# Understanding the impact of DNA ADP-ribosylation on telomere function in cancer cells

> **NIH NIH F30** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $53,974

## Abstract

RESEARCH SUMMARY/ABSTRACT
Cancer cells must employ a telomere lengthening mechanism to ensure replicative immortality. 15% of cancer
cells utilize Alternative Lengthening of Telomeres (ALT), a homologous recombination-mediated pathway.
Perturbation of the ALT mechanism can be achieved by disruption of enzymes involved in ADP-ribosylation, a
post-translational modification that regulates several cellular processes including transcription, metabolism, and
DNA repair. The pharmacological inhibition of enzymes involved in ADP-ribosylation has proven to be of
immense biomedical value in cancer therapy. Over the last 30 years, studies have primarily built on intensive
investigation of ADP-ribosylation as a modification that is exclusively found on proteins. Yet, new evidence is
emerging that nucleic acids, DNA and RNA, are direct and perhaps even the predominant sources of ADP-
ribosylation, especially in the aftermath of DNA damage. This paradigm shift has major implications for our
understanding of the physiological function of ADP-ribosylation in ALT. Thus, improving our knowledge of the
cellular targets and mechanisms of this new DNA modification will be vital for the development of enhanced
ADP-ribose-targeting therapeutics that achieve better clinical outcomes for ALT cancer patients.
 I found that telomeres, specialized structures at the ends of the chromosomes, are targets of the major
ADP-ribosylation enzymes; Poly ADP-ribose Polymerase (PARP1), Poly ADP-ribose Glycohydrolase (PARG),
and a newly identified factor known as Terminal ADP-ribose Hydrolase (TARG1). I uncovered that PARP1
coordinates the ADP-ribosylation of telomeric DNA sequences and that TARG1, acting in conjunction with
PARG, is responsible for the removal ADP-ribose from telomeric DNA. Furthermore, I show that the disruption
of TARG1 expression provokes replicative complications at ALT telomeres that may have catastrophic
consequences for cancer cell viability. In Aim 1, I will further assess the impact of DNA ADP-ribosylation and
defects in factors that regulate its removal on telomere function and ALT. In Aim 2, I will dissect the impact of
co-suppression of TARG1 and PARG, factors that regulate DNA ADP-ribosylation, on cancer cell viability, and
the contribution of telomere dysfunction therein. This study will provide new and crucial knowledge on the novel
and fundamental role of ADP-ribosylation in ALT. By exploring the impact that its deregulation has on ALT, this
study will contribute new insights into how the deregulation of ADP-ribosylation contributes to cancer treatment.

## Key facts

- **NIH application ID:** 10893378
- **Project number:** 5F30CA278287-02
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Anne Wondisford
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $53,974
- **Award type:** 5
- **Project period:** 2023-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10893378

## Citation

> US National Institutes of Health, RePORTER application 10893378, Understanding the impact of DNA ADP-ribosylation on telomere function in cancer cells (5F30CA278287-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10893378. Licensed CC0.

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