# Probing the mechanisms that control DNA repair pathway choice.

> **NIH NIH R35** · JOHNS HOPKINS UNIVERSITY · 2024 · $409,375

## Abstract

Project Summary
Genome maintenance is essential for accurate cell and tissue function. The underlying repair needs differ based
on cell type and differentiation stage. Deciphering the mechanism that govern DNA repair is of significant interest
to public health, as defects in genome maintenance can drive diseases from degenerative disorders to cancer.
Although a multitude of DNA repair factors have been identified to date, there remains a profound lack of
understanding regarding the mechanisms that ensure appropriate repair factor engagement. The repair of DNA
damage is tightly coupled to the nuclear environment in which it occurs. We hypothesize that dynamic changes
in two fundamental regulators of mammalian DNA transactions, chromatin and nuclear RNAs, are essential to
control DNA repair outcomes across distinct physiological contexts. Our long-term vision is to understand, and
manipulate, how cell state transitions, both during differentiation and in disease, exploit these mechanisms to
adjust to altered genome maintenance needs. We will pursue this goal through two complementary projects,
combining our expertise in state-of the art genomics approaches and mouse genetics with innovative cell-based
tools to study DNA repair. In the first project, we will investigate how macroH2A1, the third-most common histone
H2A variant, links chromatin plasticity to DNA repair pathway choice. MacroH2A1 is alternatively spliced during
differentiation as well as in cancer, and we and others have identified distinct DNA repair functions associated
with each splice isoform, affecting both double- and single-stranded DNA damage. We propose that, by changing
macroH2A1 isoform expression, cells have the capacity to optimize repair outcomes in response to a variety of
DNA lesions. We will use isoform-specific knockout mouse models and a screen for macroH2A1 splicing effectors
to uncover how macroH2A1 isoform plasticity affects genome maintenance and dissect its physiological
consequences. In the second project, we will investigate the contribution of RNA and its modifications to DNA
damage control. RNA is required for the recruitment of certain repair factors, and RNA modifications have been
linked to DNA repair. However, we know little about the underlying mechanisms and functional implications. We
propose that, much like chromatin, RNA provides a tunable and dynamic means to control genome maintenance.
We will combine unbiased screening approaches with targeted validation to identify the factors that link RNA, its
modifications and their downstream effectors to DNA repair factor recruitment and pathway choice. A better
understanding of the molecular mechanisms that define DNA repair capacity will have implications for diseases
driven by impaired genome maintenance.

## Key facts

- **NIH application ID:** 10842584
- **Project number:** 1R35GM153484-01
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Philipp Oberdoerffer
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $409,375
- **Award type:** 1
- **Project period:** 2024-07-29 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10842584

## Citation

> US National Institutes of Health, RePORTER application 10842584, Probing the mechanisms that control DNA repair pathway choice. (1R35GM153484-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10842584. Licensed CC0.

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