# DNA Polymerases in Nonhomologous End Joining

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2024 · $385,269

## Abstract

PROJECT SUMMARY
 Repair of chromosome breaks by Nonhomologous end joining (NHEJ) determines the
effectiveness of many cancer therapies, especially ionizing radiation. NHEJ is also essential for
assembly of antigen receptor genes (immunoglobulins and T cell receptors) required for
adaptive immunity. Here we propose to investigate the fundamental mechanism of this
pathway, with a focus on aspects relevant to the effectiveness of radiation therapy.
 We’ve previously shown repair by NHEJ is often initiated by Polymerases that add RNA to
the 3’ end of one strand of a chromosome break, which stimulates ligation of that strand. In
Aim1 we will investigate the next steps, repair of the complementary strand, and replacement of
RNA embedded in the initially repaired strand. Preliminary data argues the RNA embedded in
the first step of NHEJ is not always metabolized well, and thus may contribute to genome
instability.
 RNA incorporation also has a role in determining the choice of DSB repair pathway.
Synthesis initiated from a 11-15 nucleotide RNA primer at the 5’ ends of the DSB has been
shown to re-direct repair to the NHEJ pathway. This mechanism helps determine of the
effectiveness of therapies, including radiation therapy, that specifically target hereditary breast
cancers. However, our preliminary data indicates the RNA primer must be removed for NHEJ to
occur; in Aim 2 we will investigate a candidate mechanism for removal of the primer.
 Targeted inhibition of DNA repair pathways holds great promise as a means of improving the
effectiveness of radiation therapy. In Aim 3 we will systematically explore the consequences of
combined DNA pathway inhibition on genome stability. We will address the impact of separate
and combined inhibition of the two end joining pathways, and how pathway inhibition in both
cases differs from genetic deficiency, as well as the impact of impaired incorporation of RNA by
NHEJ polymerases.

## Key facts

- **NIH application ID:** 10820450
- **Project number:** 5R01CA097096-21
- **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:** 2024
- **Award amount:** $385,269
- **Award type:** 5
- **Project period:** 2003-07-01 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10820450

## Citation

> US National Institutes of Health, RePORTER application 10820450, DNA Polymerases in Nonhomologous End Joining (5R01CA097096-21). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10820450. Licensed CC0.

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