DNA mismatch repair greatly increases genome fidelity by recognizing and removing replication errors. In order to understand how this fidelity is maintained, it is important to uncover the relative specificities of the different components of mismatch repair. There are two major mispair recognition complexes in eukaryotes that are homologues of bacterial MutS proteins, MutSα and MutSβ, with MutSα recognizing base-base mismatches and small loop mispairs and MutSβ recognizing larger loop mispairs. Upon recognition of a mispair, the MutS complexes then interact with homologues of the bacterial MutL protein. Loops formed on the primer strand during replication lead to insertion mutations, whereas loops on the template strand lead to deletions. We show here in yeast, using oligonucleotide transformation, that MutSα has a strong bias toward repair of insertion loops, while MutSβ has an even stronger bias toward repair of deletion loops. Our results suggest that this bias in repair is due to the different interactions of the MutS complexes with the MutL complexes. Two mutants of MutLα, pms1-G882E and pms1-H888R, repair deletion mispairs but not insertion mispairs. Moreover, we find that a different MutL complex, MutLγ, is extremely important, but not sufficient, for deletion repair in the presence of either MutLα mutation. MutSβ is present in many eukaryotic organisms, but not in prokaryotes. We suggest that the biased repair of deletion mispairs may reflect a critical eukaryotic function of MutSβ in mismatch repair.
DNA mismatch repair is a major pathway that prevents both base substitution and insertion or deletion errors during replication. Most eukaryotes have two recognition complexes, MutSα and MutSβ, homologues of prokaryotic MutS and differing in their affinity for mismatches, with MutSα recognizing base-base mismatches and small insertion/deletion loops and MutSβ recognizing larger loops. We show that repair mediated by these complexes has opposite biases for insertion versus deletion mispairs with MutSα-directed repair favoring insertion loops and MutSβ-directed repair favoring deletion loops. This bias is mediated by differing interactions with downstream MutL complexes. We suggest that MutSα represents a prokaryotic MutS biased for repair of insertion loops and that MutSβ represents a new eukaryotic activity biased for repair of deletion loops.