# Analysis of BRCA1 recombination functions

> **NIH NIH R01** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2021 · $374,063

## Abstract

PROJECT SUMMARY
Error-free DNA repair initiated at the sites of replication fork stalling is critical for the prevention of genomic
instability in cycling cells. Defects in stalled fork repair have been directly implicated in cancer and other human
diseases, notably in hereditary breast and ovarian cancer (HBOC), in light of the involvement of BRCA1 and
BRCA2 in repair of stalled replication forks. Our work previously established roles for BRCA1 and BRCA2 in
regulating HR at both double strand breaks (DSBs) and in stalled fork repair. We have developed innovative
tools for quantifying homologous recombination (HR) and other repair outcomes at stalled mammalian
replication forks and, more recently, at broken replication forks. Major goals of this proposal are to define how
BRCA1 contributes to the repair of stalled or broken forks. We anticipate that its roles in response to these two
distinct lesions may be quite different. We have developed an array of cutting-edge tools to support this study,
including unique, sophisticated HR reporters that can distinguish between error-free “short tract” HR and error-
prone “long tract” HR—a replicative response likely analogous to break-induced replication as described in
yeast. One unusual aberrant replicative response that we observe at stalled forks specifically in BRCA1 mutant
cells is the formation of ~10 kb non-homologous tandem duplications (TDs). Remarkably, these highly specific
forms of structural variation are also abundant in the BRCA1-linked breast and ovarian cancer genome.
Another major goal of this proposal is to define more fully the genetic regulation of TD formation at stalled
forks. Success in this project will reveal the mechanisms that regulate mammalian stalled (or broken) fork
repair and their relationship to HBOC predisposition in unprecedented detail. This work may also identify new
molecular targets for therapy of breast and ovarian cancer.

## Key facts

- **NIH application ID:** 10296256
- **Project number:** 2R01CA095175-16
- **Recipient organization:** BETH ISRAEL DEACONESS MEDICAL CENTER
- **Principal Investigator:** Ralph Scully
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $374,063
- **Award type:** 2
- **Project period:** 2002-05-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10296256

## Citation

> US National Institutes of Health, RePORTER application 10296256, Analysis of BRCA1 recombination functions (2R01CA095175-16). Retrieved via AI Analytics 2026-06-10 from https://api.ai-analytics.org/grant/nih/10296256. Licensed CC0.

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