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Carcinogenesis Advance Access originally published online on May 25, 2006
Carcinogenesis 2006 27(12):2402-2408; doi:10.1093/carcin/bgl079
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Differing patterns of genetic instability in mice deficient in the mismatch repair genes Pms2, Mlh1, Msh2, Msh3 and Msh6

Denise Campisi Hegan, Latha Narayanan1, Frank R. Jirik1, Winfried Edelmann2, R.Michael Liskay3 and Peter M. Glazer*

Department of Therapeutic Radiology, Yale University School of Medicine PO Box 208040, New Haven, CT 06520-8040, USA
1 Department of Biochemistry and Molecular Biology, University of Calgary Calgary, Alberta, Canada T2N 4N1
2 Department of Cell Biology, Albert Einstein College of Medicine Bronx, NY 10461, USA
3 Department of Molecular and Medical Genetics, Oregon Health and Science University Portland, OR 97239, USA

*To whom correspondence should be addressed. Tel: +1 203 737 2788; Fax: +1 203 785 2630; Email: peter.glazer{at}yale.edu

Defects in genes associated with DNA mismatch repair (MMR) have been linked to hereditary colon cancer. Because the MMR pathway includes multiple factors with both overlapping and divergent functions, we sought to compare the impact of deficiencies in each of several MMR genes on genetic instability using a collection of knock-out mouse models. We investigated mutation frequencies and patterns in MMR-deficient mice using two transgenic reporter genes, supFG1 and cII, in the context of mice deficient for Pms2, Mlh1, Msh2, Msh3 or Msh6 or both Msh2 and Msh3 or both Msh3 and Msh6. We found that the mean mutation frequencies of all of the MMR-deficient mice were significantly higher than the mean mutation frequencies of wild-type mice. Mlh1-deficient mice and Msh2-deficient mice had the highest mutation frequencies in a comparison of the single nullizygous mice. Of all the mice studied, mice nullizygous for both Msh2 and Msh3 and those nullizygous for both Msh3 and Msh6 displayed the greatest overall increases in mutation frequencies compared with wild-type mice. Sequence analysis of the mutated reporter genes revealed significant differences between the individual groups of MMR-deficient mice. Taken together, our results further characterize the functions of the MMR factors in mutation avoidance and provide in vivo correlation to biochemical models of the MMR pathway.


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