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

Agnes Baross-Francis, Naila Makhani, R. Michael Liskay, Frank R. Jirik

Research output: Contribution to journalArticlepeer-review

32 Scopus citations


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 loci 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.

Original languageEnglish (US)
Pages (from-to)619-625
Number of pages7
Issue number5
StatePublished - Feb 1 2001
Externally publishedYes


  • DNA mismatch repair
  • Mlh1
  • Pms2
  • Transgenic
  • lacI

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research


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