# Examining the role of XRN2 in radio and chemo-resistance

> **NIH NIH P20** · UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR · 2020 · $216,226

## Abstract

Project Summary
Acquired or initial resistance is a major obstacle in the treatment of patients with cancer. One mechanism of
treatment resistance in tumors is the change of DNA repair pathways, especially the pathways that repair
double strand breaks (DSBs). We have gathered data implicating the transcription termination factor XRN2 in
the response to and repair of DSBs. XRN2 is a 5'-3' RNA endonuclease that degrades RNA and resolves R-
loops during transcription. We observed that loss of XRN2 leads to increased DSB formation, replication stress
and R-loop formation. We also found that cells lacking XRN2 displayed increased sensitivity to PARP1
inhibition and exposure to ionizing radiation (IR). Loss of XRN2 led to a defect in the non-homologous end-
joining pathway of DSB repair, which may be a contributing factor to IR sensitivity. However, we do not know
the mechanistic role of XRN2 in NHEJ DSB repair, which will be studied in this project. Although the
mechanism by which XRN2 promotes cell death upon PARP1 inhibition is unresolved, preliminary evidence
suggests a role for XRN2 in the homologous recombination pathway of DNA repair, which will also be
investigated in this project. Since IR exposure and PARP1 inhibitors are both used clinically as treatments for
patients with tumors, especially glioblastoma multiforme, we will also determine whether loss of XRN2 can be
part of respective combination therapies to effectively curtail tumor growth in vivo. The overarching goal of this
proposal is to study how DNA repair pathways can be manipulated to enhance cancer radio- and
chemotherapies. Results from our investigation will provide novel insights into the roles of XRN2 in DNA repair
pathways with potential translational impact.

## Key facts

- **NIH application ID:** 10017281
- **Project number:** 5P20GM103639-08
- **Recipient organization:** UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
- **Principal Investigator:** Julio Cesar Morales
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $216,226
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10017281

## Citation

> US National Institutes of Health, RePORTER application 10017281, Examining the role of XRN2 in radio and chemo-resistance (5P20GM103639-08). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10017281. Licensed CC0.

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