# Polymerase theta, genome instability, and cancer

> **NIH NIH P01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2020 · $1,856,436

## Abstract

PROJECT SUMMARY/DESCRIPTION
Polymerase theta (Pol q, gene name Polq) is essential in many hereditary breast cancers, yet loss of Pol q is
well tolerated in most normal cells. As a consequence, there has been much excitement in the development of
targeted inhibitors of Pol q for cancer therapy. However, we know little about the biological role and
mechanism of action for this large, multi-domain factor. It has thus not been possible to reconcile the disparate,
apparently context-dependent impacts of Pol q loss on mutation, chromosome aberration, and cell survival,
and the safe, effective targeting of Pol q for therapy has been largely frustrated.
In overall Aim 1, the mechanism by which full-length Pol q and Pol q domains contribute to repair will be
characterized by parallel analysis using the biochemical, structural, genetic and biophysical imaging
approaches available to our program. Full pathway reconstitution and visualization is a goal. In Overall Aim 2
we will investigate the cellular contexts that normally engage Pol q. In Overall Aim 3 we will integrate insights
gained from these other Aims to develop rationales for safer, effective targeting of Pol q in cancer therapy.
The research work will be highly coordinated within the Program Project in a framework with three Core
facilities. Substrates, proteins, and experiments will be designed with all Projects and constantly monitored with
feedback via Administrative Core A. Protein purification will be supported by Core B, and cell line construction
by Core C.
The scientific project leaders have complementary expertise: Drs. Dale Ramsden (molecular biology; Project
1), Gaorav Gupta (cancer cell biology; Project 1), Richard Wood (biochemistry, Project 2) Sylvie Doublié
(structural biology and mechanism; Project 3), and Eli Rothenberg (biophysics; Project 4). This ensemble of
complementary expertise fosters cross-fertilization of ideas beneficial to the whole team, and makes work
possible that can only be accomplished by a Program Project grant. This team also already has a long track
record of productive collaboration, and within this program project will work effectively and synergistically to
accomplish the Program’s goals. The results obtained by this Program Project will provide a fundamental
advance in the understanding of the molecular mechanisms underpinning TMEJ, and will pave the way for the
design of novel cancer therapy via Pol θ inhibition.

## Key facts

- **NIH application ID:** 9934670
- **Project number:** 1P01CA247773-01
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** DALE A RAMSDEN
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,856,436
- **Award type:** 1
- **Project period:** 2020-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9934670

## Citation

> US National Institutes of Health, RePORTER application 9934670, Polymerase theta, genome instability, and cancer (1P01CA247773-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9934670. Licensed CC0.

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