In both prokaryotes and eukaryotes DNA mismatch repair plays major roles in replicative error correction and genetic recombination. Disruption of DNA mismatch repair has also been proposed as one step in the progression of human neoplasias. In addition, DNA mismatch repair is likely to impact the DNA rearrangements and "hypermutation" characteristic of immunoglobulin diversification in higher animals. Mismatch repair might influence the rate of expansion of simple sequence repeats that underlies certain forms of human genetic disease. The overall goal of this study is to determine the roles of newly discovered yeast genes that encode polypeptides with structural similarity to bacterial and other yeast proteins known to have roles in DNA mismatch repair. We have discovered additional genes in yeast (the MLH genes) that show significant amino acid homology with the MutL gene of the bacterium E. coli, and the PMS1 gene of yeast (a mutL-like mismatch repair gene). We will determine the nucleotide sequence of the yeast MLH genes, perform the requisite gene disruptions and determine initial phenotypes of the mutants in vegetative cells, e.g. mutator effects. We will examine the role of the MLH genes in genetic recombination. We will test for functional similarity between the yeast and mammalian MLH gene products. A study of these newly found PMS1/mutL homologs should lead to a better understanding of mismatch repair in yeast. Finally, structural and functional comparisons of the yeast and mammalian MLH genes should help to guide the more demanding analysis of MLH gene functions in the mouse. %%% In all organisms DNA mismatch repair plays major roles in gene recombination and in correcting errors in gene replication. DNA mismatch repair may also be a significant factor in the development of human tumors and in certain human genetic diseases; it probably also important in the normal functioning of the immune system. The overall goal of this study is to determine the roles of newly discovered yeast genes that encode proteins with structural similarity to other proteins known to have roles in DNA mismatch repair. This study should lead to a better understanding of mismatch repair in yeast and should help to guide the more demanding analysis of the phenomenon in mammals.
