PMID:10097137

Citation	Toft, NJ, Winton, DJ, Kelly, J, Howard, LA, Dekker, M, te Riele, H, Arends, MJ, Wyllie, AH, Margison, GP and Clarke, AR (1999) Msh2 status modulates both apoptosis and mutation frequency in the murine small intestine. Proc. Natl. Acad. Sci. U.S.A. 96:3911-5
Abstract	Deficiency in genes involved in DNA mismatch repair increases susceptibility to cancer, particularly of the colorectal epithelium. Using Msh2 null mice, we demonstrate that this genetic defect renders normal intestinal epithelial cells susceptible to mutation in vivo at the Dlb-1 locus. Compared with wild-type mice, Msh2-deficient animals had higher basal levels of mutation and were more sensitive to the mutagenic effects of temozolomide. Experiments using Msh2-deficient cells in vitro suggest that an element of this effect is attributable to increased clonogenicity. Indeed, we show that Msh2 plays a role in the in vivo initiation of apoptosis after treatment with temozolomide, N-methyl-N'-nitro-N-nitrosoguanidine, and cisplatin. This was not influenced by the in vivo depletion of O6-alkylguanine-DNA-alkyltransferase after administration of O6-benzylguanine. By analyzing mice mutant for both Msh2 and p53, we found that the Msh2-dependent apoptotic response was primarily mediated through a p53-dependent pathway. Msh2 also was required to signal delayed p53-independent death. Taken together, these studies characterize an in vivo Msh2-dependent apoptotic response to methylating agents and raise the possibility that Msh2 deficiency may predispose to malignancy not only through failed repair of mismatch DNA lesions but also through the failure to engage apoptosis.
Links	PubMed PMC22394
Keywords	Animals; Apoptosis/drug effects; Apoptosis/genetics; Cells, Cultured; Cisplatin/toxicity; DNA Repair; DNA-Binding Proteins; Dacarbazine/analogs & derivatives; Dacarbazine/toxicity; Guanine/analogs & derivatives; Guanine/toxicity; Intestinal Mucosa/cytology; Intestinal Mucosa/drug effects; Intestinal Mucosa/pathology; Intestine, Small/cytology; Intestine, Small/drug effects; Intestine, Small/pathology; Methylnitronitrosoguanidine/toxicity; Mice; Mice, Inbred BALB C; Mice, Inbred Strains; Mice, Knockout; MutS Homolog 2 Protein; Mutagenesis; Mutagens/toxicity; Proto-Oncogene Proteins/deficiency; Proto-Oncogene Proteins/genetics; Proto-Oncogene Proteins/metabolism; Stem Cells/cytology; Stem Cells/physiology
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