REDUNDANCY OF SACCHAROMYCES-CEREVISIAE MS H3 AND MSH6 IN MSH2-DEPENDENT MISMATCH REPAIR

Saccharomyces cerevisiae encodes six genes, MSH1-6, which encode prote ins related to the bacterial MutS protein. In this study the role of M SH2, MSH3, and MSH6 in mismatch repair has been examined by measuring the rate of accumulating mutations and mutation spectrum in strains co ntaining different combinations of msh2, msh3, and msh6 mutations and by studying the physical interaction between the MSH2 protein and the MSH3 and MSH6 proteins. The results indicate that S. cerevisiae has tw o pathways of MSH2-dependent mismatch repair: one that recognizes sing le-base mispairs and requires MSH2 and MSH6, and a second that recogni zes insertion/deletion mispairs and requires a combination of either M SH2 and MSH6 or MSH2 and MSH3. The redundancy of MSH3 and MSH6 explain s the greater prevalence of hmsh2 mutations in HNPCC families and sugg ests how the role of hmsh3 and hmsh6 mutations in cancer susceptibilit y could be analyzed.