# The role of chromatin remodeling factors in DNA double strand break repair

> **NIH NIH R03** · OHIO STATE UNIVERSITY · 2021 · $170,000

## Abstract

7. PROJECT SUMMARY/ABSTRACT
Accurate DNA double strand break (DSB) repair is important to maintain chromosomal stability. In the absence
of DSB repair, translocations, deletions, duplications and inversions of chromosomal DNA may occur that can
drive tumorigenesis. Homologous recombination (HR) is the major mechanism for DSB repair and is highly
conserved across eukaryotes from yeast to human. HR is generally error-free because it copies any missing
information from an undamaged homologue or sister chromosome template. However, not all HR is error-free.
A number of conditions, that includes replication stress from spontaneous, chemical or physical DNA damage,
can activate error-prone recombination pathways that leads to intra-chromosomal deletions (ICDs) as well as
other chromosome rearrangements. The central HR gene RAD52 participates in both error-free and error-prone
repair. How RAD52 choses between these opposing pathways is poorly understood. It is our central hypothesis
that chromatin remodeling factors are responsible for guiding this choice.
Previous work utilizing a two-hybrid screen in the fission yeast Schizosaccharomyces pombe identified a physical
interaction between RAD52 with the histone acetyltransferase KAT5 and the histone chaperone HIRA. KAT5
(also known as TIP60 in humans; Mst1 in yeast) is required to target chromatin for remodeling as well as DNA
damage checkpoint activation. HIRA (Hip1 in yeast) functions in establishing centromeric chromatin, targeted
transcriptional repression and replication-independent histone assembly. Our preliminary data demonstrate that
KAT5 channels DSBs toward error-free repair while HIRA directs DSBs toward error-prone repair that results in
ICDs. The goal of this proposal is to understand how the physical interactions and chromatin remodeling
properties of KAT5 and HIRA impact the decision by RAD52 to function in error-free versus error-prone repair.
We propose two Specific Aims:
In Aim 1 we will perform comprehensive protein modeling to predict specific residues involved in the interactions
between KAT5, HIRA and RAD52. These residues will be altered and examined for repair pathway choice using
well-defined chromosomal recombination assays. In Aim 2 we will examine the effect of KAT5, HIRA and RAD52
mutations found in human tumors for their ability to influence error-free and/or error-prone repair pathway choice.
These studies will determine the role of chromatin remodeling in accurate DNA damage repair that is required
 to prevent genetic alterations that leads to cancer.

## Key facts

- **NIH application ID:** 10201222
- **Project number:** 1R03CA252498-01A1
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Renee Bouley
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $170,000
- **Award type:** 1
- **Project period:** 2021-05-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10201222

## Citation

> US National Institutes of Health, RePORTER application 10201222, The role of chromatin remodeling factors in DNA double strand break repair (1R03CA252498-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10201222. Licensed CC0.

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