Genome-wide contributions of the MutSα- and MutSβ-dependent DNA mismatch repair pathways to the maintenance of genetic stability in Saccharomyces cerevisiae

Abstract

The DNA mismatch repair (MMR) system is a major DNA repair system that suppresses inherited and sporadic cancers in humans. In eukaryotes the MutSα-dependent and MutSβ-dependent MMR pathways correct DNA polymerase errors. Here, we investigated these two pathways on a whole-genome level in S. cerevisiae. We found that inactivation of MutSα-dependent MMR by deletion of the MSH6 gene increases the genome-wide mutation rate by ∼17-fold, and loss of MutSβ-dependent MMR via deletion of MSH3 elevates the genome-wide mutation rate by ∼4-fold. We also found that MutSα-dependent MMR does not show a preference for protecting coding or noncoding DNA from mutations, whereas MutSβ-dependent MMR preferentially protects noncoding DNA from mutations. The most frequent mutations in the msh6Δ strain are C>T transitions, whereas 1-6-bp deletions are the most common genetic alterations in the msh3Δ strain. Strikingly, MutSα-dependent MMR is more important than MutSβ-dependent MMR for protection from 1-bp insertions, while MutSβ-dependent MMR has a more critical role in the defense against 1-bp deletions and 2-6-bp indels. We also determined that a mutational signature of yeast MSH6 loss is similar to mutational signatures of human MMR deficiency. Furthermore, our analysis showed that compared to other 5'-NCN-3' trinucleotides, 5'-GCA-3' trinucleotides are at the highest risk of accumulating C>T transitions at the central position in the msh6Δ cells and that the presence of a G/A base at the -1 position is important for the efficient MutSα-dependent suppression of C>T transitions. Our results highlight key differences between the roles of the MutSα-dependent and MutSβ-dependent MMR pathways.