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 referre d to as MutS and MutL homologues, Germline mutations in several members of these families, MSH2, MSH6, MLH1, and PMS2, but not MSH3, are responsible f or 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 rep air base-base mismatches. Msh3 -/- mice develop tumors at a late age. When the Msh3-/- and Msh6-/- mutations are combined, the tumor predisposition ph enotype is indistinguishable from Msh2-/- or Mlh1-/- mice, These results su ggest that MSH3 cooperates with MSH6 in tumor suppression.