Nature Genetics 23, 359 - 362 (1999)
HNPCC-like cancer predisposition in mice through simultaneous loss of Msh3 and Msh6 mismatch-repair protein functions
1 Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
2 Present address: Department of Radiation Genetics and Chemical Mutagenesis, Leiden University Medical Center, Leiden , The Netherlands.
3 Faculté de Médecine Necker (INSERM E9916), Université Paris V, Paris, France.
4 Department of Pathology, Duke University Medical Center , Durham, North Carolina USA.
Cancer predisposition in hereditary non-polyposis colon cancer (HNPCC) is caused by defects in DNA mismatch repair1 (MMR). Mismatch recognition is attributed to two heterodimeric protein complexes: MutS (refs 2, 3, 4, 5), a dimer of MutS homologues MSH2 and MSH6; and MutS (refs 2,7), a dimer of MSH2 and MSH3. These complexes have specific and redundant mismatch recognition capacity8, 9, 10. Whereas MSH2 deficiency ablates the activity of both dimers, causing strong cancer predisposition in mice11, 12, 13 and men14, 15, 16, loss of MSH3 or MSH6 (also known as GTBP) function causes a partial MMR defect. This may explain the rarity of MSH6 and absence of MSH3 germline mutations in HNPCC families17, 18. To test this, we have inactivated the mouse genes Msh3 (formerly Rep3 ) and Msh6 (formerly Gtmbp). Msh6-deficient mice were prone to cancer; most animals developed lymphomas or epithelial tumours originating from the skin and uterus but only rarely from the intestine. Msh3 deficiency did not cause cancer predisposition, but in an Msh6 -deficient background, loss of Msh3 accelerated intestinal tumorigenesis. Lymphomagenesis was not affected. Furthermore, mismatch-directed anti-recombination and sensitivity to methylating agents required Msh2 and Msh6, but not Msh3. Thus, loss of MMR functions specific to Msh2/Msh6 is sufficient for lymphoma development in mice, whereas predisposition to intestinal cancer requires loss of function of both Msh2/Msh6 and Msh2/Msh3.
PDF format available soon - Past Research under construction