# Unraveling DNA Polymerase Double-Strand Break Repair Strategies in Cancer

> **NIH NIH P20** · UNIV OF ARKANSAS FOR MED SCIS · 2024 · $284,335

## Abstract

Summary for Project 1 led by Research Project Leader Joonas Jamsen, PhD
 Environmental agents, endogenous cellular processes, and many cancer therapies induce accumulation of
reactive oxygen species (ROS) that lead to oxidative DNA damage and chromosomal double-strand breaks
(DSBs). DSBs are hazardous and if repaired erroneously or left unrepaired lead to cancer and disease. DSB
repair pathways counter these breaks, yet little is currently known about the molecular details and structural
transactions underlying the strategies and efficiency of mutation-prone or mutation-free repair that promote
adverse human health outcomes. The long-term goal of our research program is to uncover fundamental
mechanisms that enable DSB repair within multiprotein repair complexes. As part of the Center for Molecular
Interactions in Cancer (CMIC), this COBRE Research Project will uncover strategies of DSB repair that are
relevant to breast, ovarian, and other cancer types. We will test the central hypothesis that DNA polymerases
(pols) λ and θ coordinate an alternative microhomology-mediated end joining (MMEJ) pathway, contributing to
poly (ADP-ribose) polymerase inhibitor (PARPi) resistance in homologous recombination (HR)-deficient cancers.
To test this hypothesis, Aim 1 will employ time-resolved X-ray crystallography and cryo-electron microscopy
(cryo-EM) alongside biochemical and biophysical techniques to study the molecular features of pol λ and pol θ
activity during MMEJ. Aim 2 will study cellular mechanisms of pol λ-mediated DSB repair and the impact on
PARP inhibitor resistance. Aim 3 will develop small-molecule inhibitors to modulate DNA pols involved in DSB
repair. This cutting-edge approach also will yield fundamental discoveries into DNA repair mechanisms by
employing the state-of-the-art research environment and resources available in the COBRE-supported Structural
Biology and Biomolecular Interactions Cores. Completion of the research project will enable me to develop new
approaches for my research program. Innovative models of DSB repair will be pursued using advanced
structural, biophysical and molecular biology techniques. Our work is significant because it will provide new
insights into how pol-mediated reactions contribute to the repair of DNA damage known to impact cancer
progression and resistance to therapy. Studying DNA polymerases involved in DSB repair will provide insight
into how these reactions could be modulated to provide therapeutic approaches to impact cancer and disease.

## Key facts

- **NIH application ID:** 10769965
- **Project number:** 1P20GM152281-01
- **Recipient organization:** UNIV OF ARKANSAS FOR MED SCIS
- **Principal Investigator:** JOONAS JAMSEN
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $284,335
- **Award type:** 1
- **Project period:** 2024-03-05 → 2028-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10769965

## Citation

> US National Institutes of Health, RePORTER application 10769965, Unraveling DNA Polymerase Double-Strand Break Repair Strategies in Cancer (1P20GM152281-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10769965. Licensed CC0.

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