# Therapeutic potential of FANCM for BRCA1-linked cancer

> **NIH NIH K99** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2022 · $99,547

## Abstract

Project Summary/Abstract
Breast and ovarian cancer are among the most common cancers in women worldwide.PARP inhibitors have
shown potential for the treatment of BRCA-linked cancer, via a synthetic lethality mechanism that exploits the
HR defect. However, tumors often develop resistance to these and other drugs. Therefore, there is a pressing
need to find new, targeted treatments for BRCA-linked cancer. Genomic instability is a hallmark of cancer cells
and a potential source of tumorigenesis. A major cause of genomic instability is replication fork stalling at sites
of DNA damage or abnormal DNA structure. A limitation in the study of mammalian stalled fork repair has been
a dearth of tools with which to analyze this process in molecular detail. The Scully lab solved this problem by
adapting the Escherichia coli Tus/Ter replication fork barrier (RFB) to induce site-specific replication fork
stalling on a mammalian chromosome.
Tandem duplications (TDs) in primary cells lacking BRCA1 are induced specifically by a Tus/Ter block but not
by a conventional double strand break (DSB), indicating specificity for the stalled fork response. Intriguingly,
breast and ovarian cancers lacking BRCA1 similarly acquire large numbers of small (~10 kb) TDs, which we
have termed “Group 1” TD. Thus, the Tus/Ter system recapitulates the BRCA1-specific regulation of
Group 1 TD formation observed in human breast and ovarian cancer. I found that the stalled fork motor
protein—FANCM (product of the Fanconi anemia [FA] group M gene) acts synergistically with BRCA1 to
suppress Tus/Ter-induced TDs. Further, I discovered a novel synthetic lethal interaction between Brca1
and Fancm loss in mouse embryonic stem (ES) cells and in breast and ovarian cancer cells. These findings
suggest that FANCM may be a promising therapeutic target in BRCA1-linked breast and ovarian cancer.
My goals in this proposal are to delineate the novel FANCM-BRCA1 synthetic lethal interaction in cancer cells
and to determine the mechanism of synthetic lethality (Aim1). Further, I will explore the chromatin environment
and protein dynamics at the stalled fork and will study how alterations in these processes contribute to the
FANCM-BRCA1 synthetic lethal interaction (Aim2). I observe an epistatic role of Fancm and its downstream
target Fancd2 at Tus/Ter in promoting error free repair and suppressing error-prone repair.This critical role of
Fancm and Fancd2 in repair pathway choice at stalled forks raises the possibility that they might share similar
genetic interactions with Brca1. will identify how individual domains of FANCD2 function in repair pathway
choice at stalled forks and their genetic interaction with Brca1 (Aim 3). This holistic approach will provide a full
picture of the mechanism of FANCM-BRCA1 synthetic lethal interactions and might identify in FANCD2 a new
synthetic lethal target for cancer therapy.
I

## Key facts

- **NIH application ID:** 10446024
- **Project number:** 1K99CA252044-01A1
- **Recipient organization:** BETH ISRAEL DEACONESS MEDICAL CENTER
- **Principal Investigator:** Arvind Panday
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $99,547
- **Award type:** 1
- **Project period:** 2022-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10446024

## Citation

> US National Institutes of Health, RePORTER application 10446024, Therapeutic potential of FANCM for BRCA1-linked cancer (1K99CA252044-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10446024. Licensed CC0.

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