# Regulation of Initial Steps of Chromosomal Breaks Repair

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2020 · $317,000

## Abstract

Chromosomal breaks are repaired by high fidelity homologous recombination (HR) or by low fidelity
nonhomologous end joining (NHEJ). Both pathways are essential in maintaining genome stability as even a
minor deficiency in DSB repair pathways can result in cancer or other severe diseases. The initial processing
of DNA double strand breaks (DSBs) to single strands, a process termed DNA end resection, is the critical first
step of HR needed for loading of damage response and repair proteins. Resection is tightly controlled in the
cell cycle and determines the usage of high fidelity HR and lower fidelity NHEJ for the repair of DSBs. As
resection controls the fidelity of DSB repair it is imperative to define the mechanisms that execute or regulate
resection. In yeast and human cells, the MRN (Mre11-Rad50-Nbs1) complex initiates resection, whereas Exo1
or Sgs1-Dna2 mediates extensive resection. The objective of this proposal is to define how the initial and two
long-range resection pathways are controlled. We will establish new assays to follow DSB end resection in
fission yeast. The fission yeast system provides a number of features well conserved with human. In the first
aim, we will use newly designed assays in fission yeast to define a new function of Rad52 protein in controlling
extensive resection, to elucidate the role of noncoding RNA in resection and recombination, and to compare
resection within dense heterochromatin and loose euchromatin. In the second aim we will investigate how
different types of stress (proteotoxic, osmotic, mitochondrial) affect DSB end resection and the fidelity of DSB
repair. Crosstalk between stress response pathways and DSB repair enzymes will be investigated. A
combination of genetic, molecular biology and biochemical approaches will be used to define the precise
mechanism of resection and resection regulation. Our findings are relevant to human disease, cancer, drug
resistance and genome evolution, and will provide a framework for future investigations of the initial steps of
homologous recombination and the relationship between stress and the fidelity of DNA repair in other
organisms including human.

## Key facts

- **NIH application ID:** 9837337
- **Project number:** 5R01GM125650-03
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Grzegorz A Ira
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $317,000
- **Award type:** 5
- **Project period:** 2018-01-01 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9837337

## Citation

> US National Institutes of Health, RePORTER application 9837337, Regulation of Initial Steps of Chromosomal Breaks Repair (5R01GM125650-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9837337. Licensed CC0.

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