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 two related processes, homologous recombination and 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 bacterial mismatch repair system encoded by the mutS and mutL genes in E. coli, are highly conserved in both prokayotes and eukaryotes. Defects in human genes encoding mismatch repair enzymes have been implicated in sporadic and hereditary cancers.We are interested in understanding the molecular mechanisms involved in mismatch recognition by the MutS protein. We have examined the oligomerization of MutS protein by analytical ultracentrifugation, mass spectrometry, gel filtration and laser light scattering and determined that MutS participates in a dimer-tetramer equilibrium in which the dimer is the predominant species under physiological conditions. We have also identifed a dimerization domain of MutS that maps to a highly conserved helix-turn-helix region at the carboxy terminus of the protein. Our studies indicate that dimerization of MutS is essential for mismatch repair in vivo and for DNA binding and ATP hydrolysis in vitro. - recombination, DNA repair, mutagenesis
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