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- Title
Watching a double strand break repair polymerase insert a pro-mutagenic oxidized nucleotide.
- Authors
Jamsen, Joonas A.; Sassa, Akira; Shock, David D.; Beard, William A.; Wilson, Samuel H.
- Abstract
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 μ 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 (At). Rotation of At 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. How DNA polymerases discriminate against oxidized and undamaged nucleotides during DNA repair is not fully understood. Here, the authors reveal high-resolution timelapse X-ray crystallography snapshots of DSB repair polymerase μ undergoing DNA synthesis providing mechanistic insights into the process.
- Subjects
DNA synthesis; RIGID dynamics; X-ray crystallography; DNA polymerases; DNA repair; METAL products; POLY ADP ribose
- Publication
Nature Communications, 2021, Vol 12, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-021-21354-6