ROLE OF BRCA1 PHOSPHORYLATION IN DNA DSB REPAIR AND GENOME STABILITY MAINTENANCE

The tumor suppressor BRCA1 plays an important role in the homologous recombination (HR) pathwayof DNA double strand break (DSB) repair. From a mechanistic perspective, BRCA1 facilitates recruitment ofnucleases required for end resection, the commitment step in HR repair, yet paradoxically, BRCA1 has beenshown to inhibit the nuclease activity in vitro. It is unclear how nuclease-recruiting and -inhibiting activities ofBRCA1 can be reconciled in HR repair. From a cancer pathophysiological perspective, most BRCA1-associated breast tumors are basal-like but they originate from luminal progenitor cells, so-called cells of origin.This poses an important and largely unaddressed question: does BRCA1 influence HR repair and genomestability in a cell lineage- and genomic locus-preferred manner? Our preliminary data indicate that BRCA1 modifications signal its timely departure from DSBs and thuseffectively neutralize its nuclease-inhibiting activity at DSB. Using clinical samples, we also found that luminalcells from BRCA1 mutation carriers are particularly radiosensitive and prone to accumulation of DSBprecursors at specific genomic loci. Based on these compelling preliminary data, we hypothesize that BRCA1modifications are part of a licensing mechanism that confines the commitment step of HR to S/G2 phase. Wefurther propose that BRCA1 HR repair activity is particularly important for genetic integrity at luminal genes inluminal cells of the breast tissue. Our multidisciplinary team of laboratory and clinician scientists will combinecell culture systems with mouse genetics and human samples to test this novel hypothesis. Our proposed work seeks to validate a previously unrecognized role of BRCA1 in licensing thecommitment step in HR, thus challenging the current view of BRCA1 merely as a scaffolding protein.Furthermore, by interrogating BRCA1 HR function in the clinically relevant cell lineage and genomic regions,our work represents a significant departure from traditional cell line-focused mechanistic studies. Our proposedwork helps fill a critical knowledge gap between mechanistic investigation of BRCA1 and etiology of tissue/celllineage-specific BRCA1-associated tumor development, thus substantially advancing BRCA1-related breastcancer research.