TY - JOUR
T1 - Elevated mutant frequencies and increased C:G→T:A transitions in Mlh1-/- versus Pms2-/- murine small intestinal epithelial cells
AU - Baross-Francis, Agnes
AU - Makhani, Naila
AU - Liskay, R. Michael
AU - Jirik, Frank R.
N1 - Funding Information:
We thank L Spence for genotyping the mice, LA Wad-dleton and C Fletch for maintaining the various lines, and K Fichter at the Canadian Genetic Disease Network DNA Sequencing Core Facility. We are grateful to Dr SE Andrew for critically evaluating this manuscript. This study was supported by Grant #007137 from the National Cancer Institute of Canada, with funds from the Canadian Cancer Society (to FR Jirik), and NIH grant R01 GM32741 (to RM Liskay). A Baross-Francis was the recipient of a Natural Sciences and Engineering Research Council of Canada Graduate Scholarship.
PY - 2001/2/1
Y1 - 2001/2/1
N2 - 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.
AB - 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.
KW - DNA mismatch repair
KW - Mlh1
KW - Pms2
KW - Transgenic
KW - lacI
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U2 - 10.1038/sj.onc.1204138
DO - 10.1038/sj.onc.1204138
M3 - Article
C2 - 11313994
AN - SCOPUS:0035253196
SN - 0950-9232
VL - 20
SP - 619
EP - 625
JO - Oncogene
JF - Oncogene
IS - 5
ER -