# Role of BRCA1 phosphorylation in DNA DSB repair and genome stability maintenance

> **NIH NIH R01** · GEORGE WASHINGTON UNIVERSITY · 2020 · $1

## Abstract

The tumor suppressor BRCA1 plays an important role in the homologous recombination (HR) pathway
of DNA double strand break (DSB) repair. From a mechanistic perspective, BRCA1 facilitates recruitment of
nucleases required for end resection, the commitment step in HR repair, yet paradoxically, BRCA1 has been
shown to inhibit the nuclease activity in vitro. It is unclear how nuclease-recruiting and -inhibiting activities of
BRCA1 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 genome
stability in a cell lineage- and genomic locus-preferred manner?
 Our preliminary data indicate that BRCA1 modifications signal its timely departure from DSBs and thus
effectively neutralize its nuclease-inhibiting activity at DSB. Using clinical samples, we also found that luminal
cells from BRCA1 mutation carriers are particularly radiosensitive and prone to accumulation of DSB
precursors at specific genomic loci. Based on these compelling preliminary data, we hypothesize that BRCA1
modifications are part of a licensing mechanism that confines the commitment step of HR to S/G2 phase. We
further propose that BRCA1 HR repair activity is particularly important for genetic integrity at luminal genes in
luminal cells of the breast tissue. Our multidisciplinary team of laboratory and clinician scientists will combine
cell 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 the
commitment 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 proposed
work helps fill a critical knowledge gap between mechanistic investigation of BRCA1 and etiology of tissue/cell
lineage-specific BRCA1-associated tumor development, thus substantially advancing BRCA1-related breast
cancer research.

## Key facts

- **NIH application ID:** 9998669
- **Project number:** 5R01CA212674-05
- **Recipient organization:** GEORGE WASHINGTON UNIVERSITY
- **Principal Investigator:** YANFEN HU
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1
- **Award type:** 5
- **Project period:** 2017-08-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9998669

## Citation

> US National Institutes of Health, RePORTER application 9998669, Role of BRCA1 phosphorylation in DNA DSB repair and genome stability maintenance (5R01CA212674-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9998669. Licensed CC0.

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