Relevance ==

== Structural highlights ==

This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.

</StructureSection>
== References ==
<references/>

User:Madelyn Kasprzak/Sandbox 6

2016-04-14T04:14:11Z

Madelyn Kasprzak:

== TET Enzymes==

TET enzymes are a family of [[Dioxygenase|dioxygenases]] that are involved in the process of oxidizing methylated cytosine. Members of this family include ten-eleven translocation methylcytosine dioxygenase 1 (TET1), methylcytosine dioxygenase TET2, and methylcytosine dioxygenase TET3. The gene for the first of these proteins, TET1, was identified when it was determined to be fused to the ''Mixed Lineage Leukemia'' (MLL) gene as a result of a translocation event that occurred between chromosomes ten and eleven (hence the name). <ref>DOI 10.1038/sj.leu.2402834</ref>

<StructureSection load='5cg9' size='320' side='right' caption='TET-like protein in Naegleria gruberi in complex with DNA containing 5hmC.' scene=''>

== Structure ==
The TET enzymes have a cysteine-rich region closely followed by a double stranded beta-helix (DSBH) domain near their C-terminus.<ref name='Kinney et al.'>DOI 10.1007/978-1-4419-9967-2_3</ref> The DSBH domain contains three Fe<sup>2+</sup> binding sites and an α-ketoglutarate binding site.<ref name='Kinney et al.' /> This DSBH domain, along with the preceding cysteine-rich region, performs the main catalytic activity of these enzymes and more generally, for all α-ketoglutarate oxygenases.

In addition, TET1 has a CXXC-type zinc finger domain near the N-terminus. However, the TET1 CXXC domain lacks the conserved lysine-phenylalanine-glycine-glycine (KFGG) motif commonly seen within the CXXC domains of other DNA binding proteins, such as DNA methyltransferase-1 (DNMT1). A study conducted by Frauer et al. in 2011 showed that the isolated CXXC domain of TET1 has no DNA binding activity, which agrees with the evidence suggesting that the KFGG motif increases affinity for unmethylated DNA.<ref name='Frauer et al.'>DOI 10.1371/journal.pone.0016627</ref> Frauer et al. also speculated that the CXXC domain of TET1 may be involved with protein-protein interactions instead of DNA binding.<ref name='Frauer et al.' />

== Function ==
===Common Function===

All three TET enzymes and their isoforms are involved in the biochemical pathway that converts 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC). They also regulate the further conversions of 5hmC to 5-formylcytosine (5fC) and then 5fC to 5-carboxylcytosine (5caC).<ref name='He et al.'>DOI: 10.1126/science.1210944</ref> Although experimental data shows that TET3 does so to a lesser extent than TET1 and TET2.<ref name='He et al.' />

While the oxidation performed by TET enzymes was originally thought to be a source of DNA damage, new research has implied that this catalytic activity may actually be the initial steps of a process of DNA demethylation. This hypothesized DNA demethylation pathway starts with the conversion of 5mC to 5caC after several rounds of oxidation by TET enzymes. The next step is the removal of the modified cytosine base by thymine DNA glycosylase (TDG) which leaves an abasic site on the DNA. The last step is then the process of base excision repair in which a new unmodified cytosine is regenerated at the site, thus completing the process of DNA demethylation.<ref name='He et al.' /><ref name='Rahul M. Kohli & Yi Zhang'>DOI 10.1038/nature12750</ref>

===Specific Functions===
Experimental data shows that the TET genes have different expression patterns and at different levels, which indicates that each of the TET enzymes do not fully overlap in their functionality.

TET1 is usually expressed in fetal heart, lung, and brain tissue and in adult skeletal muscle, thymus, and ovary. It is not generally expressed in adult heart, lung, and brain tissue. Moreover, studies have shown that TET1 expression in adult brain tissue is correlated with brain cancer. This occurs through TET1’s indirect activation of brain cancer-related genes such as EGFR, AKT3, CDK6, CCND2, and BRAF through creation of 5hmC which recruits the CHTOP-methylosome complex that activates these genes.<ref>DOI 10.1016/j.celrep.2014.08.071</ref>

== Disease ==

== Relevance ==

== Structural highlights ==

This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.

</StructureSection>
== References ==
<references/>

User:Madelyn Kasprzak/Sandbox 6

2016-04-14T04:13:03Z

Madelyn Kasprzak:

== TET Enzymes==

TET enzymes are a family of [[Dioxygenase|dioxygenases]] that are involved in the process of oxidizing methylated cytosine. Members of this family include ten-eleven translocation methylcytosine dioxygenase 1 (TET1), methylcytosine dioxygenase TET2, and methylcytosine dioxygenase TET3. The gene for the first of these proteins, TET1, was identified when it was determined to be fused to the ''Mixed Lineage Leukemia'' (MLL) gene as a result of a translocation event that occurred between chromosomes ten and eleven (hence the name). <ref>DOI 10.1038/sj.leu.2402834</ref>

<StructureSection load='5cg9' size='320' side='right' caption='TET-like protein in Naegleria gruberi in complex with DNA containing 5hmC.' scene=''>

== Structure ==
The TET enzymes have a cysteine-rich region closely followed by a double stranded beta-helix (DSBH) domain near their C-terminus.<ref name='Kinney et al.'>DOI 10.1007/978-1-4419-9967-2_3</ref> The DSBH domain contains three Fe<sup>2+</sup> binding sites and an α-ketoglutarate binding site.<ref name='Kinney et al.' /> This DSBH domain, along with the preceding cysteine-rich region, performs the main catalytic activity of these enzymes and more generally, for all α-ketoglutarate oxygenases.

In addition, TET1 has a CXXC-type zinc finger domain near the N-terminus. However, the TET1 CXXC domain lacks the conserved lysine-phenylalanine-glycine-glycine (KFGG) motif commonly seen within the CXXC domains of other DNA binding proteins, such as DNA methyltransferase-1 (DNMT1). A study conducted by Frauer et al. in 2011 showed that the isolated CXXC domain of TET1 has no DNA binding activity, which agrees with the evidence suggesting that the KFGG motif increases affinity for unmethylated DNA.<ref name='Frauer et al.'>DOI 10.1371/journal.pone.0016627</ref> Frauer et al. also speculated that the CXXC domain of TET1 may be involved with protein-protein interactions instead of DNA binding.<ref name='Frauer et al.' />

== Function ==
===Common Function===

All three TET enzymes and their isoforms are involved in the biochemical pathway that converts 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC). They also regulate the further conversions of 5hmC to 5-formylcytosine (5fC) and then 5fC to 5-carboxylcytosine (5caC).<ref name='He et al.'>DOI: 10.1126/science.1210944</ref> Although experimental data shows that TET3 does so to a lesser extent than TET1 and TET2.<ref name='He et al.' />

While the oxidation performed by TET enzymes was originally thought to be a source of DNA damage, new research has implied that this catalytic activity may actually be the initial steps of a process of DNA demethylation. This hypothesized DNA demethylation pathway starts with the conversion of 5mC to 5caC after several rounds of oxidation by TET enzymes. The next step is the removal of the modified cytosine base by thymine DNA glycosylase (TDG) which leaves an abasic site on the DNA. The last step is then the process of base excision repair in which a new unmodified cytosine is regenerated at the site, thus completing the process of DNA demethylation.<ref name='He et al.' /><ref name='Rahul M. Kohli & Yi Zhang'>DOI 10.1038/nature12750</ref>

===Specific Functions===
Experimental data shows that the TET genes have different expression patterns and at different levels, which indicates that each of the TET enzymes do not fully overlap in their functionality.

== Disease ==

== Relevance ==

== Structural highlights ==

This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.

</StructureSection>
== References ==
<references/>

User:Madelyn Kasprzak/Sandbox 6

2016-04-14T04:12:19Z

Madelyn Kasprzak:

== TET Enzymes==

TET enzymes are a family of [[Dioxygenase|dioxygenases]] that are involved in the process of oxidizing methylated cytosine. Members of this family include ten-eleven translocation methylcytosine dioxygenase 1 (TET1), methylcytosine dioxygenase TET2, and methylcytosine dioxygenase TET3. The gene for the first of these proteins, TET1, was identified when it was determined to be fused to the ''Mixed Lineage Leukemia'' (MLL) gene as a result of a translocation event that occurred between chromosomes ten and eleven (hence the name). <ref>DOI 10.1038/sj.leu.2402834</ref>

<StructureSection load='5cg9' size='320' side='right' caption='TET-like protein in Naegleria gruberi in complex with DNA containing 5hmC.' scene=''>

== Structure ==
The TET enzymes have a cysteine-rich region closely followed by a double stranded beta-helix (DSBH) domain near their C-terminus.<ref name='Kinney et al.'>DOI 10.1007/978-1-4419-9967-2_3</ref> The DSBH domain contains three Fe<sup>2+</sup> binding sites and an α-ketoglutarate binding site.<ref name='Kinney et al.' /> This DSBH domain, along with the preceding cysteine-rich region, performs the main catalytic activity of these enzymes and more generally, for all α-ketoglutarate oxygenases.

In addition, TET1 has a CXXC-type zinc finger domain near the N-terminus. However, the TET1 CXXC domain lacks the conserved lysine-phenylalanine-glycine-glycine (KFGG) motif commonly seen within the CXXC domains of other DNA binding proteins, such as DNA methyltransferase-1 (DNMT1). A study conducted by Frauer et al. in 2011 showed that the isolated CXXC domain of TET1 has no DNA binding activity, which agrees with the evidence suggesting that the KFGG motif increases affinity for unmethylated DNA.<ref name='Frauer et al.'>DOI 10.1371/journal.pone.0016627</ref> Frauer et al. also speculated that the CXXC domain of TET1 may be involved with protein-protein interactions instead of DNA binding.<ref name='Frauer et al.' />

== Function ==
===Common Function===

All three TET enzymes and their isoforms are involved in the biochemical pathway that converts 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC). They also regulate the further conversions of 5hmC to 5-formylcytosine (5fC) and then 5fC to 5-carboxylcytosine (5caC).<ref name='He et al.'>DOI: 10.1126/science.1210944</ref> Although experimental data shows that TET3 does so to a lesser extent than TET1 and TET2.<ref name='He et al.' />

While the oxidation performed by TET enzymes was originally thought to be a source of DNA damage, new research has implied that this catalytic activity may actually be the initial steps of a process of DNA demethylation. This hypothesized DNA demethylation pathway starts with the conversion of 5mC to 5caC after several rounds of oxidation by TET enzymes. The next step is the removal of the modified cytosine base by thymine DNA glycosylase (TDG) which leaves an abasic site on the DNA. The last step is then the process of base excision repair in which a new unmodified cytosine is regenerated at the site, thus completing the process of DNA demethylation.<ref name='He et al.' /><ref name='Rahul M. Kohli & Yi Zhang'>DOI 10.1038/nature12750</ref>

== Disease ==

== Relevance ==

== Structural highlights ==

This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.

</StructureSection>
== References ==
<references/>

User:Madelyn Kasprzak/Sandbox 6

2016-04-14T04:11:41Z

Madelyn Kasprzak:

== TET Enzymes==

TET enzymes are a family of [[Dioxygenase|dioxygenases]] that are involved in the process of oxidizing methylated cytosine. Members of this family include ten-eleven translocation methylcytosine dioxygenase 1 (TET1), methylcytosine dioxygenase TET2, and methylcytosine dioxygenase TET3. The gene for the first of these proteins, TET1, was identified when it was determined to be fused to the ''Mixed Lineage Leukemia'' (MLL) gene as a result of a translocation event that occurred between chromosomes ten and eleven (hence the name). <ref>DOI 10.1038/sj.leu.2402834</ref>

<StructureSection load='5cg9' size='320' side='right' caption='TET-like protein in Naegleria gruberi in complex with DNA containing 5hmC.' scene=''>

== Structure ==
The TET enzymes have a cysteine-rich region closely followed by a double stranded beta-helix (DSBH) domain near their C-terminus.<ref name='Kinney et al.'>DOI 10.1007/978-1-4419-9967-2_3</ref> The DSBH domain contains three Fe<sup>2+</sup> binding sites and an α-ketoglutarate binding site.<ref name='Kinney et al.' /> This DSBH domain, along with the preceding cysteine-rich region, performs the main catalytic activity of these enzymes and more generally, for all α-ketoglutarate oxygenases.

In addition, TET1 has a CXXC-type zinc finger domain near the N-terminus. However, the TET1 CXXC domain lacks the conserved lysine-phenylalanine-glycine-glycine (KFGG) motif commonly seen within the CXXC domains of other DNA binding proteins, such as DNA methyltransferase-1 (DNMT1). A study conducted by Frauer et al. in 2011 showed that the isolated CXXC domain of TET1 has no DNA binding activity, which agrees with the evidence suggesting that the KFGG motif increases affinity for unmethylated DNA.<ref name='Frauer et al.'>DOI 10.1371/journal.pone.0016627</ref> Frauer et al. also speculated that the CXXC domain of TET1 may be involved with protein-protein interactions instead of DNA binding.<ref name='Frauer et al.' />

== Function ==
===Common Function===

All three TET enzymes and their isoforms are involved in the biochemical pathway that converts 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC). They also regulate the further conversions of 5hmC to 5-formylcytosine (5fC) and then 5fC to 5-carboxylcytosine (5caC).<ref name='He et al.'>DOI: 10.1126/science.1210944</ref> Although experimental data shows that TET3 does so to a lesser extent than TET1 and TET2.<ref name='He et al.' />

== Disease ==

== Relevance ==

== Structural highlights ==

This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.

</StructureSection>
== References ==
<references/>

User:Madelyn Kasprzak/Sandbox 6

2016-04-14T04:10:42Z

Madelyn Kasprzak:

== TET Enzymes==

TET enzymes are a family of [[Dioxygenase|dioxygenases]] that are involved in the process of oxidizing methylated cytosine. Members of this family include ten-eleven translocation methylcytosine dioxygenase 1 (TET1), methylcytosine dioxygenase TET2, and methylcytosine dioxygenase TET3. The gene for the first of these proteins, TET1, was identified when it was determined to be fused to the ''Mixed Lineage Leukemia'' (MLL) gene as a result of a translocation event that occurred between chromosomes ten and eleven (hence the name). <ref>DOI 10.1038/sj.leu.2402834</ref>

<StructureSection load='5cg9' size='320' side='right' caption='TET-like protein in Naegleria gruberi in complex with DNA containing 5hmC.' scene=''>

== Structure ==
The TET enzymes have a cysteine-rich region closely followed by a double stranded beta-helix (DSBH) domain near their C-terminus.<ref name='Kinney et al.'>DOI 10.1007/978-1-4419-9967-2_3</ref> The DSBH domain contains three Fe<sup>2+</sup> binding sites and an α-ketoglutarate binding site.<ref name='Kinney et al.' /> This DSBH domain, along with the preceding cysteine-rich region, performs the main catalytic activity of these enzymes and more generally, for all α-ketoglutarate oxygenases.

In addition, TET1 has a CXXC-type zinc finger domain near the N-terminus. However, the TET1 CXXC domain lacks the conserved lysine-phenylalanine-glycine-glycine (KFGG) motif commonly seen within the CXXC domains of other DNA binding proteins, such as DNA methyltransferase-1 (DNMT1). A study conducted by Frauer et al. in 2011 showed that the isolated CXXC domain of TET1 has no DNA binding activity, which agrees with the evidence suggesting that the KFGG motif increases affinity for unmethylated DNA.<ref name='Frauer et al.'>DOI 10.1371/journal.pone.0016627</ref> Frauer et al. also speculated that the CXXC domain of TET1 may be involved with protein-protein interactions instead of DNA binding.<ref name='Frauer et al.' />

== Disease ==

== Relevance ==

== Structural highlights ==

This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.

</StructureSection>
== References ==
<references/>

User:Madelyn Kasprzak/Sandbox 6

2016-04-14T04:09:28Z

Madelyn Kasprzak:

== TET Enzymes==

TET enzymes are a family of [[Dioxygenase|dioxygenases]] that are involved in the process of oxidizing methylated cytosine. Members of this family include ten-eleven translocation methylcytosine dioxygenase 1 (TET1), methylcytosine dioxygenase TET2, and methylcytosine dioxygenase TET3. The gene for the first of these proteins, TET1, was identified when it was determined to be fused to the ''Mixed Lineage Leukemia'' (MLL) gene as a result of a translocation event that occurred between chromosomes ten and eleven (hence the name). <ref>DOI 10.1038/sj.leu.2402834</ref>

<StructureSection load='5cg9' size='320' side='right' caption='TET-like protein in Naegleria gruberi in complex with DNA containing 5hmC.' scene=''>

== Structure ==
The TET enzymes have a cysteine-rich region closely followed by a double stranded beta-helix (DSBH) domain near their C-terminus.<ref name='Kinney et al.'>DOI 10.1007/978-1-4419-9967-2_3</ref> The DSBH domain contains three Fe<sup>2+</sup> binding sites and an α-ketoglutarate binding site.<ref name='Kinney et al.' /> This DSBH domain, along with the preceding cysteine-rich region, performs the main catalytic activity of these enzymes and more generally, for all α-ketoglutarate oxygenases.

== Disease ==

== Relevance ==

== Structural highlights ==

This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.

</StructureSection>
== References ==
<references/>

User:Madelyn Kasprzak/Sandbox 6

2016-04-14T04:08:50Z

Madelyn Kasprzak:

== TET Enzymes==

TET enzymes are a family of [[Dioxygenase|dioxygenases]] that are involved in the process of oxidizing methylated cytosine. Members of this family include ten-eleven translocation methylcytosine dioxygenase 1 (TET1), methylcytosine dioxygenase TET2, and methylcytosine dioxygenase TET3. The gene for the first of these proteins, TET1, was identified when it was determined to be fused to the ''Mixed Lineage Leukemia'' (MLL) gene as a result of a translocation event that occurred between chromosomes ten and eleven (hence the name). <ref>DOI 10.1038/sj.leu.2402834</ref>

<StructureSection load='5cg9' size='320' side='right' caption='TET-like protein in Naegleria gruberi in complex with DNA containing 5hmC.' scene=''>

== Structure and Function ==

== Disease ==

== Relevance ==

== Structural highlights ==

This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.

</StructureSection>
== References ==
<references/>

User:Madelyn Kasprzak/Sandbox 6

2016-04-14T04:07:55Z

Madelyn Kasprzak:

== TET Enzymes==
TET enzymes are a family of [[Dioxygenase|dioxygenases]] that are involved in the process of oxidizing methylated cytosine. Members of this family include ten-eleven translocation methylcytosine dioxygenase 1 (TET1), methylcytosine dioxygenase TET2, and methylcytosine dioxygenase TET3. The gene for the first of these proteins, TET1, was identified when it was determined to be fused to the ''Mixed Lineage Leukemia'' (MLL) gene as a result of a translocation event that occurred between chromosomes ten and eleven (hence the name). <ref>DOI 10.1038/sj.leu.2402834</ref>

== Function ==

== Disease ==

== Relevance ==

== Structural highlights ==

This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.

</StructureSection>
== References ==
<references/>

User:Madelyn Kasprzak/Sandbox 6

2016-04-14T04:05:37Z

Madelyn Kasprzak: New page: ==TET Enzyme== <StructureSection load='1stp' size='340' side='right' caption='Caption for this structure' scene=''> This is a default text for your page '''Madelyn Kasprzak/Sandbox 6'''. C...

==TET Enzyme==
<StructureSection load='1stp' size='340' side='right' caption='Caption for this structure' scene=''>
This is a default text for your page '''Madelyn Kasprzak/Sandbox 6'''. Click above on '''edit this page''' to modify. Be careful with the < and > signs.
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.

== Function ==

== Disease ==

== Relevance ==

== Structural highlights ==

This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.

</StructureSection>
== References ==
<references/>

User:Madelyn Kasprzak

2016-04-14T04:04:10Z

Madelyn Kasprzak:

* Full Real Name: Madelyn Kasprzak

* Position: Student

* Institution (NO ABBREVIATIONS): James Madison University

* City, State/Province, Country: Harrisonburg, VA, USA

* Field of Expertise or Study: Biology

*[[User:Madelyn Kasprzak/Sandbox 92021]]

*[[User:Madelyn Kasprzak/Sandbox 1]]

*[[User:Madelyn Kasprzak/Sandbox 24242]]

*[[User:Madelyn Kasprzak/Sandbox 6]]

User:Madelyn Kasprzak/Sandbox 24242

2016-04-14T03:56:03Z

Madelyn Kasprzak: Sandbox 1 Crashed (server bug), so here's a reboot

=TET Enzymes=
TET enzymes are a family of [[Dioxygenase|dioxygenases]] that are involved in the process of oxidizing methylated cytosine. Members of this family include ten-eleven translocation methylcytosine dioxygenase 1 (TET1), methylcytosine dioxygenase TET2, and methylcytosine dioxygenase TET3. The gene for the first of these proteins, TET1, was identified when it was determined to be fused to the ''Mixed Lineage Leukemia'' (MLL) gene as a result of a translocation event that occurred between chromosomes ten and eleven (hence the name). <ref>DOI 10.1038/sj.leu.2402834</ref>

<StructureSection load='5cg9' size='320' side='right' caption='TET-like protein in Naegleria gruberi in complex with DNA containing 5hmC.' scene=''>

== Structure ==
The TET enzymes have a cysteine-rich region closely followed by a double stranded beta-helix (DSBH) domain near their C-terminus.<ref name='Kinney et al.'>DOI 10.1007/978-1-4419-9967-2_3</ref> The DSBH domain contains three Fe<sup>2+</sup> binding sites and an α-ketoglutarate binding site.<ref name='Kinney et al.' /> This DSBH domain, along with the preceding cysteine-rich region, performs the main catalytic activity of these enzymes and more generally, for all α-ketoglutarate oxygenases.

In addition, TET1 has a CXXC-type zinc finger domain near the N-terminus. However, the TET1 CXXC domain lacks the conserved lysine-phenylalanine-glycine-glycine (KFGG) motif commonly seen within the CXXC domains of other DNA binding proteins, such as DNA methyltransferase-1 (DNMT1). A study conducted by Frauer et al. in 2011 showed that the isolated CXXC domain of TET1 has no DNA binding activity, which agrees with the evidence suggesting that the KFGG motif increases affinity for unmethylated DNA.<ref name='Frauer et al.'>DOI 10.1371/journal.pone.0016627</ref> Frauer et al. also speculated that the CXXC domain of TET1 may be involved with protein-protein interactions instead of DNA binding.<ref name='Frauer et al.' />

== Function ==
===Common Function===

All three TET enzymes and their isoforms are involved in the biochemical pathway that converts 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC). They also regulate the further conversions of 5hmC to 5-formylcytosine (5fC) and then 5fC to 5-carboxylcytosine (5caC).<ref name='He et al.'>DOI: 10.1126/science.1210944</ref> Although experimental data shows that TET3 does so to a lesser extent than TET1 and TET2.<ref name='He et al.' />

While the oxidation performed by TET enzymes was originally thought to be a source of DNA damage, new research has implied that this catalytic activity may actually be the initial steps of a process of DNA demethylation. This hypothesized DNA demethylation pathway starts with the conversion of 5mC to 5caC after several rounds of oxidation by TET enzymes. The next step is the removal of the modified cytosine base by thymine DNA glycosylase (TDG) which leaves an abasic site on the DNA. The last step is then the process of base excision repair in which a new unmodified cytosine is regenerated at the site, thus completing the process of DNA demethylation.<ref name='He et al.' /><ref name='Rahul M. Kohli & Yi Zhang'>DOI 10.1038/nature12750</ref>

===Specific Functions===
Experimental data shows that the TET genes have different expression patterns and at different levels, which indicates that each of the TET enzymes do not fully overlap in their functionality.

TET1 is usually expressed in fetal heart, lung, and brain tissue and in adult skeletal muscle, thymus, and ovary. It is not generally expressed in adult heart, lung, and brain tissue. Moreover, studies have shown that TET1 expression in adult brain tissue is correlated with brain cancer. This occurs through TET1’s indirect activation of brain cancer-related genes such as EGFR, AKT3, CDK6, CCND2, and BRAF through creation of 5hmC which recruits the CHTOP-methylosome complex that activates these genes.<ref>DOI 10.1016/j.celrep.2014.08.071</ref>

TET2 is broadly expressed, but it is especially highly expressed in hematopoietic cells, which develop into blood cells. Regarding this, it is suggested that TET2 plays a role in hematopoiesis due to the presence of TET2 mutations in many myelodysplastic syndromes.<ref>DOI 10.1182/blood-2009-03-210039</ref><ref>DOI 10.1056/NEJMoa0810069</ref><ref>DOI 10.1038/ng.391</ref>

TET3 is highly expressed in zygotes and is involved with epigenetic chromatin reprogramming in the zygote after fertilization. Specifically, it plays a role in DNA demethylation of the paternal pronucleus before implantation.<ref name='Rahul M. Kohli & Yi Zhang' />

== Disease ==

== Structural highlights ==

</StructureSection>

== References ==
<references/>

User:Madelyn Kasprzak/Sandbox 24242

2016-04-14T03:53:58Z

==TET Enzyme==
<StructureSection load='1stp' size='340' side='right' caption='Caption for this structure' scene=''>
This is a default text for your page '''Madelyn Kasprzak/Sandbox 24242'''. Click above on '''edit this page''' to modify. Be careful with the < and > signs.
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.

== Structure and Function ==

== Mutation and Diseases ==

== Structural highlights ==

This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.

</StructureSection>
== References ==
<references/>

User:Madelyn Kasprzak

2016-04-14T03:52:52Z

Madelyn Kasprzak:

User:Madelyn Kasprzak/Sandbox 1

2016-04-14T03:37:34Z

Madelyn Kasprzak: Added Specific Functions for the TET1-3 enzymes

User:Madelyn Kasprzak/Sandbox 1

2016-04-14T02:39:16Z

Madelyn Kasprzak: Move StructureSection tag back to enclosing Structure, Function, Disease, Relevance, and Structural highlights. Also made minor formatting edits.

==TET Enzymes==
TET enzymes are a family of [[Dioxygenase|dioxygenases]] that are involved in the process of oxidizing methylated cytosine. Members of this family include ten-eleven translocation methylcytosine dioxygenase 1 (TET1), methylcytosine dioxygenase TET2, and methylcytosine dioxygenase TET3. The gene for the first of these proteins, TET1, was identified when it was determined to be fused to the ''Mixed Lineage Leukemia'' (MLL) gene as a result of a translocation event that occurred between chromosomes ten and eleven (hence the name). <ref>DOI 10.1038/sj.leu.2402834</ref>

<StructureSection load='5cg9' size='400' side='right' caption='TET-like protein in Naegleria gruberi in complex with DNA containing 5hmC.' scene=''>

== Structure ==
The TET enzymes have a cysteine-rich region closely followed by a double stranded beta-helix (DSBH) domain near their C-terminus.<ref name='Kinney et al.'>DOI 10.1007/978-1-4419-9967-2_3</ref> The DSBH domain contains three Fe<sup>2+</sup> binding sites and an α-ketoglutarate binding site.<ref name='Kinney et al.' /> This DSBH domain, along with the preceding cysteine-rich region, performs the main catalytic activity of these enzymes and more generally, for all α-ketoglutarate oxygenases.

In addition, TET1 has a CXXC-type zinc finger domain near the N-terminus. However, the TET1 CXXC domain lacks the conserved lysine-phenylalanine-glycine-glycine (KFGG) motif commonly seen within the CXXC domains of other DNA binding proteins, such as DNA methyltransferase-1 (DNMT1). A study conducted by Frauer et al. in 2011 showed that the isolated CXXC domain of TET1 has no DNA binding activity, which agrees with the evidence suggesting that the KFGG motif increases affinity for unmethylated DNA.<ref name='Frauer et al.'>DOI 10.1371/journal.pone.0016627</ref> Frauer et al. also speculated that the CXXC domain of TET1 may be involved with protein-protein interactions instead of DNA binding.<ref name='Frauer et al.' />

== Function ==
All three TET enzymes and their isoforms are involved in the biochemical pathway that converts 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC). They also regulate the further conversions of 5hmC to 5-formylcytosine (5fC) and then 5fC to 5-carboxylcytosine (5caC).<ref name='He et al.'>DOI: 10.1126/science.1210944</ref> Although experimental data shows that TET3 does so to a lesser extent than TET1 and TET2.<ref name='He et al.' />

While the oxidation performed by TET enzymes was originally thought to be a source of DNA damage, new research has implied that this catalytic activity may actually be the initial steps of a process of DNA demethylation. This hypothesized DNA demethylation pathway starts with the conversion of 5mC to 5caC after several rounds of oxidation by TET enzymes. The next step is the removal of the modified cytosine base by thymine DNA glycosylase (TDG) which leaves an abasic site on the DNA. The last step is then the process of base excision repair in which a new unmodified cytosine is regenerated at the site, thus completing the process of DNA demethylation.<ref name='He et al.' /><ref>DOI 10.1038/nature12750</ref>

== Disease ==

== Relevance ==

== Structural highlights ==

</StructureSection>

== References ==
<references/>

User:Madelyn Kasprzak/Sandbox 1

2016-04-14T02:27:54Z

Madelyn Kasprzak: Moved the StructureSection tag to not enclose anything and made it larger to 400px

==TET Enzymes==
TET enzymes are a family of [[Dioxygenase|dioxygenases]] that are involved in the process of oxidizing methylated cytosine. Members of this family include ten-eleven translocation methylcytosine dioxygenase 1 (TET1), methylcytosine dioxygenase TET2, and methylcytosine dioxygenase TET3. The gene for the first of these proteins, TET1, was identified when it was determined to be fused to the ''Mixed Lineage Leukemia'' (MLL) gene as a result of a translocation event that occurred between chromosomes ten and eleven (hence the name). <ref>DOI 10.1038/sj.leu.2402834</ref>

<StructureSection load='5cg9' size='400' side='right' caption='TET-like protein in Naegleria gruberi in complex with DNA containing 5hmC.' scene=''>
</StructureSection>

== Structure ==
The TET enzymes have a cysteine-rich region closely followed by a double stranded beta-helix (DSBH) domain near their C-terminus.<ref name='Kinney et al.'>DOI 10.1007/978-1-4419-9967-2_3</ref> The DSBH domain contains three Fe<sup>2+</sup> binding sites and an α-ketoglutarate binding site.<ref name='Kinney et al.' /> This DSBH domain, along with the preceding cysteine-rich region, performs the main catalytic activity of these enzymes and more generally, for all α-ketoglutarate oxygenases. In addition, TET1 has a CXXC-type zinc finger domain near the N-terminus. However, the TET1 CXXC domain lacks the conserved lysine-phenylalanine-glycine-glycine (KFGG) motif commonly seen within the CXXC domains of other DNA binding proteins, such as DNA methyltransferase-1 (DNMT1). A study conducted by Frauer et al. in 2011 showed that the isolated CXXC domain of TET1 has no DNA binding activity, which agrees with the evidence suggesting that the KFGG motif increases affinity for unmethylated DNA.<ref name='Frauer et al.'>DOI 10.1371/journal.pone.0016627</ref> Frauer et al. also speculated that the CXXC domain of TET1 may be involved with protein-protein interactions instead of DNA binding.<ref name='Frauer et al.' />

== Function ==
All three TET enzymes and their isoforms are involved in the biochemical pathway that converts 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC). They also regulate the further conversions of 5hmC to 5-formylcytosine (5fC) and then 5fC to 5-carboxylcytosine (5caC).<ref name='He et al.'>DOI: 10.1126/science.1210944</ref> Although experimental data shows that TET3 does so to a lesser extent than TET1 and TET2.<ref name='He et al.' /> While the oxidation performed by TET enzymes was originally thought to be a source of DNA damage, new research has implied that this catalytic activity may actually be the initial steps of a process of DNA demethylation. This hypothesized DNA demethylation pathway starts with the conversion of 5mC to 5caC after several rounds of oxidation by TET enzymes. The next step is the removal of the modified cytosine base by thymine DNA glycosylase (TDG) which leaves an abasic site on the DNA. The last step is then the process of base excision repair in which a new unmodified cytosine is regenerated at the site, thus completing the process of DNA demethylation.<ref name='He et al.' /><ref>DOI 10.1038/nature12750</ref>

== Disease ==

== Relevance ==

== Structural highlights ==

== References ==
<references/>

User:Madelyn Kasprzak/Sandbox 1

2016-04-14T02:25:58Z

Madelyn Kasprzak: Tried moving the StructureSection tag to enclose only the Structure section

==TET Enzymes==
TET enzymes are a family of [[Dioxygenase|dioxygenases]] that are involved in the process of oxidizing methylated cytosine. Members of this family include ten-eleven translocation methylcytosine dioxygenase 1 (TET1), methylcytosine dioxygenase TET2, and methylcytosine dioxygenase TET3. The gene for the first of these proteins, TET1, was identified when it was determined to be fused to the ''Mixed Lineage Leukemia'' (MLL) gene as a result of a translocation event that occurred between chromosomes ten and eleven (hence the name). <ref>DOI 10.1038/sj.leu.2402834</ref>

<StructureSection load='5cg9' size='300' side='right' caption='TET-like protein in Naegleria gruberi in complex with DNA containing 5hmC.' scene=''>

== Structure ==
The TET enzymes have a cysteine-rich region closely followed by a double stranded beta-helix (DSBH) domain near their C-terminus.<ref name='Kinney et al.'>DOI 10.1007/978-1-4419-9967-2_3</ref> The DSBH domain contains three Fe<sup>2+</sup> binding sites and an α-ketoglutarate binding site.<ref name='Kinney et al.' /> This DSBH domain, along with the preceding cysteine-rich region, performs the main catalytic activity of these enzymes and more generally, for all α-ketoglutarate oxygenases. In addition, TET1 has a CXXC-type zinc finger domain near the N-terminus. However, the TET1 CXXC domain lacks the conserved lysine-phenylalanine-glycine-glycine (KFGG) motif commonly seen within the CXXC domains of other DNA binding proteins, such as DNA methyltransferase-1 (DNMT1). A study conducted by Frauer et al. in 2011 showed that the isolated CXXC domain of TET1 has no DNA binding activity, which agrees with the evidence suggesting that the KFGG motif increases affinity for unmethylated DNA.<ref name='Frauer et al.'>DOI 10.1371/journal.pone.0016627</ref> Frauer et al. also speculated that the CXXC domain of TET1 may be involved with protein-protein interactions instead of DNA binding.<ref name='Frauer et al.' />

</StructureSection>

== Function ==
All three TET enzymes and their isoforms are involved in the biochemical pathway that converts 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC). They also regulate the further conversions of 5hmC to 5-formylcytosine (5fC) and then 5fC to 5-carboxylcytosine (5caC).<ref name='He et al.'>DOI: 10.1126/science.1210944</ref> Although experimental data shows that TET3 does so to a lesser extent than TET1 and TET2.<ref name='He et al.' /> While the oxidation performed by TET enzymes was originally thought to be a source of DNA damage, new research has implied that this catalytic activity may actually be the initial steps of a process of DNA demethylation. This hypothesized DNA demethylation pathway starts with the conversion of 5mC to 5caC after several rounds of oxidation by TET enzymes. The next step is the removal of the modified cytosine base by thymine DNA glycosylase (TDG) which leaves an abasic site on the DNA. The last step is then the process of base excision repair in which a new unmodified cytosine is regenerated at the site, thus completing the process of DNA demethylation.<ref name='He et al.' /><ref>DOI 10.1038/nature12750</ref>

== Disease ==

== Relevance ==

== Structural highlights ==

== References ==
<references/>