The mismatch repair system is a major DNA repair system that has been conserved from bacteria to humans. It maintains genome stability by removing DNA replication errors, preventing homeologous recombination, and participating in the cytotoxic response to irreparable DNA damage. Genome stability provided by the mismatch repair system protects humans from both sporadic and inherited cancers. Although mismatch repair is error-free in the majority of genomic sites, it is error-prone at certain genomic loci. Mutations formed by error-prone mismatch repair have both beneficial and detrimental consequences for human health. All functions of the mismatch repair system depend on its ability to process DNA mismatches. The initial step in processing of mismatch-containing DNA by the eukaryotic mismatch repair system is recognition of the mismatch by MutS? or MutS?. The steps that occur downstream from the mismatch recognition step are not well understood. Recent progress in the field has revealed a eukaryotic mismatch repair mechanism that relies on the 5??3? exonuclease activity of Exo1. However, significant genetic, epidemiological, and biochemical evidence has suggested that the Exo1-dependent mechanism is not the only mechanism in eukaryotic mismatch repair. During our preliminary studies we have discovered that there are novel mechanisms in eukaryotic mismatch repair. The goal of this project is to define these novel mechanisms in the yeast S. cerevisiae and human cells. The proposed studies will take advantage of our unique expertise in the mismatch repair field and will utilize a diverse array of genetic and biochemical approaches, fluorescence microscopy of live cells, and next generation sequencing. The results will provide novel insights into the mechanisms in mismatch repair and will help to develop innovative approaches to prevent and treat human diseases caused by defects in mismatch repair.
Inactivation of the mismatch repair system causes ~15% of sporadic cancers in several human organs and is the molecular basis of two cancer predisposition syndromes. Several anticancer therapies exploit the ability of the mismatch repair system to initiate apoptosis in cancer cells damaged with DNA methylators. The results of the proposed research will reveal novel mechanisms and players in mismatch repair and will facilitate the development of new approaches to prevent and treat human diseases caused by defects in mismatch repair.