Msh2 status modulates both apoptosis and mutation frequency in the murine small intestine

Deficiency in genes involved in DNA mismatch repair increases susceptibilit y to cancer, particularly of the colorectal epithelium. Using Msh2 null mic e, we demonstrate that this genetic defect renders normal intestinal epithe lial cells susceptible to mutation in vivo at the Dlb-1 locus. Compared wit h wild-type mice, Msh2-deficient animals had higher basal levels of mutatio n and were more sensitive to the mutagenic effects of temozolomide. Experim ents using Msh2-deficient cells in vitro suggest that an element of this ef fect is attributable to increased clonogenicity. Indeed, we show that Msh2 plays a role in the in vivo initiation of apoptosis after treatment with te mozolomide, N-methyl-N'-nitro-N-nitro-soguanidine, and cisplatin, This was not influenced by the in,vivo depletion of O-6-alkylguanine-DNA-alkyltransf erase after administration of O-6-benzylguanine, By analyzing mice mutant f or both Msh2 and p53, we found that the Msh2-dependent apoptotic response w as primarily mediated through a p53-dependent pathway. Msh2 also was requir ed to signal delayed p53-independent death. Taken together, these studies c haracterize an in vivo Msh2-dependent apoptotic response to methylating age nts and raise the possibility that Msh2 deficiency may predispose to malign ancy not only through failed repair of mismatch DNA lesions but also throug h the failure engage apoptosis.