# Cellular requirements for Pol theta function

> **NIH NIH P01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2020 · $331,927

## Abstract

PROJECT SUMMARY
This project will investigate mammalian DNA polymerase θ (Pol θ), the defining enzyme for repair of DNA
double-strand breaks by polymerase theta-mediated end joining (TMEJ). This is Project 1 (“Cellular
requirements for Pol θ”) which is part of a Program Project titled, “Polymerase theta, genome instability, and
cancer”.
TMEJ mechanism and biological role is not well understood. Importantly, loss of Pol θ is tolerated in normal
cells but is lethal in many cancers, making it an attractive target for cancer therapy. Unfortunately, the major
knowledge gaps in both the mechanism of action and biological role for Pol θ have undercut the development
of safe, effective targeting strategies.
Project 1 will identify requirements for Pol θ function by leveraging existing specialized cellular assays and a
robust platform for identifying genetic interactions. We will additionally develop new methods to probe the
different roles of Pol θ in cellular repair.
This project aims to fill several major gaps in knowledge:
In Aim 1 “We will identify requirements for cellular TMEJ”. We will use cell lines defective in specific Pol
q activities and other factors linked to TMEJ, and assess the impact of these defects on cellular TMEJ.
In Aim 2 “We will determine cellular contexts that engage TMEJ”. We will assess the extent to which blocks to
late steps in another repair pathway engage TMEJ (2A). We will also employ high throughput sequencing to
investigate the impact of Pol θ loss on genomic scars caused by a chemotherapeutic agent (2B).
In Aim 3 “We will employ a genetic screen to identify new mediators of TMEJ”. We will identify a set of genes in
the same pathway as Pol θ, by finding those genes that when mutated are lethal in a panel of cells defective in
other repair pathways that renders them acutely dependent on TMEJ for survival.
The research work will be highly coordinated within the Program Project with the other three Projects and the
three Cores. Our combined diverse approaches include molecular biology, biochemistry, structural biology, and
biophysics. We will employ mutants and initiate experiments based on results shared with projects 2, 3, and 4,
which will be constantly monitored with feedback via Core A. Protein purification will be supported by Core B,
and cell line construction by Core C.

## Key facts

- **NIH application ID:** 9934671
- **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:** $331,927
- **Award type:** 1
- **Project period:** 2020-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9934671

## Citation

> US National Institutes of Health, RePORTER application 9934671, Cellular requirements for Pol theta function (1P01CA247773-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9934671. Licensed CC0.

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