# Cooption of the DNA Damage Response For Epigenetic Regulation of Inflammation

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2022 · $423,750

## Abstract

Project Summary
Complex organisms are able to rapidly induce select genes among thousands in response to diverse
environmental cues. This occurs in the context of large genomes condensed with histone proteins into
chromatin. The macrophage response to pathogen sensing, for example, rapidly engages highly conserved
signaling pathways and transcription factors (TFs) for coordination of inflammatory gene induction. Enriched
integration of histone H3.3, the ancestral histone H3 variant, is a feature of inflammatory genes and, in general,
dynamically regulated chromatin and transcription. The amino-terminal H3.3 `tail' differs from the other H3
proteins by a single amino acid, a serine at position 31. However, little is known of how (or which) features of
H3.3, conserved from yeast to human, might enable rapid and high-level transcription. We have recently
discovered a potent function for H3.3-specific histone phosphorylation (H3.3S31ph) in inflammatory gene
transcription and surprising evidence that non-canonical activity of the DNA-damage response (DDR) pathway
mediates this histone phosphorylation. Thus, we hypothesize that the DDR pathway is coopted for epigenetic
regulation of inflammatory genes. In Aim 1 we will identify the factors and sequence of events that link DDR
factors and H3.3S31ph to rapid inflammatory gene transcription and reveal the function of cross-talk between
DDR and chromatin (H3.3S31ph) by employing novel histone mutant mouse models. Specifically, our
experiments will enable us to distinguish between several candidate “paths” to H3.3S31ph and amplification of
transcription, including Topoisomerase dependency, and DNA break-dependent and -independent pathways.
In Aim 2 we will identify how DDR-mediated H3.3S31ph uniquely regulates Pol II dynamics at select
inflammatory genes to amplify their transcription. More generally, these studies will identify dedicated
mechanisms that enable inflammatory gene induction with important implications for understanding
inflammation and for informing more selective therapeutic strategies for diverse inflammatory diseases.

## Key facts

- **NIH application ID:** 10305601
- **Project number:** 5R01AI148416-03
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Steven Zvi Josefowicz
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $423,750
- **Award type:** 5
- **Project period:** 2019-12-01 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10305601

## Citation

> US National Institutes of Health, RePORTER application 10305601, Cooption of the DNA Damage Response For Epigenetic Regulation of Inflammation (5R01AI148416-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10305601. Licensed CC0.

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