Studies in the model eukaryote Saccharomyces cerevisiae have revealed that homologous recombination (HR) is an important tool for the repair of chromosomes injured by various mutagenic chemicals including alkylating agents and DNA cross-linking agents, and by ionizing radiations that cause DNA double strand breaks. HR also participates in the repair of stalled replication forks and incomplete telomeres. Proteins encoded by evolutionarily conserved genes of the RAD52 epistasis group catalyze the HR reaction. The goal of this project is to elucidate the functional role of the Shu1-Shu2-Csm2-Psy3 (Shu) complex of S. cerevisiae. Several genetic investigations of the Shu complex have revealed that it is an integral component of the RAD52 group, but to date, no mechanistic information is available on the Shu complex. In light of this knowledge gap, we have purified the Shu complex and found that it interacts physically with key components of the HR pathway. Building off of our preliminary findings, the specific aims of this proposal are to: 1) define the biochemical properties of the Shu complex and determine their functional relevance in vivo, and 2) delineate how the Shu complex functions in HR by examining its effects upon the well- understood activities of its interaction partners. These studies seek to shed light on the evolutionarily conserved mechanisms by which the HR pathway maintains genomic integrity. Defects in HR leads to diseases predisposing to cancer in humans, including familial breast and ovarian cancers, Fanconi anemia, Werner's syndrome, and Bloom's syndrome. As such, the results of this work will contribute to a broader understanding of cancer biology.
Cancers are characterized by genomic instability and rearrangements, which can be induced by exposure of cells to DNA damaging agents such as ionizing radiation. The proposed studies will better our understanding of the mechanisms by which cells avoid deleterious genome rearrangements via the process of homologous recombination.
|Gaines, William A; Godin, Stephen K; Kabbinavar, Faiz F et al. (2015) Promotion of presynaptic filament assembly by the ensemble of S. cerevisiae Rad51 paralogues with Rad52. Nat Commun 6:7834|
|Liu, Yan; Gaines, William A; Callender, Tracy et al. (2014) Down-regulation of Rad51 activity during meiosis in yeast prevents competition with Dmc1 for repair of double-strand breaks. PLoS Genet 10:e1004005|
|Busygina, Valeria; Gaines, William A; Xu, Yuanyuan et al. (2013) Functional attributes of the Saccharomyces cerevisiae meiotic recombinase Dmc1. DNA Repair (Amst) 12:707-12|