# Base Excision Repair: Mechanisms of DNA Damage Access and Repair in Chromatin

> **NIH NIH F32** · UNIVERSITY OF KANSAS MEDICAL CENTER · 2021 · $65,994

## Abstract

Project Summary/Abstract
Despite the packaging of eukaryotic DNA into chromatin through repeating units known as the nucleosomes, it
is constantly damaged via reactive oxygen species (ROS). 8oxo-guanine (8oxoG) is a common form of DNA
damage resulting from the oxidation of guanine. If not repaired, 8oxoG is mutagenic, causing G to T transversion
mutations that can initiate and promote genomic instability and ultimately human disease, such as cancer. The
cells primary defense against 8oxoG is the base excision repair (BER) pathway. Two BER proteins involved in
the initial recognition and removal of 8oxoG are 8oxoG DNA glycosylase 1 (OGG1) and apurinic/apyrimidinic
endonuclease 1 (APE1). OGG1 and APE1 must find, access, and repair genomic DNA damage in complex
chromatin structures, where the DNA is packaged into nucleosomes. Nucleosomes present a significant barrier
to the activities of OGG1 and APE1, which is alleviated when the damage is positioned near the nucleosome
entry/exit site. Importantly, the entry/exit site is known to be highly dynamic and undergoes spontaneous and
reversible unwrapping and rewrapping of the nucleosomal DNA, thus providing access to the DNA for protein
binding. Nucleosome dynamics are further regulated through post-translational modifications (PTMs) to the
nucleosome, which allow the cell to fine-tune access to the DNA under different cellular conditions. Despite it
being critical to understanding how oxidative DNA damage is repaired within chromatin, mechanistic insight into
how OGG1 and APE1 accomplish this remains elusive. To this end, the overarching goal of this proposal is to
reveal how OGG1 and APE1 access and process DNA damage in a chromatin environment. The proposal is
based on the hypothesize that nucleosomal DNA dynamics and histone PTMs are key regulatory determinants
for OGG1 and APE1 to access and process DNA damage. To test this hypothesis, three specific aims have been
developed that integrate powerful and complementary biophysical techniques to provide extensive insight into
DNA damage and repair in chromatin by OGG1 and APE1. Aim 1 will determine how nucleosomal DNA dynamics
regulate OGG1 and APE1 access to DNA damage using single-molecule fluorescence microscopy. Aim 2 will
determine how histone PTMs further regulate DNA damage access and processing by OGG1 and APE1 using
single-molecule fluorescence microscopy and DNA enzymology. Finally, Aim 3 will elucidate the molecular basis
for OGG1 and APE1 interactions with damaged nucleosomes using cryo-electron microscopy. Completion of
these aims will provide a comprehensive understanding of how DNA damage is repaired in the context of
chromatin, while providing training in state-of-the-art biophysical techniques. This innovative proposal will be
carried out at the University of Kansas Medical Center under the guidance of an excellent mentorship team. In
addition to the research component, the proposal incorporates a training plan that emphasizes career a...

## Key facts

- **NIH application ID:** 10154528
- **Project number:** 1F32GM140718-01
- **Recipient organization:** UNIVERSITY OF KANSAS MEDICAL CENTER
- **Principal Investigator:** Tyler Mathew Weaver
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $65,994
- **Award type:** 1
- **Project period:** 2020-12-16 → 2022-12-15

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10154528

## Citation

> US National Institutes of Health, RePORTER application 10154528, Base Excision Repair: Mechanisms of DNA Damage Access and Repair in Chromatin (1F32GM140718-01). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10154528. Licensed CC0.

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