A NATURALLY-OCCURRING HPMS2 MUTATION CAN CONFER A DOMINANT-NEGATIVE MUTATOR PHENOTYPE

Defects in mismatch repair (MMR) genes result in a mutator phenotype b y inducing microsatellite instability (MI), a characteristic of heredi tary nonpolyposis colorectal cancers (HNPCC) and a subset of sporadic colon tumors. Present models describing the mechanism by which germ li ne mutations in MMR genes predispose kindreds to HNPCC suggest a ''two -hit'' inactivation of both alleles of a particular MMR gene. Here we present experimental evidence that a nonsense mutation at codon 134 of the hPMS2 gene is sufficient to reduce MMR and induce MI in cells con taining a wild-type hPMS2 allele. These results have significant impli cations for understanding the relationship between mutagenesis and car cinogenesis and the ability to generate mammalian cells with mutator p henotypes.