# Does overexpression of DNA polymerase theta sensitize cancers to G-quadruplex binding drugs?

> **NIH NIH R21** · MICHIGAN STATE UNIVERSITY · 2020 · $202,275

## Abstract

Project Summary
My laboratory studies DNA double strand breaks (DSBs)1. Two primary pathways are utilized to repair DSBs2,
Homology directed repair (HDR) and classical non-homologous end joining (c-NHEJ)3. An alternative NHEJ
pathway (a-NHEJ) functions when c-NHEJ has been disabled4, and DNA polymerase theta (polQ) is central to
this pathway5. This was first shown by studying DSBs at G-quadruplexes6.
DNA repair factors function as tumor suppressors7, and defects in HDR or c-NHEJ promote genomic instability
and cancer8. Although polQ deficiency promotes genomic instability, lack of polQ does not promote cancer. In
fact, loss of polQ protects ATM deficient mice from thymic lymphoma9. Moreover, polQ is over-expressed in
numerous cancers [breast, stomach, lung, colon, lymphoid, skin] and overexpression is highly correlated with
poorer outcomes10-12. Thus, polQ actually shares some characteristics with tumor oncogenes.
It has been shown that the G-quadruplex binding drug, pyridostatin, induces DSBs13. We examined numerous
c-NHEJ defective cells and establish that all the core c-NHEJ components are essential for maximal cell survival
after pyridostatin exposure. In contrast (and to our surprise), polQ ablation markedly enhances cell survival after
pyridostatin exposure.
We suggest a model whereby pyridostatin and polQ become trapped at G-quadruplex structures
during replication causing replication fork collapse and DSBs. More importantly, these preliminary
data suggest that the many cancer types that overexpress polQ might be particularly sensitive to
drugs that target G-quadruplex structures and suggest an obvious synthetic lethal approach to
enhance therapeutics that target G-quadruplexes.

## Key facts

- **NIH application ID:** 9932937
- **Project number:** 5R21CA240875-02
- **Recipient organization:** MICHIGAN STATE UNIVERSITY
- **Principal Investigator:** Katheryn D Meek
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $202,275
- **Award type:** 5
- **Project period:** 2019-06-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9932937

## Citation

> US National Institutes of Health, RePORTER application 9932937, Does overexpression of DNA polymerase theta sensitize cancers to G-quadruplex binding drugs? (5R21CA240875-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9932937. Licensed CC0.

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