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 journalArticle

31 Scopus citations

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 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
JournalOncogene
Volume20
Issue number5
DOIs
StatePublished - Feb 1 2001

Keywords

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

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Fingerprint Dive into the research topics of 'Elevated mutant frequencies and increased C:G→T:A transitions in Mlh1<sup>-/-</sup> versus Pms2<sup>-/-</sup> murine small intestinal epithelial cells'. Together they form a unique fingerprint.

  • Cite this