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

Joonas A. Jamsen, Akira Sassa, David D. Shock, William A. Beard and Samuel H. Wilson ()
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Joonas A. Jamsen: National Institute of Environmental Health Sciences, National Institutes of Health
Akira Sassa: Chiba University
David D. Shock: National Institute of Environmental Health Sciences, National Institutes of Health
William A. Beard: National Institute of Environmental Health Sciences, National Institutes of Health
Samuel H. Wilson: National Institute of Environmental Health Sciences, National Institutes of Health

Nature Communications, 2021, vol. 12, issue 1, 1-12

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-21354-6

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