Novel dominant mutations in Saccharomyces cerevisiae MSH6

Inherited mutations in the mismatch repair (MMR) genes MSH2 and MLH1 are fo und in most hereditary nonpolyposis colon cancer (HNPCC) patients studied(1 ). Eukaryotic MMR uses two partially redundant mispair-recognition complexe s, Msh2p -Msh6p and Msh2p-Msh3p (ref. 2). Inactivation of MSH2 causes high rates of accumulation of both base-substitution and frameshift mutations. M utations in MSH6 or MSH3 cause partial defects in MMR, with inactivation of MSH6 resulting in high rates of base-substitution mutations and low rates of frameshift mutations; inactivation of MSH3 results in low rates of frame shift mutations. These different mutator phenotypes provide an explanation for the observation that MSH2 mutations are common in HNPCC families, where as mutations in MSH3 and MSH6 are rare(1,3-5). We have identified novel mis sense mutations in Saccharomyces cerevisiae MSH6 that appear to inactivate both Msh2p-Msh6p- and Msh2p-Msh3p-dependent MMR. Our work suggests that suc h mutations may underlie some cases of inherited cancer susceptibility simi lar to those caused by MSH2 mutations.