# Understanding and Targeting the R-Loop-Mediated DNA Damage Response at Telomeres

> **NIH NIH R01** · DUKE UNIVERSITY · 2024 · $349,874

## Abstract

Project Summary
Oxidative DNA damage is frequently generated by radiation, chemicals, and endogenous oxygen radicals,
contributing to genomic instability during both aging and tumorigenesis. Oxidative damage at telomeres can
lead to telomere loss or attrition, which triggers cellular senescence and limits the lifespan of dividing cells.
While it is clear that oxygen radicals can inflict multiple types of DNA lesions, how these lesions are repaired at
telomeres is still largely unknown. By inducibly and locally generating reactive oxygen species (ROS) at
telomeres, we discovered a novel DNA repair pathway critical for the protection of cells against telomeric
oxidative damage. This pathway is activated by ROS-induced R-loops, and is mediated by break-induced
replication (BIR), a process that “jumpstarts” DNA synthesis at collapsed replication forks. In parallel with our
studies on the oxidative damage response at telomeres, we also investigated how cancer cells maintain
telomeres to bypass senescence. In particular, we have molecularly dissected the alternative lengthening of
telomere (ALT) pathway, which is used by ~10-15% of human cancers to extend telomeres. Interestingly, we
found that ALT is also an R-loop-triggered and BIR-mediated repair pathway. The unexpected similarities
between the repair pathway dealing with telomeric oxidative damage and the ALT pathway lead us to
hypothesize that these telomere repair pathways are mechanistically linked. Furthermore, cancer cells hijack
the R-loop and BIR-mediated repair pathway to extend telomeres and bypass senescence. In Aim 1, we will
systematically delineate the R-loop and BIR-mediated pathway that repairs telomeric oxidative damage, and
investigate if this pathway contributes to ALT activation in cancer cells. In Aim 2, we will develop strategies to
exploit the cellular dependency on the R-loop and BIR-mediated ALT pathway, which may allow us to
selectively kill ALT+ cancer cells and aged cells harboring high telomeric oxidative damage. Our studies may
establish a new link between cellular aging and tumorigenesis, and provide new opportunities to eliminate
cancer cells by targeting a hijacked DNA repair pathway. These studies may have transformative impacts at
the interface between aging and cancer research, opening a new avenue to future preclinical and clinical
investigations.

## Key facts

- **NIH application ID:** 10905013
- **Project number:** 5R01CA282939-02
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Li Lan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $349,874
- **Award type:** 5
- **Project period:** 2023-08-10 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10905013

## Citation

> US National Institutes of Health, RePORTER application 10905013, Understanding and Targeting the R-Loop-Mediated DNA Damage Response at Telomeres (5R01CA282939-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10905013. Licensed CC0.

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