Mutation in any of five human DNA mismatch repair (MMR) gene homologs, MSH2, MSH6, MLH1, PSM2 and PMS1, contributes to both hereditary and spontaneous cancers. As a primary example., hereditary non-polyposis colorectal cancer (HNPCC) is frequently associated with germline mutations in the MMR genes and accounts for approximately 5% of the total colorectal cancer burden.. Such results have provided support for the notion that a mutator phenotype is common underlying feature of tumor cells. Interestingly, amongst HNPCC kindreds MLH1 and MHS2 families are common whereas PSMS2 and PMS1 families are rare. Mice defective in Msh2, M1h1, Msh6 and Pms2 all develop tumors, although the respective tumor spectra differ. Most notably, whereas Mlh1-deficient mice developed lymphomas and tumors characteristic of HNPCC, e.g. intestinal tumors and sebaceous gland tumors, Pms2- deficient mice developed primarily lymphomas and sarcomas were not susceptible to intestinal tumors. Interestingly, amongst HNPCC kindreds MLH1 and MSH2 families are common, whereas PSM2 and PSM1 families are rare. Mice defective in Msh2, Mlh1, Msh6 and Pms 2 will develop tumors, although the respective tumor spectra differ. Most notably, whereas Mlh1-deficient mice developed lymphomas and tumors characteristic of HNPCC, e.g. intestinal tumors and sebaceous gland tumors, Pms2-deficient mice developed primarily lymphomas and sarcomas but were not susceptible to intestinal tumors. This tumor spectra difference and the lack of PMS2 kindreds are especially perplexing for at least two reasons: 1) Mlh1p and Pms2p act as a heterodimer while fulfilling the major """"""""MutL"""""""" role during MMR in both yeast and mammalian cells, and 2) Multiple tissues of mice lacking either functional Mlhlp or Pms2p both show strong mutator phenotypes. Such results raise several important issues such as whether an increase in mutation is sufficient for the development of HNPCC-like tumors, whether other MMR-related functions, besides mutation avoidance are differentially affected by Mlhl versus. Pms2 deficiency, and whether the """"""""backup"""""""" pathways exist for MMR functions. We will address such issues by studying further mice defective in each of the MutL homologs, Mlhl, Pms1 and Pms2. We will examine intestinal tumor susceptibility associated with Mlh1 or Pms2 null mutation in C57BL/6 and 129/Sv backgrounds. We will study mice with mutations in two MutL homologs by monitoring tumor formation and mutation. We will determine the effect of Mlh1-versus Pms2-deficiency on cellular responses to DNA damaging agents, We will test for cooperative or synergistic , effects of inactivation mutations in Mlhl1 (or Pms2) and IL-10 as a means to address relationships interactions between MMR deficiency and inflammatory bowel disease.
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