Contributions of replicative and translesion DNA polymerases to mutagenic bypass of canonical and atypical UV photoproducts

Brittany N. Vandenberg, Marian F. Laughery, Cameron Cordero, Dalton Plummer, Debra Mitchell, Jordan Kreyenhagen, Fatimah Albaqshi, Alexander J. Brown, Piotr A. Mieczkowski, John J. Wyrick () and Steven A. Roberts ()
Additional contact information
Brittany N. Vandenberg: Washington State University
Marian F. Laughery: Washington State University
Cameron Cordero: Washington State University
Dalton Plummer: Washington State University
Debra Mitchell: Washington State University
Jordan Kreyenhagen: Washington State University
Fatimah Albaqshi: Washington State University
Alexander J. Brown: Washington State University
Piotr A. Mieczkowski: University of North Carolina
John J. Wyrick: Washington State University
Steven A. Roberts: Washington State University

Nature Communications, 2023, vol. 14, issue 1, 1-11

Abstract: Abstract UV exposure induces a mutation signature of C > T substitutions at dipyrimidines in skin cancers. We recently identified additional UV-induced AC > TT and A > T substitutions that could respectively cause BRAF V600K and V600E oncogenic mutations. The mutagenic bypass mechanism past these atypical lesions, however, is unknown. Here, we whole genome sequenced UV-irradiated yeast and used reversion reporters to delineate the roles of replicative and translesion DNA polymerases in mutagenic bypass of UV-lesions. Our data indicates that yeast DNA polymerase eta (pol η) has varied impact on UV-induced mutations: protecting against C > T substitutions, promoting T > C and AC > TT substitutions, and not impacting A > T substitutions. Surprisingly, deletion rad30Δ increased novel UV-induced C > A substitutions at CA dinucleotides. In contrast, DNA polymerases zeta (pol ζ) and epsilon (pol ε) participated in AC > TT and A > T mutations. These results uncover lesion-specific accurate and mutagenic bypass of UV lesions, which likely contribute to key driver mutations in melanoma.

Date: 2023
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DOI: 10.1038/s41467-023-38255-5

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