User:Xiang Chen/Sandbox 2: Difference between revisions
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=TET Enzymes= | = 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> | 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> | ||
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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> | 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=== | ===Specific Functions=== | ||
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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> | 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> | 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' /> | 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 == | == 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 == | == 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> | </StructureSection> | ||
== References == | == References == | ||
<references/> | <references/> | ||
