# Investigating contributions of BRCA2 DNA-binding domains toward maintaining genome integrity

> **NIH NIH F30** · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · 2024 · $45,318

## Abstract

ABSTRACT
Conserved mechanisms exist to eliminate DNA damage, which, if left unrepaired, can cause gene mutations and
genome rearrangements to trigger neoplastic cell transformation and oncogenesis. In particular, homologous
recombination (HR) represents a high-fidelity tool for the repair of DNA double-strand breaks (DSBs), interstrand
crosslinks, and collapsed DNA replication forks. Proper execution of HR requires the tumor suppressor BRCA2
(Breast Cancer 2). Germline mutations in BRCA2 lead to breast and ovarian cancer and also the cancer-prone
syndrome Fanconi anemia. Moreover, somatic driver BRCA2 mutations are found in a variety of cancer types.
Further work is necessary to elucidate the mechanistic role of BRCA2 in HR repair. Importantly, the research
proposed herein will help define the contributions of two distinct DNA binding domains toward the function of
BRCA2 as a “recombination mediator,” specifically in facilitating the assembly of complexes of the RAD51
recombinase on single-stranded DNA derived from the processing of DSBs. Our central hypothesis posits that
the two DNA-binding domains within BRCA2 play an essential role in guiding BRCA2-dependent DSB repair and
replication fork preservation through the engagement of single-stranded DNA and DNA structures present in
processed DSBs. We will conduct a variety of biochemical, genetic, and cell biological studies under two specific
aims to test this central tenet. Throughout these experiments, we will delineate how genetic mutations within
each DNA binding domain affect key aspects of HR and replication fork preservation. The results from this
fellowship project will not only expand our understanding of how the BRCA2 DNA-binding domains contribute to
the maintenance of genome stability, but they will also shed light on how mutations within these domains
ultimately cause malignancy. Furthermore, we expect our findings to help identify new targets and pathway pivot
points for the development of novel cancer therapeutics.

## Key facts

- **NIH application ID:** 10814337
- **Project number:** 5F30CA260908-04
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
- **Principal Investigator:** Francisco Neal
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $45,318
- **Award type:** 5
- **Project period:** 2021-05-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10814337

## Citation

> US National Institutes of Health, RePORTER application 10814337, Investigating contributions of BRCA2 DNA-binding domains toward maintaining genome integrity (5F30CA260908-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10814337. Licensed CC0.

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