The importance of maintaining genome stability is reflected in several biological phenomena. First, there are multiple mechanisms for the repair of damaged DNA, and these mechanisms are highly conserved from prokaryotes to eukaryotes. Second, disruptions in repair processes in humans cause some hereditary cancers and devastating diseases, such as xeroderma pigmentosa, ataxia telangiectasia and Cockayne's syndrome. Finally, destabilization recombination between sequences of similar yet imperfect homology (""""""""homeologous"""""""" sequences) is strictly regulated to avoid gross chromosomal rearrangements. One system involved in the maintenance of genome stability is the mismatch repair (MMR) pathway. Not only is MMR required for repair of replication errors, it also inhibits recombination between homeologous sequences that could be deleterious to the cell. The ease of genetic and molecular manipulation of the budding yeast, Saccharomyces cerevisiae, makes this organism in extremely useful system for the study of MMR in eukaryotes. The importance of the MMR genes in genome metabolism is demonstrated by the high mutation rate and elevated levels of homeologous recombination in yeast MMR mutants. Although studies of interactions of MMR proteins with proteins involved in replication have elucidated the role MMR plays in post-replicative repair, surprisingly little is known about the interactions between MMR and other proteins required for the inhibition of homeologous recombination. In order to understand how this inhibition is carried out, I propose to utilize a homeologous recombination assay system in yeast to 1) analyze strains mutant in known genes suspected of playing a role in this process and 2) conduct a novel screen for mutants that are defective specifically in the regulation of homeologous recombination. The results from both objectives should elucidate the mechanism for regulation of recombination and enhance our understanding of the genesis of genomic stability.
| Spell, Rachelle Miller; Jinks-Robertson, Sue (2004) Examination of the roles of Sgs1 and Srs2 helicases in the enforcement of recombination fidelity in Saccharomyces cerevisiae. Genetics 168:1855-65 |
