# Restoring genome stability and tumor suppression in BRCA1 deficient cells

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2021 · $523,500

## Abstract

PROJECT SUMMARY/ABSTRACT:
As central mediators of the DNA damage response, the BRCA1 and BRCA2 proteins normally act to preserve
genome integrity. Indeed, their genome maintenance functions are thought to be a major, if not the principal,
means by which BRCA1/2 suppress tumor formation in normal cells. In particular, BRCA1 and BRCA2 are
required for double-strand DNA break repair by homologous recombination (DSBR-HR). However, recent
studies have uncovered another BRCA1/2 function that also preserves genome stability and thus potentially
contributes to the tumor suppression activity of both proteins. During DNA replication, BRCA1 and BRCA2
have been shown to promote genome integrity by protecting stalled replication forks (SRFs) from nucleolytic
degradation. These findings raise critical questions regarding the mechanisms of BRCA1/2 tumor suppression
and the prospects for therapeutic targeting of the BRCA1/2 pathway. For example, is the tumor suppression
activity of the BRCA1/2 pathway mediated through its ability to promote DSBR-HR or SRF stability, or both?
Also, can the DSBR-HR or SRF stability functions of BRCA1/2 be restored for prophylactic and/or therapeutic
purposes in women who carry BRCA1/2 mutations? Our preliminary studies have uncovered a novel
mechanism by which SRF stability can be reconstituted in BRCA1 mutant cells. In particular, we show that
depletion of SMARCAL1, a DNA translocase implicated in replication fork dynamics, restores both SRF
stability and chromosome integrity in BRCA1-deficient cells subjected to replication stress. On the basis of
these results, we hypothesize that inappropriate remodeling of replication forks by SMARCAL1 in BRCA1-
deficient cells can increase genome instability and thereby predispose these cells to breast cancer. To test
these hypotheses, we will 1) define the mechanisms by which SMARCAL1 inactivation rescues SRF stability
and chromosomal integrity in BRCA1-deficient cells, and 2) determine whether tumor suppression activity can
be restored to BRCA1-mutant cells by SMARCAL1 inhibition.

## Key facts

- **NIH application ID:** 10064997
- **Project number:** 5R01CA227450-03
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** RICHARD J BAER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $523,500
- **Award type:** 5
- **Project period:** 2019-01-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10064997

## Citation

> US National Institutes of Health, RePORTER application 10064997, Restoring genome stability and tumor suppression in BRCA1 deficient cells (5R01CA227450-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10064997. Licensed CC0.

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