# Control of histone ubiquitylation during the cell cycle

> **NIH NIH R35** · MASSACHUSETTS GENERAL HOSPITAL · 2024 · $420,000

## Abstract

PROJECT SUMMARY
The site-specific ubiquitylation of histone proteins can dictate whether a gene gets expressed or silenced, thus,
this type of modification is indispensable for normal development and cellular homeostasis. By contrast, the
mis-regulation of histone ubiquitylation can result in developmental lethality, neurodegeneration, and aging.
~1–2% of histone H2B is mono-ubiquitylated (H2Bub1) during interphase, ranking this protein alongside some
of the most ubiquitylated by abundance. H2Bub1 has been shown to promote gene expression through
multiple mechanisms. Strikingly, H2Bub1 disappears from metaphase chromosomes and reaccumulates as
cells exit from mitosis, but considering recent reports, which challenge the long-held view that histones function
to condense chromatin into higher-order structures in vivo, why the state of H2B ubiquitylation needs to be
reset during each cell cycle is incompletely understood. Thus, there is a pressing need to elucidate why and
how H2Bub1 is stripped from mitotic chromosomes. Multiple deubiquitylases (DUBs) have been shown to
catalyze the removal of ubiquitin from H2Bub1, nonetheless, it remains to be seen how they cooperate with
one another, if there are yet unidentified DUBs specific for H2Bub1, the genomic sites they regulate, and when
they function during the cell cycle. Our working hypothesis posits that each H2Bub1-specific DUB targets
overlapping but distinct genomic regions to ensure the rapid clearance of H2Bub1 on mitotic chromosomes. To
address this hypothesis, we will use a multidisciplinary approach, integrating classical biochemical approaches
with global measurements. More specifically, we propose to identify the key DUBs that target H2Bub1, to
elucidate the extent of their redundancy, to characterize their mechanisms of action, and to examine how they
influence gene expression throughout the cell cycle. Though this work aims to uncover the purpose of histone
deubiquitylation during mitosis, we also expect to gain new insights into the basic principles of ubiquitin-
dependent gene regulation, including mechanisms of spatiotemporal control, cooperativity and interplay
between DUBs, and crosstalk with other chromatin-modifying enzymes. Finally, our work will have major
implications in how dividing cells maintain their transcriptional memory to ensure the faithful propagation of
cellular identity to future generations, and this study will have a positive impact by providing a fresh context for
understanding ubiquitin-dependent disorders and may reveal how best to develop therapeutic strategies to
combat these diseases.

## Key facts

- **NIH application ID:** 10916241
- **Project number:** 5R35GM146933-03
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Eugene Oh
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $420,000
- **Award type:** 5
- **Project period:** 2022-09-20 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10916241

## Citation

> US National Institutes of Health, RePORTER application 10916241, Control of histone ubiquitylation during the cell cycle (5R35GM146933-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10916241. Licensed CC0.

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