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

Oncogene
A Baross-FrancisF R Jirik

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 t...Continue Reading

References

Sep 15, 1991·Proceedings of the National Academy of Sciences of the United States of America·S W KohlerJ M Short
Mar 24, 1990·Lancet·S FishelC Versaci
Dec 1, 1990·Genetic Analysis, Techniques and Applications·S W KohlerJ M Short
Oct 1, 1995·Trends in Biochemical Sciences·R D Kolodner
Aug 20, 1996·Proceedings of the National Academy of Sciences of the United States of America·J HuangM G Dunlop
Jan 1, 1996·Annual Review of Biochemistry·P Modrich, R Lahue
Oct 18, 1996·Cell·K W Kinzler, B Vogelstein
Apr 1, 1997·Proceedings of the National Academy of Sciences of the United States of America·L NarayananP M Glazer
Oct 29, 1997·Proceedings of the National Academy of Sciences of the United States of America·S OlschwangG Thomas
Jun 17, 1998·Proceedings of the National Academy of Sciences of the United States of America·J G HermanS B Baylin
Jun 26, 1998·Current Opinion in Cell Biology·T A Prolla
Aug 11, 1998·Nature Genetics·A Di CristofanoP P Pandolfi
Aug 26, 1998·The Journal of Pathology·N J Toft, M J Arends
Oct 15, 1998·Proceedings of the National Academy of Sciences of the United States of America·H Flores-Rozas, R D Kolodner
Jan 6, 1999·Mutation Research·J Jiricny
Feb 26, 1999·The Journal of Biological Chemistry·S GuerretteR Fishel
Mar 11, 1999·Current Opinion in Genetics & Development·R D Kolodner, G T Marsischky
Jun 9, 1999·Proceedings of the National Academy of Sciences of the United States of America·X YaoN Arnheim
Sep 1, 1999·Proceedings of the National Academy of Sciences of the United States of America·J M WheelerW F Bodmer
Sep 28, 1999·Oncogene·J HeyerR Kucherlapati
Nov 5, 1999·The Journal of Biological Chemistry·M RäschleJ Jiricny

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Citations

Mar 4, 2005·Molecular Genetics and Genomics : MGG·Monica Guhamajumdar, Barbara B Sears
Jun 8, 2002·Mutation Research·Chi Y ShinMitchell S Turker
Dec 10, 2002·Mechanisms of Ageing and Development·Tetsuya OnoHironobu Ikehata
Feb 6, 2010·Journal of Proteome Research·Surendra DasariDavid L Tabb
Aug 9, 2011·Genome Biology and Evolution·Michael Lynch
Jan 15, 2002·Nucleic Acids Research·Martijn E T DolléJan Vijg
Nov 6, 2002·Proceedings of the National Academy of Sciences of the United States of America·Edmund WongWinfried Edelmann
Mar 14, 2002·Proceedings of the National Academy of Sciences of the United States of America·Rachel B CervantesPeter J Stambrook
Oct 19, 2010·Seminars in Cancer Biology·Bradley D PrestonAlan J Herr
Dec 9, 2004·Biochimica Et Biophysica Acta·Joanna Zabkiewicz, Alan R Clarke
Dec 13, 2005·Mutation Research·Joseph G ShaddockBarbara L Parsons
Aug 23, 2011·Biochimica Et Biophysica Acta·Cristina AlbuquerqueRon Smits

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