DNA helicases are ubiquitous and vast in number, serving important roles in various facets of chromosome metabolism, including transcription, DNA replication, and DNA repair. We have been interested in a unique class of helicases called the RecQ family, with five distinct members in humans. Genetic defects in three of these helicases, viz., BLM, RTS, and WRN, give rise to human syndromes associated with cancer predisposition. Importantly, genetic ablation of RecQ5 also engenders cancer susceptibility in mice. Thus, the RecQ helicases are clearly important for genome maintenance and cancer avoidance. The BLM helicase, mutations in which being the cause of the radiation-sensitive and cancer-prone disorder Bloom's syndrome, functions in two critical stages of homologous recombination (HR)- mediated chromosome damage repair, namely, in the resection of DNA double-strand breaks and the dissolution of the double Holliday Junction, a late HR intermediate. Defects in BLM and its partner proteins thus lead to impaired initiation of homologous repair, frequent sister chromatid exchanges, and chromosome aberrations. Even though RECQ5 has not yet been associated with a human disease, its ablation in mice results in cancer susceptibility. RECQ5-deficient cells exhibit DNA damage sensitivity, elevated sister chromatid exchanges and HR events, and are prone to chromosomal rearrangements upon genotoxic stress. RECQ5 physically interacts with the RAD51 recombinase and displaces RAD51 from DNA. These results implicate RECQ5 as a tumor suppressor that acts by preventing inappropriate HR events via the disruption of RAD51-DNA nucleoprotein filaments. In this renewal project, we will strive to delineate the multi-faceted role of BLM in HR repair and regulation, and to also define the mechanism underlying the novel role of RECQ5 as an anti-recombinase.
Failure to properly repair damaged chromosomes or regulate the repair process compromises the integrity of the genome and can lead to cancer formation. The proposed studies will define the role of two human RecQ helicases and their partner proteins in the homologous recombinational repair of chromosomes that harbor radiation-induced DNA double-strand breaks and other deleterious lesions. The results will make a major contribution toward delineating the mechanism of DNA homology- directed chromosome damage repair and its regulation in human cells, and have strong relevance to radiation and cancer biology.
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