# Deciphering the mechanisms of PARP1 activity in telomere integrity

> **NIH NIH R00** · THOMAS JEFFERSON UNIVERSITY · 2020 · $248,999

## Abstract

Deciphering the mechanisms of PARP1 activity in telomere integrity
The goals of this project are to define poly(ADP-ribose) polymerase 1 (PARP1) roles in telomere preservation
under normal conditions and after environmental genotoxic exposure. My strong background in the PARP field
and my ongoing training in telomere biology, place me in a unique position to successfully complete this
project. In the long term, this project will lay the foundation for me to establish an independent research
program investigating roles for PARPs in genome stability and human health. Telomeres consist of TTAGGG
repeat arrays bound by the 6-member shelterin protein complex, and are lengthened by the reverse
transcriptase telomerase in stem cells and most cancer cells. Telomere attrition and dysfunction can arise
from exposure to various environmental agents and are associated with aging-related diseases and cancer.
Previous studies have implicated PARP1 in telomere maintenance, but the mechanisms are poorly
understood. PARP1 synthesizes poly(ADP-ribose) (PAR) and this activity is critical for genome maintenance
by facilitating DNA repair pathways and regulating DNA replication during replication stress. The central
hypothesis of this proposal is that PARP1 preserves telomere integrity by modulating the activities of the
telomere shelterin proteins and telomerase. In support of this, I demonstrated that shelterin proteins as well as
telomerase, bind to PAR. I also observed that PAR binding stimulates telomerase activity in vitro. Aim 1 will
define interactions between PARP1 and the various shelterin proteins under normal conditions and after
genotoxic insult, and the roles for these interactions in telomeric DNA repair. We will test for PARylation of
shelterin proteins, and will define their affinity for PAR. Oxidative and alkylating DNA damage will be induced
with H2O2 and MNNG respectively, and 8-oxoguanine will be locally induced at telomeres using an innovative
targeting system. We will follow PARP1 recruitment to telomeres after DNA damage, and will measure DNA
repair rates and telomere aberrations in PARP1 proficient and deficient cells. Aim 2 will examine PARP1 roles
in regulating telomerase. We will examine PAR binding to reported putative PAR binding motifs (PBMs) in the
hTERT subunit, and will examine the effect on telomerase activity by mutating these PBMs. We will monitor
telomere length alterations in cells expressing wild type and PBM mutant hTERT, and telomerase recruitment
to telomeres in PARP1 proficient and deficient cells. Aim 3 will test PARP1 roles in telomere preservation
upon replication stress induced with aphidicholin or G-quadruplex ligands. We will examine the recruitment of
PARP1 to telomeres, and replication progression at telomeres in PARP1 proficient and deficient cells using the
established single molecule analysis of replicated DNA (SMARD) assay. Completion of this project will uncover
new interactions and relationships between PARP1 ...

## Key facts

- **NIH application ID:** 9852308
- **Project number:** 5R00ES027028-04
- **Recipient organization:** THOMAS JEFFERSON UNIVERSITY
- **Principal Investigator:** Elise Fouquerel
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $248,999
- **Award type:** 5
- **Project period:** 2019-02-01 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9852308

## Citation

> US National Institutes of Health, RePORTER application 9852308, Deciphering the mechanisms of PARP1 activity in telomere integrity (5R00ES027028-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9852308. Licensed CC0.

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