Mutation in any one of five human DNA mismatch repair (MMR )gene homologs, MSH2, MSH6,MLH1, PMS2 and PMS1, contributes to both hereditary and spontaneous cancers. As a primary example, hereditary nonpolyposis 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 one underlying feature of tumor cells. Interestingly, amongst HNPCC kindreds MLH1 and MSH2 families are common, whereas PMS2 and PMS1 families are rare. Mice defective in Msh2, MM, Msh6 and Pms2 all develop tumors, although the respective tumor spectra differ. Most notably, whereas Mlhl-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) Mlhlp 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 vs. Pms2 deficiency, and whether """"""""backup"""""""" pathways exist for MMR functions. We will address such issues by studying further mice defective in each of the MutL homologs, Mlhl, Pmsl and Pms2. We will examine intestinal tumor susceptibility associated with Mlhl 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 tumor spectrum and mutation levels of mice expressing a dominant negative Pms2 mutation. We will determine the effect of Mlhl- versus Pms2-deficiency on cellular responses to DNA damaging agents. We will test for cooperative, or synergistic, effects of inactivating mutations in Mlhl (or Pms2) and IL-10 as a means to address relationships/interactionsbetween MMR deficiency and inflammatory bowel disease.
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