# Project 2: BRCA1-dependent DNA End Resection and Regulation via the 53BP1 Axis

> **NIH NIH P01** · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · 2024 · $541,923

## Abstract

PROJECT SUMMARY/ABSTRACT
DNA double strand breaks (DSBs) are induced by genotoxic agents such as ionizing radiation, chemotherapeutic
agents, and during encounters of the DNA replication machinery with DNA damage. The two major, mechanistically
distinct DSB repair pathways are non-homologous DNA end joining (NHEJ) and DNA homology-directed repair
(HDR). NHEJ is efficient but error-prone. HDR is inherently accurate and represents the preferred repair tool for
DNA replication-associated DSBs. HDR commences with the resection of the 5’-terminated strand at break ends
to generate a DNA tail that serves as the template for assembly of the RAD51 recombinase filament. DSB repair
pathway choice is linked to cell cycle progression and is determined by whether or not a DSB undergoes extensive
resection. Long-range resection is principally mediated by the 5’-3’ exonuclease EXO1 or the BLM helicase-
DNA2 endonuclease. The chromatin reader 53BP1 nucleates the formation of a higher order ensemble that harbors
the CTC1-STN1-TEN1 (CST) complex at DSB ends to block end resection in the G1 phase of the cell cycle. The
restrictive action of the 53BP1 axis is alleviated by BRCA1-BARD1 in S and G2 phases via mechanisms that are
poorly understood. Thus, BRCA1-deficient tumors, on account of their HDR-deficiency, are particularly vulnerable
to PARP inhibitors (PARPi) due to synthetic lethality. However, dysfunction in the 53BP1 axis leads to HDR
restoration and PARPi resistance.
 We have discovered that 53BP1 binds double-stranded DNA. We hypothesize that DNA binding by 53BP1 is
germane for its role in the recruitment of downstream factors and the imposition of DSB repair pathway choice.
Importantly, we find that the CST complex physically interacts with and inhibits EXO1 as well as BLM-DNA2, while
BRCA1-BARD1 efficiently overcomes these restrictive activities of CST. We hypothesize that CST acts via
physical interaction with resection enzymes and association with ssDNA to attenuate DNA end resection while
BRCA1-BARD1 counters CST by disrupting these inhibitory interactions and by stimulating resection enzymes.
To elucidate the underpinnings of the DNA end resection restriction circuitry, we will (1) determine the biological
role of DNA binding by 53BP1, (2) delineate how CST interferes with the activity of the 5’-3’ exonuclease EXO1
and of the helicase-endonuclease complex BLM-DNA2 in DNA end resection, and (3) interrogate BRCA1-BARD1
for its ability to overcome the restriction of DNA end resection imposed by CST.
 Our studies and synergy with Project 1 and Project 3 will elucidate the intricate regulatory networks that control
DNA end resection onset and efficiency. These collaborative endeavors will not only illuminate the mechanistic
principles of DSB repair pathway choice but will also exert a major impact in our understanding of how DSBs and
stressed DNA replication forks lead to cancer and will provide actionable information to help guide the development
of targ...

## Key facts

- **NIH application ID:** 10847789
- **Project number:** 1P01CA275717-01A1
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
- **Principal Investigator:** Sandeep Burma
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $541,923
- **Award type:** 1
- **Project period:** 2024-09-01 → 2029-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10847789

## Citation

> US National Institutes of Health, RePORTER application 10847789, Project 2: BRCA1-dependent DNA End Resection and Regulation via the 53BP1 Axis (1P01CA275717-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10847789. Licensed CC0.

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