# Connecting BRCA1 functions with DNA crosslink sensitivity

> **NIH NIH R35** · MEDICAL UNIVERSITY OF SOUTH CAROLINA · 2020 · $373,750

## Abstract

Project Summary
To counter the accumulation of DNA damage, eukaryotic cells employ an intricate network of pathways that
promote damage recognition, checkpoint signaling, and DNA repair. Components of the damage response
network have been linked to various genetic disorders that are typified by hypersensitivity to DNA damaging
agents and cancer predisposition. In particular, the tumor suppressor BRCA1 has been described as a master
regulator of genome stability due to its involvement in various aspects of the damage response. Despite
BRCA1's established role in the development of breast and ovarian cancers, a molecular understanding of its
functions remains limited. We recently showed that Xenopus egg extracts recapitulate BRCA1 functions
observed in human and mouse models, providing a soluble, highly amenable system for future mechanistic
studies. Initially, we will focus on BRCA1's newly described role in dismantling the replicative helicase after it
collides with a DNA crosslink. Unloading the CMG helicase complex (comprised of Cdc45, MCM2-7, and
GINS) is required to access and repair the underlying lesion, suggesting that helicase eviction may be a
fundamental mechanism of DNA damage tolerance. We will also identify how BRCA1's functions are
connected to cellular sensitivity, enabling us to devise and test new strategies for improved crosslink-based
therapeutics. Going forward, we will extend our analysis to additional BRCA1 functions to establish a
comprehensive understanding of BRCA1's many roles in DNA repair and tumor suppression.

## Key facts

- **NIH application ID:** 9934237
- **Project number:** 5R35GM119512-05
- **Recipient organization:** MEDICAL UNIVERSITY OF SOUTH CAROLINA
- **Principal Investigator:** David Thomas Long
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $373,750
- **Award type:** 5
- **Project period:** 2016-09-01 → 2021-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9934237

## Citation

> US National Institutes of Health, RePORTER application 9934237, Connecting BRCA1 functions with DNA crosslink sensitivity (5R35GM119512-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9934237. Licensed CC0.

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