# FANCM in repair of stalled replication forks

> **NIH NIH R01** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2021 · $395,738

## Abstract

Replication fork stalling at sites of abnormal DNA structure is a recognized cause of genomic instability.
Increased replication fork stalling (“replication stress”) is a common feature of cancer cells, suggesting that
defective processing of the stalled fork is a common mechanism of genomic instability in cancer. The Fanconi
Anemia (FA) pathway has a major role in the metabolism and repair of stalled replication forks. FA is a rare,
autosomal recessive (or X-linked) disease caused by inactivation of any one of several FA genes. The clinical
manifestations of FA include childhood anemia and progressive bone marrow failure, together with short
stature and congenital defects affecting a wide variety of organs. The risk of cancer, including solid tumors, is
elevated, with particularly high incidence of acute myelogenous leukemia. The gene encoding an early
responder of FA pathway, FANCM, is found mutated in some breast cancers. The FA pathway overlaps
functionally with the BRCA pathway of hereditary breast/ovarian cancer predisposition—a critical regulator of
homologous recombination. The FA pathway is also activated by replication stress, indicating a general role for
the FA genes in human cancer and in many other diseases. Thus, deciphering the mechanisms of action of the
FA pathway has broad significance for human health. We recently adapted the Escherichia coli Tus/Ter
replication fork arrest complex for use in mammalian cells and have used it to quantify both error-free and
error-prone homologous recombination induced by a mammalian chromosomal replication fork block. More
recently, we identified a novel aberrant repair product of replication fork arrest in mammalian cells, in which
small (<10 kb) microhomology-mediated tandem duplications form at the site of replication arrest. FANCM
plays a crucial role in suppressing these aberrant repair products at stalled forks. In work proposed here, we
will use novel tools, recently developed by the Scully lab, to analyze how FANCM regulates homologous
recombination at stalled replication forks. We will identify the mechanisms by which FANCM suppresses
tandem duplication at stalled forks. Success in this work will lead to the identification of new targets for therapy
in cancer and other human diseases.

## Key facts

- **NIH application ID:** 10149966
- **Project number:** 5R01CA217991-05
- **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:** $395,738
- **Award type:** 5
- **Project period:** 2017-06-28 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10149966

## Citation

> US National Institutes of Health, RePORTER application 10149966, FANCM in repair of stalled replication forks (5R01CA217991-05). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10149966. Licensed CC0.

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