7ksw
From Proteopedia
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== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
| - | Oxidized dGTP (8-oxo-7,8-dihydro-2 -deoxyguanosine triphosphate, 8-oxodGTP) insertion by DNA polymerases strongly promotes cancer and human disease. How DNA polymerases discriminate against oxidized and undamaged nucleotides, especially in error-prone double strand break (DSB) repair, is poorly understood. High-resolution time-lapse X-ray crystallography snapshots of DSB repair polymerase mu undergoing DNA synthesis reveal that a third active site metal promotes insertion of oxidized and undamaged dGTP in the canonical anti-conformation opposite template cytosine. The product metal bridged O8 with product oxygens, and was not observed in the syn-conformation opposite template adenine ( | + | Oxidized dGTP (8-oxo-7,8-dihydro-2 -deoxyguanosine triphosphate, 8-oxodGTP) insertion by DNA polymerases strongly promotes cancer and human disease. How DNA polymerases discriminate against oxidized and undamaged nucleotides, especially in error-prone double strand break (DSB) repair, is poorly understood. High-resolution time-lapse X-ray crystallography snapshots of DSB repair polymerase mu undergoing DNA synthesis reveal that a third active site metal promotes insertion of oxidized and undamaged dGTP in the canonical anti-conformation opposite template cytosine. The product metal bridged O8 with product oxygens, and was not observed in the syn-conformation opposite template adenine (A(t)). Rotation of A(t) into the syn-conformation enabled undamaged dGTP misinsertion. Exploiting metal and substrate dynamics in a rigid active site allows 8-oxodGTP to circumvent polymerase fidelity safeguards to promote pro-mutagenic double strand break repair. |
Watching a double strand break repair polymerase insert a pro-mutagenic oxidized nucleotide.,Jamsen JA, Sassa A, Shock DD, Beard WA, Wilson SH Nat Commun. 2021 Apr 6;12(1):2059. doi: 10.1038/s41467-021-21354-6. PMID:33824325<ref>PMID:33824325</ref> | Watching a double strand break repair polymerase insert a pro-mutagenic oxidized nucleotide.,Jamsen JA, Sassa A, Shock DD, Beard WA, Wilson SH Nat Commun. 2021 Apr 6;12(1):2059. doi: 10.1038/s41467-021-21354-6. PMID:33824325<ref>PMID:33824325</ref> | ||
Current revision
DNA Polymerase Mu, dGTP:Ct Reaction State Ternary Complex, 10 mM Mg2+ (10min)
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