title: Elevated mutant frequencies and increased C : G-->T : A transitions in Mlh1-/- versus Pms2-/- murine small intestinal epithelial cells.
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 lambda-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.
authors: Centre for Molecular Medicine and Therapeutics and the Department of Medicine, University of British Columbia, Vancouver, BC, V5Z 4H4, Canada.
authors: A
authors: A
authors: Baross-Francis
authors: N
authors: N
authors: Makhani
authors: R M
authors: RM
authors: Liskay
authors: F R
authors: FR
authors: Jirik
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000251:Adenosine Triphosphatases; D000818:Animals; D020137:Base Pair Mismatch / Q000235:genetics; D002352:Carrier Proteins; D003433:Crosses, Genetic; D004252:DNA Mutational Analysis; D045643:DNA Repair Enzymes; D004268:DNA-Binding Proteins; D004847:Epithelial Cells / Q000502:physiology; D005260:Female; D007414:Intestinal Neoplasms / Q000235:genetics; D007421:Intestine, Small / Q000166:cytology / Q000502:physiology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D009363:Neoplasm Proteins / Q000235:genetics*; D009687:Nuclear Proteins; D017354:Point Mutation
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C501486:MLH1 protein, human; C501485:Mlh1 protein, mouse; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D000251:Adenosine Triphosphatases; C499533:Pms2 protein, mouse; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D045643:DNA Repair Enzymes