1u4b: Difference between revisions

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[[Image:1u4b.gif|left|200px]]<br /><applet load="1u4b" size="~~450~~" color="white" frame="true" align="right" spinBox="true"

[[Image:1u4b.gif|left|200px]]<br /><applet load="1u4b" size="350" color="white" frame="true" align="right" spinBox="true"

caption="1u4b, resolution 1.60Å" />

'''Extension of an adenine-8oxoguanine mismatch'''<br />

==Overview==

Aerobic respiration generates reactive oxygen species that can damage, guanine residues and lead to the production of 8-oxoguanine (8oxoG), the, major mutagenic oxidative lesion in the genome. Oxidative damage is, implicated in ageing and cancer, and its prevalence presents a constant, challenge to DNA polymerases that ensure accurate transmission of genomic, information. When these polymerases encounter 8oxoG, they frequently, catalyse misincorporation of adenine in preference to accurate, incorporation of cytosine. This results in the propagation of G to T, transversions, which are commonly observed somatic mutations associated, with human cancers. Here, we present sequential snapshots of a, high-fidelity DNA polymerase during both accurate and mutagenic, replication of 8oxoG. Comparison of these crystal structures reveals that, 8oxoG induces an inversion of the mismatch recognition mechanisms that, normally proofread DNA, such that the 8oxoG.adenine mismatch mimics a, cognate base pair whereas the 8oxoG.cytosine base pair behaves as a, mismatch. These studies reveal a fundamental mechanism of error-prone, replication and show how 8oxoG, and DNA lesions in general, can form, mismatches that evade polymerase error-detection mechanisms, potentially, leading to the stable incorporation of lethal mutations.

Aerobic respiration generates reactive oxygen species that can damage guanine residues and lead to the production of 8-oxoguanine (8oxoG), the major mutagenic oxidative lesion in the genome. Oxidative damage is implicated in ageing and cancer, and its prevalence presents a constant challenge to DNA polymerases that ensure accurate transmission of genomic information. When these polymerases encounter 8oxoG, they frequently catalyse misincorporation of adenine in preference to accurate incorporation of cytosine. This results in the propagation of G to T transversions, which are commonly observed somatic mutations associated with human cancers. Here, we present sequential snapshots of a high-fidelity DNA polymerase during both accurate and mutagenic replication of 8oxoG. Comparison of these crystal structures reveals that 8oxoG induces an inversion of the mismatch recognition mechanisms that normally proofread DNA, such that the 8oxoG.adenine mismatch mimics a cognate base pair whereas the 8oxoG.cytosine base pair behaves as a mismatch. These studies reveal a fundamental mechanism of error-prone replication and show how 8oxoG, and DNA lesions in general, can form mismatches that evade polymerase error-detection mechanisms, potentially leading to the stable incorporation of lethal mutations.

==About this Structure==

1U4B is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Geobacillus_stearothermophilus Geobacillus stearothermophilus] with SUC, SO4 and MG as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/DNA-directed_DNA_polymerase DNA-directed DNA polymerase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.7.7 2.7.7.7] Full crystallographic information is available from [http://~~ispc~~.weizmann.ac.il/oca-bin/ocashort?id=1U4B OCA].

1U4B is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Geobacillus_stearothermophilus Geobacillus stearothermophilus] with <scene name='pdbligand=SUC:'>SUC</scene>, <scene name='pdbligand=SO4:'>SO4</scene> and <scene name='pdbligand=MG:'>MG</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/DNA-directed_DNA_polymerase DNA-directed DNA polymerase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.7.7 2.7.7.7] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1U4B OCA].

==Reference==

Line 14:

[[Category: Geobacillus stearothermophilus]]

[[Category: Protein complex]]

[[Category: Beese, L.S.]]

[[Category: Beese, L S.]]

[[Category: Carell, T.]]

[[Category: Hsu, G.W.]]

[[Category: Hsu, G W.]]

[[Category: Ober, M.]]

[[Category: MG]]

Line 23:

[[Category: dna polymerase i; dna replication; klenow fragment; protein-dna complex; 8oxoguanine; dna lesion; translation replication]]

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@@ Line 1: / Line 1: @@
-[[Image:1u4b.gif|left|200px]]<br /><applet load="1u4b" size="450" color="white" frame="true" align="right" spinBox="true"
+[[Image:1u4b.gif|left|200px]]<br /><applet load="1u4b" size="350" color="white" frame="true" align="right" spinBox="true"
 caption="1u4b, resolution 1.60&Aring;" />
 '''Extension of an adenine-8oxoguanine mismatch'''<br />
 ==Overview==
-Aerobic respiration generates reactive oxygen species that can damage, guanine residues and lead to the production of 8-oxoguanine (8oxoG), the, major mutagenic oxidative lesion in the genome. Oxidative damage is, implicated in ageing and cancer, and its prevalence presents a constant, challenge to DNA polymerases that ensure accurate transmission of genomic, information. When these polymerases encounter 8oxoG, they frequently, catalyse misincorporation of adenine in preference to accurate, incorporation of cytosine. This results in the propagation of G to T, transversions, which are commonly observed somatic mutations associated, with human cancers. Here, we present sequential snapshots of a, high-fidelity DNA polymerase during both accurate and mutagenic, replication of 8oxoG. Comparison of these crystal structures reveals that, 8oxoG induces an inversion of the mismatch recognition mechanisms that, normally proofread DNA, such that the 8oxoG.adenine mismatch mimics a, cognate base pair whereas the 8oxoG.cytosine base pair behaves as a, mismatch. These studies reveal a fundamental mechanism of error-prone, replication and show how 8oxoG, and DNA lesions in general, can form, mismatches that evade polymerase error-detection mechanisms, potentially, leading to the stable incorporation of lethal mutations.
+Aerobic respiration generates reactive oxygen species that can damage guanine residues and lead to the production of 8-oxoguanine (8oxoG), the major mutagenic oxidative lesion in the genome. Oxidative damage is implicated in ageing and cancer, and its prevalence presents a constant challenge to DNA polymerases that ensure accurate transmission of genomic information. When these polymerases encounter 8oxoG, they frequently catalyse misincorporation of adenine in preference to accurate incorporation of cytosine. This results in the propagation of G to T transversions, which are commonly observed somatic mutations associated with human cancers. Here, we present sequential snapshots of a high-fidelity DNA polymerase during both accurate and mutagenic replication of 8oxoG. Comparison of these crystal structures reveals that 8oxoG induces an inversion of the mismatch recognition mechanisms that normally proofread DNA, such that the 8oxoG.adenine mismatch mimics a cognate base pair whereas the 8oxoG.cytosine base pair behaves as a mismatch. These studies reveal a fundamental mechanism of error-prone replication and show how 8oxoG, and DNA lesions in general, can form mismatches that evade polymerase error-detection mechanisms, potentially leading to the stable incorporation of lethal mutations.
 ==About this Structure==
-U4B is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Geobacillus_stearothermophilus Geobacillus stearothermophilus] with SUC, SO4 and MG as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/DNA-directed_DNA_polymerase DNA-directed DNA polymerase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.7.7 2.7.7.7] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1U4B OCA].
+U4B is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Geobacillus_stearothermophilus Geobacillus stearothermophilus] with <scene name='pdbligand=SUC:'>SUC</scene>, <scene name='pdbligand=SO4:'>SO4</scene> and <scene name='pdbligand=MG:'>MG</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/DNA-directed_DNA_polymerase DNA-directed DNA polymerase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.7.7 2.7.7.7] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1U4B OCA].
 ==Reference==
@@ Line 14: / Line 14: @@
 [[Category: Geobacillus stearothermophilus]]
 [[Category: Protein complex]]
-[[Category: Beese, L.S.]]
+[[Category: Beese, L S.]]
 [[Category: Carell, T.]]
-[[Category: Hsu, G.W.]]
+[[Category: Hsu, G W.]]
 [[Category: Ober, M.]]
 [[Category: MG]]
@@ Line 23: / Line 23: @@
 [[Category: dna polymerase i; dna replication; klenow fragment; protein-dna complex; 8oxoguanine; dna lesion; translation replication]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Sun Nov 25 03:17:30 2007''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 15:20:29 2008''