# Elucidating factors that modulate mammalian DNA repair to improve genome editing

> **NIH NIH R35** · UNIVERSITY OF WISCONSIN-MADISON · 2024 · $388,750

## Abstract

Project Summary/Abstract
Genome editing is an exciting avenue for treating common and rare genetic diseases, and the advent of
CRISPR/Cas technologies has accelerated the development of this therapeutic option. These therapies rely on
cellular DNA repair machinery to install their edits, so changes in the balance between DNA repair pathways
result in different editing patterns. This dependency on endogenous DNA repair has led to considerable variability
in editing efficiency between cell types or even among targets in the same cell. Thus, a long-term goal of my
laboratory is to investigate factors that modify the efficacy of genome editing and to develop strategies that
address these shortcomings. Histone modifications play a role in many cellular processes, including
transcriptional regulation and DNA repair. Recent evidence found that histone modifications correlate with biases
for specific DNA repair pathways. However, given their role in multiple processes, interpreting the effects of
individual histone modifications has been challenging. I will dissect these effects to define the role of histone
modifications in the repair of double-strand breaks by innovating a platform that recruits histone modifiers to
thousands of break sites in parallel. This work will determine whether histone modifications influence DNA repair
and uncover properties of the target site that predict these effects. For genome editing to reach its therapeutic
potential, precise control of DNA repair is required. I will identify peptides from the human proteome that alter
the repair of double-strand breaks. To do this, I will adapt a peptide screening platform I developed to investigate
DNA repair. The peptides will reveal critical protein-protein interactions and other methods for altering DNA
repair. The completion of these projects will significantly advance our understanding of mammalian DNA repair
and has the potential to improve genome editing therapies.

## Key facts

- **NIH application ID:** 10897123
- **Project number:** 5R35GM150462-02
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Gaelen T Hess
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $388,750
- **Award type:** 5
- **Project period:** 2023-08-01 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10897123

## Citation

> US National Institutes of Health, RePORTER application 10897123, Elucidating factors that modulate mammalian DNA repair to improve genome editing (5R35GM150462-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10897123. Licensed CC0.

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