# Mechanisms of ubiquitin signaling in chromatin-mediated processes

> **NIH NIH R35** · JOHNS HOPKINS UNIVERSITY · 2021 · $882,305

## Abstract

PROJECT SUMMARY
Post-translational modifications of the histone proteins that package DNA play a central role in regulating
transcription and repair of DNA damage. The goal of this research program is to determine the molecular
mechanism by which attachment of the small protein, ubiquitin, to histone proteins functions in concert
with modifications including methylation and acetylation to regulate gene expression and maintain
genome integrity. Since misregulation of histone ubiquitination and methylation characterizes many
cancers, the results of these studies can be used to design new drugs that target the molecular
machines involved in these pathways. A major focus of this research program will be on the mechanism
by which monoubiquitination of histone H2B triggers a cascade of events needed to activate gene
transcription, including methylation of histone H3 and recruitment of histone chaperones that assist RNA
polymerase in transcribing DNA through a chromatin template. A combination of x-ray crystallography,
cryo-electron microscopy and NMR, single molecule biophysics, solution biochemistry and cell-based
approaches will be used to study how coactivator complexes such as SAGA bind their chromatin
substrates and combine histone deubiquitination, acetylation and recognition of histone methylation to
activate transcription. We will also study the mechanism by which H2B ubiquitination triggers histone
methylation and determine the distinct mechanism by which different deubiquitinating enzymes mediate
nucleosome dynamics. Another aspect of ubiquitin signaling to be addressed in this program is the
mechanism by which ubiquitin chains attached to sites of DNA alkylation damage recruit repair enzymes.
The molecular insights that will result from the proposed studies will provide a foundation for developing
new chemotherapies that target cancers for which there currently are no effective treatments.

## Key facts

- **NIH application ID:** 10129396
- **Project number:** 5R35GM130393-03
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Cynthia Wolberger
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $882,305
- **Award type:** 5
- **Project period:** 2019-02-14 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10129396

## Citation

> US National Institutes of Health, RePORTER application 10129396, Mechanisms of ubiquitin signaling in chromatin-mediated processes (5R35GM130393-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10129396. Licensed CC0.

---

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