Watching a double strand break repair polymerase insert a pro-mutagenic oxidized nucleotide.

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 (A_t). Rotation of A_t into the syn-conformation enabled undamaged dGTP misinsertion. Ex

SUBMITTER: Jamsen JA 

PROVIDER: S-EPMC8024293 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature