EVIDENCE FOR INVOLVEMENT OF YEAST PROLIFERATING CELL NUCLEAR ANTIGEN IN DNA MISMATCH REPAIR

DNA mismatch repair plays a key role in the maintenance of genetic fid elity. Mutations in the human mismatch repair genes hMSH2, hMLR1, hPMS 1, and hPMS2 are associated with hereditary nonpolyposis colorectal ca ncer. The proliferating cell nuclear antigen (PCNA) is essential for D NA replication, where it acts as a processivity factor. Here, we ident ify a point mutation, pol30-104, in the Saccharomyces cerevisiae POL30 gene encoding PCNA that increases the rate of instability of simple r epetitive DNA sequences and raises the rate of spontaneous forward mut ation. Epistasis analyses with mutations in mismatch repair genes MSH2 , MLH1, and PMS1 suggest that the pol30-104 mutation impairs MSH2/ MLH 1/PMS1-dependent mismatch repair, consistent with the hypothesis that PCNA functions in mismatch repair. MSH2 functions in mismatch repair w ith either MSH3 or MSH6, and the MSH2 MSH3 and MSH2-MSH6 heterodimers have a role in the recognition of DNA mismatches. Consistent with the genetic data, we find specific interaction of PCNA with the MSH2-MSH3 heterodimer.