# Mechanistic insight into oxidative stress-mediated genome instability

> **NIH NIH R35** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2022 · $380,270

## Abstract

Mechanistic insight into oxidative stress-mediated genome instability
Summary:
Genome instability is characterized by genetic alterations ranging from DNA base mutations to chromosome
rearrangements that are drivers of many inherited human diseases, various types of cancer and premature
ageing. Chromosome instability, especially, results from inaccurate chromosomal segregation caused by
telomere and centromere dysfunction. Numerous epidemiologic studies have highlighted the central role of
oxidative stress exposures in the occurrence of telomere and centromere dysfunction. Critically, however, the
mechanisms underlying the dysfunction are not clearly understood. Oxidative stress results from an imbalance
between the production of reactive oxygen species and cellular antioxidant defenses. It arises from endogenous
sources as well as from environmental sources (mitochondria metabolism, UV light, air pollution, cigarette
smoke). Its ubiquity highlights the importance of properly understanding its impacts on human health. A major
impact of oxidative stress is the induction of oxidative DNA damage that are repaired by the base excision repair
(BER) pathway in which poly(ADP-ribose) polymerases (PARPs) are major actors. PARP1 and PARP2 are
responsible for the poly(ADP-ribosyl)ation, a post-translational modification of proteins that modulates the
recruitment and interactions of their protein targets. The goals of this proposal are to (i) uncover the mechanisms
of oxidative stress-mediated genome instability with a focus on its impact on telomeres and centromeres, two
genomic loci crucial for genome stability and (ii) decipher the contribution of PARP enzymes in the protection of
telomeric and centromeric DNA upon oxidative DNA damage. More specifically, we aim to evaluate the impact
of chronic induction of oxidized DNA bases and BER single strand break intermediates on centromere and
telomere integrity. We will also identify and assess the impact of poly(ADP-ribosyl)ation on centromeric and
telomeric protein targets. To this end, we will leverage a unique and innovative chemoptogenetic tool that induces
oxidative DNA damage locally at telomeres and at centromeres without impacting the rest of the genome. This
will allow us to unequivocally link phenotypic changes and PARP dependent mechanisms to the telomeric or
centromeric lesions. These projects will fill a long-standing gap of knowledge on how poly(ADP-ribosyl)ation
orchestrates DNA repair at two crucial regions of the genome. They will also shed light on how oxidative stress,
a ubiquitous factor of genome instability, can drive numerous human diseases. Ultimately, our work will
contribute to the development of novel therapeutic strategies targeting specific regions of the genome and inform
the rational design and use of the PARP inhibitors already widely used in cancer treatments.

## Key facts

- **NIH application ID:** 10456916
- **Project number:** 5R35GM142982-03
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Elise Fouquerel
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $380,270
- **Award type:** 5
- **Project period:** 2021-08-01 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10456916

## Citation

> US National Institutes of Health, RePORTER application 10456916, Mechanistic insight into oxidative stress-mediated genome instability (5R35GM142982-03). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10456916. Licensed CC0.

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