INACTIVATION OF THE MOUSE MSH2 GENE RESULTS IN MISMATCH REPAIR DEFICIENCY, METHYLATION TOLERANCE, HYPERRECOMBINATION, AND PREDISPOSITION TOCANCER

To investigate the role of the presumed DNA mismatch repair (MMR) gene Msh2 in genome stability and tumorigenesis, we have generated cells a nd mice that are deficient for the gene. Msh2-deficient cells have los t mismatch binding and have acquired microsatellite instability, a mut ator phenotype, and tolerance to methylating agents. Moreover, in thes e cells, homologous recombination has lost dependence on complete iden tity between interacting DNA sequences, suggesting that Msh2 is involv ed in safeguarding the genome from promiscuous recombination. Msh2-def icient mice display no major abnormalities, but a significant fraction develops lymphomas at an early age. Thus, Msh2 is involved in MMR, co ntrolling several aspects of genome stability; loss of MMR-controlled genome stability predisposes to cancer.