# Homology-directed repair: BRCA2 and RAD51 paralogs

> **NIH NIH R35** · SLOAN-KETTERING INST CAN RESEARCH · 2020 · $704,502

## Abstract

Project Summary/Abstract
Homologous recombination, i.e., homology-directed repair (HDR), is a major repair pathway for double-strand
breaks (DSBs), including lesions arising during DNA replication. HDR mutants are characterized by genomic
instability and sensitivity to DNA damaging agents such as interstrand cross-linking agents like cisplatin and
poly(ADP-ribose) polymerase inhibitors, both of which are used in cancer treatment. Several proteins central to
the HDR pathway are tumor suppressors, notably the breast and ovarian cancer suppressor BRCA2, which
promotes the function of RAD51, the critical protein for homologous strand exchange. RAD51 paralogs are
also key HDR proteins and have also been identified both as tumor suppressors and as proteins that affect
therapy response. These HDR proteins are essential. Individuals with germline mutations are constitutionally
heterozygous, but tumors typically have somatic undergone loss of heterozygosity (LOH), losing the wild-type
allele, presumably as an early step in tumor initiation.
 This proposal has an overarching goal of integrating our understanding how HDR proteins act to
maintain genomic stability and cell and tissue homeostasis, how they come to be “lost” in cells, and how their
function can be restored. Thus, this broad goal impacts tumor initiation, therapy response, and therapy
resistance. It incorporates molecular analysis of HDR protein function, with a particular focus on BRCA2, and
delineates how cells respond to HDR protein loss, including how they escape cell death to allow tumor
formation. Within this goal is understanding tumor initiation from the standpoint of determining mechanisms of
LOH that lead to HDR protein loss, as well as uncovering factors that affect LOH frequencies. While HDR
protein loss sensitizes tumors to targeted therapies, HDR function is often restored by secondary mutations,
leading to therapy resistance. Understanding which mutations are susceptible to reversion and how therapy
impacts reversion is of major interest. Finally, HDR within tissues is also part of this integrated goal, in
particular, within the fallopian tube epithelium, which is considered the tissue of origin of high-grade serous
ovarian cancers.

## Key facts

- **NIH application ID:** 10053589
- **Project number:** 1R35CA253174-01
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** Maria Jasin
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $704,502
- **Award type:** 1
- **Project period:** 2020-08-01 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10053589

## Citation

> US National Institutes of Health, RePORTER application 10053589, Homology-directed repair: BRCA2 and RAD51 paralogs (1R35CA253174-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10053589. Licensed CC0.

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