We seek to understand at a molecular level the various ways by which an organism maintains the integrity of its genome while accommodating the need for genetic diversity. Our research efforts currently focus on a key DNA repair pathway, DNA mismatch repair. Mismatch repair, exemplified by the E. coli methyl-directed mismatch repair pathway, targets base pair mismatches that arise through DNA replication errors, homologous recombination and spontaneous DNA damage. Components of the mismatch repair system encoded by the mutS and mutL genes are highly conserved throughout evolution, and inactivation of mismatch repair results in a large increase in the rate of spontaneous mutation. Defects in human mismatch repair enzymes have been implicated in sporadic and hereditary cancers. Building on previous work, the crystal structure of a MutS-ADP-mismatch complex reveals key residues in the composite ATPase active site and conformational changes induced by nucleotide binding. Biochemical experiments provide evidence for a key intermediate in mismatch repair involving a complex of MutS and MutL bound to a DNA mismatch. Formation of this complex that signals downstream events in repair requires ATP.
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