# DNA Repair Pathways Choice to Regulate Therapeutic Resistance in Cancer Cells

> **NIH NIH R01** · CLEVELAND CLINIC LERNER COM-CWRU · 2020 · $366,954

## Abstract

Project Summary
 BRCA1 or BRCA2 mutations increase the risk of several cancers, including breast, ovarian, prostate, and
pancreatic cancers. Cells with dysfunctional BRCA1 or BRCA2 gene expression suffer defects in performance
of double strand break (DSB) repair mechanisms including homologous recombination (HR) and non-
homologous DNA end joining (NHEJ). Cancer treatments exploit this characteristic, the best example of which
is the PARP inhibitors (PARPi), which show “synthetic lethality” with BRCA1 or BRCA2 deficiency due to HR
repair defects in BRCA1 or BRCA2-deficient cancer cells. However, resistance to PARPi is a major clinical
problem in BRCA-mutated cancers. Unexpectedly, loss of the DNA repair protein 53BP1 renders BRCA1-
deficient cancer cells resistant to PARPi and radiation treatment, indicating that loss of 53BP1 expression is at
least one scenario by which therapeutic resistance may arise in BRCA-mutated cancers. We and others reported
recently that mechanistically, 53BP1 acts as an adaptor protein and controls two downstream sub-pathways,
one mediated by PTIP and Artemis and the other mediated by RIF1 and MAD2L2, to coordinate pathologic DSB
repair pathway choices in BRCA1-deficient cells. However, the direct upstream regulator(s) of 53BP1 function
in DNA repair and cellular response to PARPi and/or irradiation in BRCA-mutated cancers remain unknown. Our
recent studies have uncovered several 53BP1-binding proteins that regulates 53BP1 stability, modulates 53BP1
access to DSBs and functions in DNA repair through post-translational modification of 53BP1. Thus, our
overall hypothesis is that previously unrecognized 53BP1 repair pathways confer PARPi resistance that can
be targeted therapeutically in BRCA-mutated cancers. To address this hypothesis, we propose 3 specific aims:
Aim 1: Determine the mechanism underlying TIRR regulation of 53BP1 at DSBs. Aim 2: Determine the role(s)
of NUDT16 in 53BP1 regulation and in DNA repair pathways. Aim 3: Reveal the functional significance of
HDGFRP3 in damage-induced 53BP1 localization, and DNA repair. Knowledge such as this is essential in
identifying those patients with BRCA-mutated cancers who will most benefit from PARPi-based therapies.

## Key facts

- **NIH application ID:** 9815960
- **Project number:** 5R01CA222195-02
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** ZIHUA GONG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $366,954
- **Award type:** 5
- **Project period:** 2018-12-01 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9815960

## Citation

> US National Institutes of Health, RePORTER application 9815960, DNA Repair Pathways Choice to Regulate Therapeutic Resistance in Cancer Cells (5R01CA222195-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9815960. Licensed CC0.

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