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

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 eta) 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 rad30 Delta increased novel UV-induced C > A substitutions at CA dinucleotides. In contrast, DNA polymerases zeta (pol zeta) and epsilon (pol epsilon) 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. Vandenberg et al. identify differing roles of yeast DNA polymerases during accurate and mutagenic synthesis past common and rare ultraviolet light photoproducts. Similar mechanisms may contribute to driver mutations causing skin cancer in humans.