Elevated mutant frequencies and increased C : G -> T : A transitions in Mlh1(-/-) versus Pms2(-/-) murine small intestinal epithelial cells

Mutations in DNA mismatch repair (MMR) genes are associated with increased genomic instability and susceptibility to cancer. Mice rendered deficient i n either Mlh1 or Pms2 as a result of gene targeting are prone to tumorigene sis, particularly, lymphomas, In addition, although Mlh1(-/-) mice also dev elop small intestinal adenomas and adenocarcinomas, Pms2(-/-) animals remai n free of such tumors. To establish whether this phenotypic dichotomy might he associated with quantitative and/or qualitative difference in genomic i nstability in these mice, we determined small intestinal epithelial cell DN A mutant frequency and mutation using a transgenic lambda -phage lacI repor ter Mutant frequencies obtained from both Mlh1(-/-) and Pms2(-/-) mice reve aled elevations of 18 and 13-fold, respectively, as compared to their wild- type littermates. interestingly, we found that C:G-->T:A transitions, were significantly elevated in MlH1 (/-) mice, accounting in large measure for t he 1.5-fold lacI mutant frequency increase seen in these animals, We hypoth esize that the increased level of C:G-->T:A mutations may explain, in part, why Mlh1(-/) mice, but not Pms2(-/-) mice, develop small intestinal tumors , Furthermore, the difference in the lacI mutational spectrum of Mlh1 and P ms2(-/-) mice suggests that other MutL-like heterodimers may play important roles in the repair of G : T mispairs arising within murine small intestin al epithelial cells.