# Deubiquitinases in Cell Cycle Control

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2022 · $352,617

## Abstract

DEUBIQUITINASES IN CELL CYCLE CONTROL
Project Summary
Ubiquitin signaling contributes to virtually all aspects of cell physiology and is implicated in aging and disease.
The covalent conjugation of polyubiquitin chains onto substrates triggers their degradation by the proteasome,
as well as various other cellular outcomes. Ubiquitination is carried out by an enzymatic cascade of ubiquitin
activators (E1), conjugators (E2) and ligases (E3). During normal cell cycles the ubiquitin system plays an
essential and conserved role in remodeling the protein landscape. Ubiquitin substrates are determined by E3
ligases and much of our understanding of ubiquitin signaling has focused on the identity, substrates and
mechanisms of E3s. However, ubiquitination is reversible, and ubiquitin is removed from substrates by catalytic
proteases termed DUBs (deubiquitinases). Despite their critical role in sculpting the proteome, much less is
known about the identity, substrates and mechanisms of DUBs in cell cycle progression, when compared to their
E3 counterparts. Nevertheless, dysregulation of both E3s and DUBs alters cell cycle progression and has
deleterious effects on genome integrity. Moreover, both E3s and DUBs can be perturbed in pathologies such as
cancer, contributing to the biochemical and phenotypic features of disease. Thus, defining the identity, substrates
and mechanisms of DUBs in cell cycle is essential to understanding how normal cell proliferation and genome
stability are maintained and coordinated. We hypothesize that DUBs are essential for cell cycle progression and
chromosome stability and are equally important as their E3 counterparts. We address this hypothesis in three
specific aims, that combine complementary techniques, and which focus on the role of DUBs in major cell cycle
transitions. In Aims 1 and 2 we investigate Cezanne/OTUD7B, an ovarian tumor family deubiquitinase, that we
recently demonstrated is cell cycle regulated and which controls the M to G1 transition. In Aim 1, we will
determine substrates for Cezanne using proteomics approaches, define mechanisms of DUB-substrate
interactions, and the role of Cezanne in the degradation of substrates at M/G1. In Aim 2, we will expand this
analysis to determine how Cezanne is itself regulated, both at the level of its abundance and activity, and then
determine how these regulatory systems influence its role in cell division. Finally, in Aim 3, we determine the
role of DUBs in a second major cell cycle transition, G1/S. The G1/S boundary is a major barrier to proliferation
in normal and cancer cell cycles and relies heavily on ubiuqitin signaling. However, little is known about DUBs
involved in G1/S. We will use computational approaches and loss-of-function screens, to identify and then
investigate DUBs that control G1/S. Collectively, this proposal will fill significant knowledge gaps in the cell cycle,
ubiquitin and DUB fields, related to roles and mechanisms of DUBs in proliferation and ge...

## Key facts

- **NIH application ID:** 10359802
- **Project number:** 5R01GM134231-03
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Michael James Emanuele
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $352,617
- **Award type:** 5
- **Project period:** 2020-05-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10359802

## Citation

> US National Institutes of Health, RePORTER application 10359802, Deubiquitinases in Cell Cycle Control (5R01GM134231-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10359802. Licensed CC0.

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