Elevated mutant frequencies and increased C : G-->T : A transitions in Mlh1-/- versus Pms2-/- murine small intestinal epithelial cells.
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.
Baross-Francis
A
A
Centre for Molecular Medicine and Therapeutics and the Department of Medicine, University of British Columbia, Vancouver, BC, V5Z 4H4, Canada.
Makhani
N
N
Liskay
R M
RM
Jirik
F R
FR
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
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