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- Title
Elevated mutant frequencies and increased C : G→T : A transitions in Mlh1<sup>-/-</sup> versus Pms2<sup>-/-</sup> murine small intestinal epithelial cells.
- Authors
Baross-Francis, Agnes; Makhani, Naila; Liskay, R Michael; Jirik, Frank R
- Abstract
Mutations in DNA mismatch repair (MMR) genes are associated with increased genomic instability and susceptibility to cancer. Mice rendered deficient in either Mlh1 or Pms2 as a result of gene targeting are prone to tumorigenesis, particularly, lymphomas. In addition, although Mlh1-/- mice also develop small intestinal adenomas and adenocarcinomas, Pms2-/- animals remain free of such tumors. To establish whether this phenotypic dichotomy might be associated with a quantitative and/or qualitative difference in genomic instability in these mice, we determined small intestinal epithelial cell DNA mutant frequency and mutation spectrum using a transgenic λ-phage lacI reporter system. Mutant frequencies obtained from both Mlh1-/- and Pms2-/- mice revealed 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 the 1.5-fold lacI mutant frequency increase seen in these animals. We hypothesize 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 Pms2-/- mice suggests that other MutL-like heterodimers may play important roles in the repair of G : T mispairs arising within murine small intestinal epithelial cells. Oncogene (2001) 20, 619–625.
- Subjects
EPITHELIAL cells; LYMPHOMAS; ADENOCARCINOMA; CARCINOGENESIS; PMS genes
- Publication
Oncogene, 2001, Vol 20, Issue 5, p619
- ISSN
0950-9232
- Publication type
Article
- DOI
10.1038/sj.onc.1204138