The importance of the mismatch repair system in humans is evidenced by the fact that inheritance of a defective allele in one of several mismatch repair genes will, with high probability, lead to cancer, usually colorectal cancer. There is increasing evidence that some of the most important substrates for the mismatch repair system involve damaged DNA, including types of damage likely to be produced by normal cellular processes, especially oxidative processes in the cell. The overall goal of this proposal is to examine the interactions of mismatch repair proteins with DNA lesions and mismatches likely to be found in the cell as a consequence of normal endogenous processes. These experiments will help to test the hypothesis that mismatch repair is important for preventing mutations due to damaged DNA.
The specific aims of this proposal are to determine the interaction of yeast and human MutSalpha with substrates containing specific damaged nucleotides, to determine the effect of MutLalpha on the binding of these lesions by MutSalpha, and to examine mismatch repair, in vitro, of substrates containing these various lesions.
