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

Jamsen, Joonas A.; Sassa, Akira; Shock, David D.; Beard, William A.; Wilson, Samuel H.

doi:10.1038/s41467-021-21354-6

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

Journal Article · Tue Apr 06 00:00:00 EDT 2021 · Nature Communications

DOI:https://doi.org/10.1038/s41467-021-21354-6· OSTI ID:1783881

^[1]; Sassa, Akira ^[2]; Shock, David D. ^[1]; Beard, William A. ^[1]; ^[1]

National Institutes of Health (NIH), Triangle Park, NC (United States). National Institute of Environmental Health Sciences (NIEHS)
Chiba University (Japan)

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. 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.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES); National Institutes of Health (NIH); National Institute of Environmental Health Sciences (NIEHS); Japan Society for the Promotion of Science (JSPS, KAKENHI)

Grant/Contract Number:: W-31109-ENG-38

OSTI ID:: 1783881

Journal Information:: Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 12; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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