# Polymerase Theta Mediated End Joining: Mechanism and Essential Functions in Repair of Chromosome Breaks

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2020 · $465,647

## Abstract

Project Summary/Abstract
Repair of chromosome breaks is essential for normal cell growth, protects against and promotes cancer-
causing genome rearrangements, and determines the effectiveness of many cancer therapies. In recent work
our group implicated DNA polymerase theta in a pathway for repairing chromosome breaks that favors short
sequence repeats (microhomologies). In Aim 1 we will outline the steps in Theta mediated end joining (TMEJ)
– its molecular mechanism - and determine the requirements for each step. We will employ a combination of
defined extrachromosomal substrates, analysis of repair of a targeted chromosomal break, and quantitative
assessments of effects on cell growth and viability when cells are defective in various steps. In aim 2 we will
clarify the relationship between Theta mediated end joining and another pathway for repair of chromosome
breaks, homologous recombination. Specifically, we will investigate how defects in BRCA1 and 53BP1, genes
involved in early steps common to both TMEJ and homologous recombination, impact the choice between
repair by these two pathways. We will then also address the importance of the TMEJ pathway as an alternative
to Holliday junction resolution, a late step specific to the homologous recombination pathway. We will exploit
assays for chromosomal end structure and repair, as well as genetic tools available through use of the
invertebrate model D. melanogaster. In aim 3 we will systematically look for novel genetic interactions with
Polymerase theta that are important for both general cell viability and cellular resistance to ionizing radiation.
We will employ a lentiviral vector based CRISPR library that was curated to focus on a subset of 310 genes
relevant to the DNA damage response. The proposed experiments will speak to how an important but as-yet
poorly understood pathway works, and especially when and why it represents the best solution to various
problems encountered in the course of repair of chromosome breaks.

## Key facts

- **NIH application ID:** 9926844
- **Project number:** 5R01CA222092-03
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** DALE A RAMSDEN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $465,647
- **Award type:** 5
- **Project period:** 2018-06-15 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9926844

## Citation

> US National Institutes of Health, RePORTER application 9926844, Polymerase Theta Mediated End Joining: Mechanism and Essential Functions in Repair of Chromosome Breaks (5R01CA222092-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9926844. Licensed CC0.

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