# Regulation of BRCA-dependent Genome Repair via the 53BP1 Axis

> **NIH NIH P01** · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · 2024 · $2,556,071

## Abstract

ABSTRACT
DNA double-strand breaks (DSB)s occur upon exposure of cells to ionizing radiation and chemicals in the
environment, and when DNA replication forks become impeded by lesions and obstacles then
subsequently collapse. Two mechanistically distinct DSB repair pathways, namely, homology-directed
repair (HDR) and non-homologous DNA end-joining (NHEJ), are responsible for the removal of the majority
of DSBs. Whereas HDR is mostly accurate, NHEJ, while efficient, often entails loss of DNA sequence
during repair, and can also generate chromosome translocations and replication fork fusions. Failure of
NHEJ or HDR leads to heightened engagement of alternate end-joining (AltEJ) and single-strand annealing
(SSA), highly mutagenic and otherwise minor pathways, as repair tools. As such, the choice of DSB repair
pathway has a major impact on the maintenance of genome stability, preventing neoplastic transformation
of cells, and oncogenesis. Our Program Project brings together seven leading NIH-funded laboratories
within a highly collaborative and synergistic realm to delineate the mechanisms of HDR and replication fork
maintenance, and how HDR is negatively regulated to favor the use of NHEJ as DSB repair tool. We have
assembled three Shared Resource Cores to provide state-of-the-art services in the production of high
quality protein preparations for mechanistic experiments, biophysical and structural analyses of protein-
ligand interactions and precise measurement of binding constants, and also cellular analyses of DSB repair
and replication fork maintenance. Altogether, we are exceptionally well poised to leverage our deep
knowledge of DSB repair mechanisms and leadership to understand how the tumor suppressors BRCA1-
BARD1 and BRCA2 function to promote HDR and to overcome the HDR restrictive action of the epigenetic
mark reader 53BP1 and its associated factors such as DYNLL1 and the hetero-trimeric CTC1-STN1-TEN1
complex. As such, our Program Project will not only exert a major impact in elucidating mechanisms of
DSB repair pathway choice and cancer drug resistance, but will also identify novel targets and pathways
pivot points to guide the development of new therapeutic strategies to treat incalcitrant breast, ovarian and
other cancers.

## Key facts

- **NIH application ID:** 10847786
- **Project number:** 1P01CA275717-01A1
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
- **Principal Investigator:** Patrick Sung
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $2,556,071
- **Award type:** 1
- **Project period:** 2024-09-01 → 2029-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10847786

## Citation

> US National Institutes of Health, RePORTER application 10847786, Regulation of BRCA-dependent Genome Repair via the 53BP1 Axis (1P01CA275717-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10847786. Licensed CC0.

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