# Regulation of DNA Excision Repair in Chromatin

> **NIH NIH R01** · WASHINGTON STATE UNIVERSITY · 2020 · $343,407

## Abstract

PROJECT SUMMARY
Maintenance of genomic integrity is fundamental to life. DNA damage occurs spontaneously and ubiquitously
from endogenous (e.g., reactive oxygen species) and environmental sources (e.g., ultraviolet (UV) light),
inflicting mutagenic and cytotoxic lesions upon the genome that drive the progression of cancer and aging.
Cellular excision repair (ER) pathways, including base excision repair (BER) and nucleotide excision repair
(NER), are a critical 'first line of defense' responsible for recognizing and removing DNA lesions.
 The overall objective of this proposal is to understand how ER pathways access DNA lesions that are
'buried' in different types of genomic chromatin. Previous studies have shown that histone post-translational
modifications (PTMs) and ATP-dependent chromatin remodelers (ACR) are important for ER of DNA lesions in
chromatin. However, it is not known how these chromatin remodeling activities and histone PTMs operate
during repair on the diverse spectrum of distinct chromatin types in eukaryotic cells. To address this question,
we have developed genome-wide methods to map the formation and repair of UV-induced cyclobutane
pyrimidine dimers (CPDs) and methyl methanesulfonate (MMS)-induced N-methylpurine (NMP) base lesions.
Our published study and preliminary data indicate that the CPD-seq and NMP-seq methods can be used to
map DNA lesions across the yeast and human genomes at single nucleotide resolution. To better understand
the genomic roles of ACRs in ER, we will use the CPD-seq and NMP-seq methods to measure repair in yeast
and human cells depleted of different classes of ACRs (Aim I). Histone acetylation is an important PTM
associated with DNA damage responses. Our preliminary data suggest that the Esa1/TIP60 histone
acetyltransferase (HAT) complex plays a novel role in ER. To test this hypothesis, we will characterize the
roles of Esa1/TIP60 and other HATs in regulating ER in both yeast and human cells (Aim II). Our preliminary
data indicate that histone acetylation activity in cell-free repair extracts is important for repair of base lesions
occluded in nucleosomes. These findings provide the foundation of Aim III, which will identify histone PTMs
associated with BER, and characterize their functional role in BER of nucleosomes. Finally, we will investigate
the detailed molecular mechanisms by which histone acetylation and ACRs regulate the activity of purified
BER enzymes on mononucleosome and oligonucleosome substrates in vitro containing 'designed' DNA base
lesions (Aim IV).
 This proposal is an ongoing investigation of the effects of DNA packaging in chromatin on the two major
ER pathways (NER and BER) found in cells. As all eukaryotes, including humans, must deal with this
`packaging paradox' for surveillance of the genome, results from these studies are relevant to the broad
spectrum of cancer etiology, prevention and treatment.

## Key facts

- **NIH application ID:** 9972943
- **Project number:** 5R01ES028698-03
- **Recipient organization:** WASHINGTON STATE UNIVERSITY
- **Principal Investigator:** Michael J Smerdon
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $343,407
- **Award type:** 5
- **Project period:** 2018-08-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9972943

## Citation

> US National Institutes of Health, RePORTER application 9972943, Regulation of DNA Excision Repair in Chromatin (5R01ES028698-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9972943. Licensed CC0.

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