# OXIDATIVE STRESS AND BASE MODIFICATIONS IN REGULATORY DNA

> **NIH NIH R01** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2020 · $305,000

## Abstract

ABSTRACT
Reactive oxygen species (ROS) with the potential to modify genomic and mitochondrial DNA are formed
from exposure to radiation, environmental toxins, and endogenous chemistries resulting from
inflammation, allergies, injury and metabolism. Oxidative stress leads to myriad effects on the cell,
notably changes in gene expression and mutagenesis, and ultimately contributes to numerous age-
related diseases including cancer, neurological disorders, diabetes and others. Recent work in this
laboratory has shown that the common guanine oxidation product 8-oxo-7,8-dihydroguanine (OG) is not
only a pre-mutagenic lesion, but also a base modification that impacts gene expression when present in
potential G-quadruplex-forming sequences of regulatory regions of the genome. This epigenetic-like
DNA modification is proposed to be written by chromatin remodeling in addition to exposure to ROS,
while it is read and erased by the base excision repair (BER) pathway, including OGG1 and APE1,
critical members of BER. The specific aims of this project will first augment recent results toward whole-
genome sequencing of DNA for OG at single-nucleotide resolution via “OG-Seq” and related methods for
other modifications read by BER. The approach uses a novel chemical ligation strategy that is shown to
be superior to OG antibodies in providing unbiased pull-down of OG-containing fragments for PCR
amplification and next-generation sequencing. The sequencing methods will be applied in Aim 2 to
address the hypothesis that base modifications resulting from oxidative stress are non-uniformly
distributed in the genome, that G-quadruplex sequences are hotspots for oxidation, and that they
subsequently impact gene induction. Both cancerous and noncancerous cell lines will be studied using
various types of oxidative stress that mimic, for example, the inflammatory response or heme overload.
The impact of chromatin remodeler LSD1 and chromatin opening via HDAC inhibitors will be examined in
Aim 3. The overall outcome will be a deeper understanding of the relationship between oxidative stress
and disease by defining where and when these epigenetic-like modifications occur in DNA.

## Key facts

- **NIH application ID:** 9922326
- **Project number:** 5R01GM129267-03
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Cynthia J Burrows
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $305,000
- **Award type:** 5
- **Project period:** 2018-08-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9922326

## Citation

> US National Institutes of Health, RePORTER application 9922326, OXIDATIVE STRESS AND BASE MODIFICATIONS IN REGULATORY DNA (5R01GM129267-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9922326. Licensed CC0.

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