期刊
NATURE COMMUNICATIONS
卷 12, 期 1, 页码 -出版社
NATURE RESEARCH
DOI: 10.1038/s41467-021-21354-6
关键词
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资金
- U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38]
- National Institutes of Health-NIEHS [Z01-ES050158, Z01-ES050161, 1K99ES029572-01]
- JSPS KAKENHI [16K16195]
- Grants-in-Aid for Scientific Research [16K16195] Funding Source: KAKEN
The study demonstrates how DNA polymerases discriminate against oxidized and undamaged nucleotides during error-prone double strand break repair, through high-resolution time-lapse X-ray crystallography snapshots of DSB repair polymerase mu undergoing DNA synthesis.
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. 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 mu undergoing DNA synthesis providing mechanistic insights into the process.
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