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

> **NIH NIH P20** · UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR · 2022 · $189,934

## 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:** 10455523
- **Project number:** 5P20GM103639-10
- **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:** 2022
- **Award amount:** $189,934
- **Award type:** 5
- **Project period:** 2012-09-05 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10455523

## Citation

> US National Institutes of Health, RePORTER application 10455523, Examining the role of XRN2 in radio and chemo-resistance (5P20GM103639-10). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10455523. Licensed CC0.

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