A. Baross-francis et al., Elevated mutant frequencies and increased C : G -> T : A transitions in Mlh1(-/-) versus Pms2(-/-) murine small intestinal epithelial cells, ONCOGENE, 20(5), 2001, pp. 619-625
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.