Studies Of DNA Mismatch Repair

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Summary of Work: The goals of this project are to understand the biochemistry and genetics of MMR in normal eukaryotic cells, and how mutations in MMR genes lead to environmentally associated human diseases. This year we investigated the mechanism by which cadmium inhibits MMR. We previously showed that chronic exposure of yeast to low microM concentrations of cadmium, a known human carcinogen, results in hypermutability. The mutation specificity along with responses in proofreading-deficient and MMR-deficient mutants strongly suggested that cadmium reduces the capacity for MMR of small misalignments and base-base mismatches. This year we published biochemical support for the hypothesis that cadmium inhibits MMR by impairing the DNA binding and ATP hydrolysis functions of Msh2-Msh6, and by extrapolation, Msh2-Msh3. We also published a comprehensive review of the biochemistry of DNA MMR. Rare DNA synthesis errors are corrected by post-replication DNA mismatch repair (MMR). In addition to their functions in repairing replication errors, some eukaryotic MMR proteins also participate in other DNA transactions that are important for genome stability, toxicity and human health. These include critical environmental stress-response pathways such as repair of double-strand DNA breaks and DNA damage surveillance to signal apoptosis. MMR proteins also prevent recombination between DNA sequences with imperfect homology, they participate in meiotic recombination, and they modulate both somatic hypermutation of immunoglobulin genes and the stability or triplet repeat sequences whose instability is associated with certain hereditary degenerative diseases. Loss of MMR increases mutation rates and decreases apoptosis in response to certain forms of DNA damage, ultimately leading to cancer. Mutations in certain MMR genes result in infertility. The goals of this project are to understand the biochemistry and genetics of MMR protein function in normal eukaryotic cells, and how mutations in MMR genes lead to environmentally associated diseases.