# Mechanistic Characterization of the First Steps of Human DNA Break Repair

> **NIH NIH R01** · UNIVERSITY OF TEXAS AT AUSTIN · 2020 · $299,268

## Abstract

Project Summary
Our genome encodes critical information that is required for the healthy function of every cell, tissue, and
organ. However, genomic DNA is continuously accumulating toxic damage that arises during normal cellular
processes, or is caused by environmental conditions such as sunlight and chemical carcinogens. Double-
stranded DNA breaks (DSBs) are the most dangerous lesions. DSBs occur when both strands of the DNA
double helix are broken in close proximity to each other, fragmenting the chromosome into two distinct pieces.
If unrepaired, even a single DSB can initiate cellular dysfunction, malignant transformation, and tumor growth.
Our cells can repair DSBs via two distinct pathways: error-prone non-homologous end joining or high-fidelity
homologous recombination. Remarkably, the primary molecular steps that determine the DNA repair pathway
are still not completely known. Thus, there is a critical need to understand how healthy cells repair their
fragmented DNA and how disruptions in these processes can lead to cancer.
 Our long-term goal is to understand how specialized DNA repair proteins serve as the molecular
caretakers of the genome. To achieve this goal, we pioneered a unique in vitro microscopy technique that can
image multiple enzymes and record their biochemical activities as they repair DNA in real time. Using this
technique, the Aims in this proposal will investigate how a group of human enzymes coordinate the first steps
of DSB repair. First, we will determine how the Mre11/Rad50/Nbs1 (MRN) complex acts as the molecular
sensor for DSBs in the context of chromatin. Second, we will investigate how MRN recruits additional enzymes
to the DSB, and how these enzymes process a nucleosome-coated DNA track. Third, we will determine how
MRN directs repair towards the homologous recombination pathway. In sum, our studies will elucidate the first
critical steps of DSB repair and answer the long-standing question of how these enzymes biochemically define
the DSB repair pathway. Ultimately, this knowledge will be required for developing new diagnostics and
therapeutics that specifically target cancer cells that have lost the ability to correctly repair their genomes.

## Key facts

- **NIH application ID:** 10001540
- **Project number:** 5R01GM120554-05
- **Recipient organization:** UNIVERSITY OF TEXAS AT AUSTIN
- **Principal Investigator:** ILYA J FINKELSTEIN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $299,268
- **Award type:** 5
- **Project period:** 2016-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10001540

## Citation

> US National Institutes of Health, RePORTER application 10001540, Mechanistic Characterization of the First Steps of Human DNA Break Repair (5R01GM120554-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10001540. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*