# Supplement to Promote Diversity

> **NIH NIH R35** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $19,675

## Abstract

A. Parent Grant R35
Summary.
Numerous studies in human populations, human tissue, animal models and cell culture demonstrate that
environmental genotoxic and oxidative stress are associated with accelerated telomere shortening and
dysfunction. Telomeres at chromosome ends are essential for genome stability and sustained cell proliferation,
and dysfunctional telomeres contribute to degenerative diseases and carcinogenesis in humans. The goals of
this project are to advance exciting discoveries and highly innovative work from two NIEHS funded R01 awards
investigating the consequences of nucleobase damage and excision repair at telomeres. The overarching
hypothesis for this R35 proposal is that telomere shortening and dysfunction caused by environmental
genotoxic and oxidative stress, occurs via formation of specific base lesions and toxic repair intermediates that
directly interfere with telomere replication and maintenance. Working with collaborators we pioneered a highly
innovative chemoptogenetic tool that selectively induces DNA lesions at telomeres. This technology is
transformative because targeting well-defined base damage to telomeres allows us to unequivocally attribute
phenotypic changes and health outcomes to the induced telomere lesions, eliminating confounding effects of
damage elsewhere. We fully validated this system for the targeted formation of a common oxidative guanine
lesion at telomeres, and remarkably, we discovered that the chronic generation of this lesion induces profound
hallmarks of telomere dysfunction that mimic genetic loss of telomere shelterin proteins. This project will probe
and uncover the mechanisms of DNA lesion induced telomere loss and dysfunction. A major strategy is to
extend and modify this flexible technology in a phased approach for introducing base damage, toxic repair
intermediates, bulky monoadducts, and other lesion types. We will measure various cellular and telomeric
endpoints after lesion induction and will use candidate and unbiased approaches to identify proteins required
to protect telomeres against the various forms of environmentally relevant DNA damage. This
chemoptogenetic tool has been adapted for use in model organisms, and as the R35 evolves we will translate
what we learn in cell culture to experiments in transgenic zebrafish and mice. Using this system, we will
generate telomeric damage in key organs and cell types and will measure the impact on organ function and
health. This program will lead to significant advances in mechanistic understanding of how environmentally
relevant forms of telomeric DNA lesions impact telomere function, cellular function, and organism health.
Ultimately, knowledge gained from this program will be highly valuable for developing new strategies that 1)
preserve telomeres to ameliorate the effects of genotoxic and oxidative stress in healthy cells or conversely,
that 2) inhibit telomere maintenance in malignant cells to arrest proliferation.

## Key facts

- **NIH application ID:** 10937205
- **Project number:** 3R35ES030396-05S1
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Patricia L Opresko
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $19,675
- **Award type:** 3
- **Project period:** 2019-06-01 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10937205

## Citation

> US National Institutes of Health, RePORTER application 10937205, Supplement to Promote Diversity (3R35ES030396-05S1). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10937205. Licensed CC0.

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