Tuesday, April 16, 2024
4/16/2024
ABSTRACT Genomic instability is a hallmark of cancer, enabling the generation of mutations and gross chromosomal rearrangements to drive neoplastic cell transformation and oncogenesis. A variety of conserved DNA repair mechanisms eliminate DNA damage, and defects in these DNA repair pathways lead to genomic instability and cancer. Homologous recombination (HR) is one such DNA repair pathway, which mediates the accurate repair of highly toxic double-strand DNA breaks (DSBs) and damaged DNA replication forks. BRCA1 and its obligate binding partner BARD1, both suppressors of breast, ovarian, and other cancers, fulfill multifaceted roles in HR. Specifically, the BRCA1-BARD1 complex influences DSB repair pathway choice and enhances the efficiency of several HR steps, including the nucleolytic processing of DNA lesions, the assembly of DSB repair nucleoprotein complexes that harbor the recombinase RAD51, and DNA strand invasion. We posit that the DNA and RAD51 binding attributes of BRCA1-BARD1 are germane for the DSB repair and replication fork maintenance functions of this tumor suppressor complex. To help fill major knowledge gaps, this fellowship proposal strives to delineate RAD51 and DNA interaction interfaces in BRCA1-BARD1 and to elucidate the mechanistic roles of these biochemical attributes in HR-mediated DNA repair and the protection of stressed and damaged DNA replication forks. Our objectives will be accomplished through biochemical and cell-based studies under two specific aims. The results of our endeavors will clarify the functional relevance of clinical mutations within BRCA1-BARD1 domains and create new avenues for the development of novel therapeutics to target tumors deficient in DNA repair.
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