# Early events in double-strand break repair in local, genomic and metabolic contexts

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $330,756

## Abstract

Project Summary / Abstract
Chromosomal rearrangements have multiple impacts on human health in cancer, inherited genetic disease,
and normal tissue function. While less frequent than single-nucleotide changes, structural variants are
disproportionately impactful because they alter genome continuity and change many base pairs at once.
Rearrangements mainly arise through DNA double-strand breaks (DSBs) because they disrupt chromosomal
integrity. Over many years this project has engaged basic studies of the molecular mechanisms of DSB repair
and chromosomal mutagenesis conducted mainly in yeast, specifically nonhomologous end joining (NHEJ) and
how it and other repair pathways such as homologous recombination (HR) contribute to genome maintenance.
We will continue to exploit yeast to explore a set of critical contextual influences that determine the flux through
DSB repair toward variable outcomes, focusing on contexts for which a single-cell eukaryote is an ideal
experimental system. This project will specifically investigate some of the earliest events in DSB repair that
occur soon after recognition of the break and coincident with the commitment to a repair mechanism. At the
smallest scale, we will exploit novel single-base resolution resection and protein occupancy assays to explore
the impact of local sequence on DSB repair, in particular on specific protein functions in the initial stages of
DSB resection in vivo. At the genomic scale, we will follow up our recent findings to understand how nuclear
and functional properties of different DSB locations influence mutagenic outcome frequencies through DSB
movement. At the cellular scale, we will expand our focus to investigate the mechanisms by which metabolic
signaling in response to carbon source interacts with the DNA damage response and cell cycle, which our prior
work identifies as an important and underexplored aspect of DSB repair regulation. Results will provide novel
insights into how these cellular processes normally preserve the genome and how rearrangements result when
they are perturbed by environmental or genetic factors.

## Key facts

- **NIH application ID:** 10848327
- **Project number:** 5R01GM120767-17
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** THOMAS EDWARD WILSON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $330,756
- **Award type:** 5
- **Project period:** 2004-08-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10848327

## Citation

> US National Institutes of Health, RePORTER application 10848327, Early events in double-strand break repair in local, genomic and metabolic contexts (5R01GM120767-17). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10848327. Licensed CC0.

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