# Mechanisms Underlying Replication Stress And Genome Instability Upon BRCA2 Deficiency

> **NIH NIH R01** · UNIVERSITY OF MASSACHUSETTS BOSTON · 2022 · $348,844

## Abstract

PROJECT SUMMARY
BRCA2 mutation carriers are highly predisposed to breast and ovarian cancer (60% risk for breast cancer and
30-40% for ovarian cancer), and also have increased risk for other cancers like prostate and pancreatic.
However, the mechanisms underlying these phenomena are still poorly understood. The molecular pathogenic
steps, especially the earliest ones that drive the transition of normal cells (BRCA2mut/+) in a BRCA2 mutation
carrier to tumor cells are largely unknown. Experiments detailed in this proposal will provide valuable clues to
what those early steps could be. The knowledge and understanding of the way a normal, presumably healthy
cell in BRCA2 mutation carrying individual starts becoming a tumor cell, will give us a much-needed early
advantage to help design preventive strategies and contribute towards decreasing B2 mutant cancer incidence.
The experimental strategy described in this proposal is based on our recently published work that shows
increased single stranded DNA (ssDNA) accumulation in BRCA2 deficient cells, and on our preliminary data that
shows high abasic site and uracil accumulation in BRCA2 deficient cells. Our preliminary data also shows
defective nucleotide excision repair (NER) pathway in BRCA2 deficient cells. Based on our strong preliminary
data, we propose to study the role of APOBEC/AID family of cytosine deaminases in generating abasic sites in
BRCA2 deficient cells. We will also use BRCA2 patient derived tissue to design new ways to classify variants of
unknown significance and also learn how increased abasic site and uracil in B2 heterozygous cells could
contribute to genomic instability and tumorigenesis. Finally, we will also study whether BRCA2 deficient cells are
defective in NER when undergoing replication stress, and if this weakness in BRCA2 mutant tumors could be
targeted by combination drug therapy.
 This study provides an opportunity to address the question of early DNA damaging events that drive
BRCA2 mutant tumorigenesis, and has the potential to provide the much needed, critical information that will
help with the design of effective cancer prevention and therapeutic strategies for BRCA2 mutation bearing
women.

## Key facts

- **NIH application ID:** 10504242
- **Project number:** 1R01CA273696-01
- **Recipient organization:** UNIVERSITY OF MASSACHUSETTS BOSTON
- **Principal Investigator:** Shailja Pathania
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $348,844
- **Award type:** 1
- **Project period:** 2022-09-01 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10504242

## Citation

> US National Institutes of Health, RePORTER application 10504242, Mechanisms Underlying Replication Stress And Genome Instability Upon BRCA2 Deficiency (1R01CA273696-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10504242. Licensed CC0.

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