The mismatch repair system promotes DNA polymerase zeta-dependent translesion synthesis in yeast.

DNA lesions that block replication can be bypassed by error-prone or error-free mechanisms. Error-prone mechanisms rely on specialized translesion synthesis (TLS) DNA polymerases that directly replicate over the lesion, whereas error-free pathways use an undamaged duplex as a template for lesion bypass. In the yeast Saccharomyces cerevisiae, most mutagenic TLS of spontaneous and induced DNA damage relies on DNA polymerase zeta (Polzeta) activity. Here, we use a distinct mutational signature produced by Polzeta in a frameshift-reversion assay to examine the role of the yeast mismatch repair (MMR) system in regulating Polzeta-dependent mutagenesis. Whereas MMR normally reduces mutagenesis by removing errors introduced by replicative DNA polymerases, we find that the MMR system is required for Polzeta-dependent mutagenesis. In the absence of homologous recombination, however, the error-prone Polzeta pathway is not affected by MMR status. These results demonstrate that MMR promotes Polzeta-dependent mutagenesis by inhibiting an alternative, error-free pathway that depends on homologous recombination. Finally, in contrast to its ability to remove mistakes made by replicative DNA polymerases, we show that MMR fails to efficiently correct errors introduced by Polzeta.