The DNA Mismatch Repair Genes Msh3 and Msh6 Cooperate in Intestinal Tumor Suppression

Repair of mismatches in DNA in mammalian cells is mediated by a complex of proteins that are members of two highly conserved families of genes referred to as MutS and MutL homologues. Germline mutations in several members of these families, MSH2 , MSH6 , MLH1 , and PMS2 , but not MSH3 , are responsible for hereditary non-polyposis colorectal cancer. To examine the role of MSH3 , we generated a mouse with a null mutation in this gene. Cells from Msh3−/− mice are defective in repair of insertion/deletion mismatches but can repair base-base mismatches. Msh3−/− mice develop tumors at a late age. When the Msh3−/− and Msh6−/− mutations are combined, the tumor predisposition phenotype is indistinguishable from Msh2−/− or Mlh1−/− mice. These results suggest that MSH3 cooperates with MSH6 in tumor suppression.