# Investigating DNA polymerase O in replication stress and cancer therapy

> **NIH NIH R01** · SCRIPPS RESEARCH INSTITUTE, THE · 2024 · $607,250

## Abstract

Principal Investigator: Wu, Xiaohua
Project Summary
 Replication stress often occurs when DNA replication is disrupted, leading to DNA double-strand
break (DSB) formation. Replication stress can also be triggered by oncogene expression and is
associated with tumor development. Notably, replication stress creates vulnerabilities in cancer cells that
can be exploited for cancer treatment. Nevertheless, our understanding of the detailed DNA repair
mechanisms upon fork breakage due to replication stress, as well as our capacity to effectively target the
associated vulnerabilities for cancer treatment, remains limited.
 DNA polymerase θ (POLQ) is a specialized DNA polymerase critical for DSB repair, and
compromised POLQ function leads to genomic instability and radiation sensitivity. Substantial evidence
suggests that POLQ plays an important role in microhomology-mediated end joining (MMEJ). Given the
prevalence of microhomologies at cancer breakpoints, POLQ-mediated MMEJ is thought to be involved
in promoting genome instability associated with cancer, but the precise underlying mechanism remains
unclear. In this study, we discovered a unique role of POLQ in repair of DSBs linked to fork breakage,
revealing a new mechanism that requires POLQ to cope with replication stress.
 Based on the role of POLQ in repair of damaged forks, we found that inhibiting POLQ leads to
cell death under replication stress, and this effect is significantly intensified when ATR is inhibited. We
propose that combined therapeutic strategy utilizing POLQ inhibitors and ATR inhibitors would
synergistically eradicate cancer cells experiencing high replication stress. Given the current proposed
use of POLQ inhibitors is primarily for treating BRCA-deficient tumors, this study will substantially
broaden the application of POLQ inhibitors.
 We hypothesize that the role of POLQ in repairing broken forks forms the basis for treating
replication-stressed cancer cells with POLQ inhibitors and ATR inhibitors, and propose to investigate the
mechanism behind POLQ-mediated MMEJ in repair of broken forks. We will examine how POLQ is
engaged to repair replication-associated DSBs and study the collaborative functions of POLQ-mediated
MMEJ and break-induced replication (BIR) in repairing broken forks. We will use cell-based assay and
xenograft mouse model to explore cancer therapeutic strategy of using POLQ inhibitors and ATR
inhibitors. This study will not only shed light on the role of POLQ-mediated MMEJ in coping with
replication stress, but will also lay the groundwork for potential cancer treatments by targeting cancer
vulnerabilities associated with replication stress. Since replication stress is highly associated with cancer,
this study will additionally bring insights into the DNA repair mechanisms that modulate genome integrity
during tumor development.

## Key facts

- **NIH application ID:** 10996851
- **Project number:** 1R01CA294646-01
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** Xiaohua Wu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $607,250
- **Award type:** 1
- **Project period:** 2024-09-01 → 2029-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10996851

## Citation

> US National Institutes of Health, RePORTER application 10996851, Investigating DNA polymerase O in replication stress and cancer therapy (1R01CA294646-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10996851. Licensed CC0.

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