ArticlebioRxiv : the preprint server for biology2024
USP37 prevents unscheduled replisome unloading through MCM complex deubiquitination.
Derek L Bolhuis, Dalia Fleifel, Thomas Bonacci, Xianxi Wang, Brandon L Mouery, Jeanette Gowen Cook, Nicholas G Brown, Michael J Emanuele
Abstract readPreprint
In one paragraphArticle in bioRxiv : the preprint server for biology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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5 · Who and what moneyAuthors and funding
8 authors.
Derek L BolhuisDepartment of Biochemistry and Biophysics and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
Dalia FleifelDepartment of Biochemistry and Biophysics and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
Thomas BonacciDepartment of Pharmacology and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA.
Xianxi WangDepartment of Pharmacology and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA.
Brandon L MoueryCurriculum in Genetics and Molecular Biology, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
Jeanette Gowen CookDepartment of Biochemistry and Biophysics and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599, USA.ORCID 0000-0003-0849-7405 Nicholas G BrownDepartment of Pharmacology and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA.
Michael J EmanueleDepartment of Pharmacology and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA.
Funding
Virology Research Program (Program 4)P30CA016086 · NCI · UNIV OF NORTH CAROLINA CHAPEL HILL · PI Deborah F. Tate · 1985 to 2026
$201.5MMOLECULAR AND CELLULAR BIOPHYSICS TRAINING PROGRAMT32GM008570 · NIGMS · UNIV OF NORTH CAROLINA CHAPEL HILL · PI KUHLMAN, BRIAN A, SLEP, KEVIN C · 1995 to 2022
$5.1MSpindle Assembly Checkpoint SilencingR35GM128855 · NIGMS · UNIV OF NORTH CAROLINA CHAPEL HILL · PI Nicholas Gene Brown · 2018 to 2026
$4.1MCell Cycle Dynamics that Ensure Genome MaintenanceR35GM141833 · NIGMS · UNIV OF NORTH CAROLINA CHAPEL HILL · PI COOK, JEANETTE GOWEN · 2021 to 2025
$2.8MProteostasis signaling in cell cycle controlR35GM153250 · NIGMS · UNIV OF NORTH CAROLINA CHAPEL HILL · PI Michael James Emanuele · 2024 to 2026
$1.9MCell cycle paths as a framework for understanding drug resistance in tumor cell subpopulationsR01CA280482 · NCI · UNIV OF NORTH CAROLINA CHAPEL HILL · PI Jeanette Gowen Cook, Michael James Emanuele · 2024 to 2026
$1.8MDeubiquitinases in Cell Cycle ControlR01GM134231 · NIGMS · UNIV OF NORTH CAROLINA CHAPEL HILL · PI EMANUELE, MICHAEL JAMES · 2020 to 2023
$1.6MNCI NIH HHS P30 CA016086NCI NIH HHS R01 CA280482NIGMS NIH HHS R01 GM134231NIGMS NIH HHS R35 GM128855NIGMS NIH HHS R35 GM141833NIGMS NIH HHS R35 GM153250NIGMS NIH HHS T32 GM008570
6 · The paper itselfAbstract
The CMG helicase (CDC45-MCM2-7-GINS) unwinds DNA as a component of eukaryotic replisomes. Replisome (dis)assembly is tightly coordinated with cell cycle progression to ensure genome stability. However, factors that prevent premature CMG unloading and replisome disassembly are poorly described. Since disassembly is catalyzed by ubiquitination, deubiquitinases (DUBs) represent attractive candidates for safeguarding against untimely and deleterious CMG unloading. We combined a targeted loss-of-function screen with quantitative, single-cell analysis to identify human USP37 as a key DUB preventing replisome disassembly. We demonstrate that USP37 maintains active replisomes on S-phase chromatin and promotes normal cell cycle progression. Proteomics and enzyme assays revealed USP37 interacts with the CMG complex to deubiquitinate MCM7, thus antagonizing replisome disassembly. Significantly, USP37 protects normal epithelial cells from oncoprotein-induced replication stress. Our findings reveal USP37 to be critical to the maintenance of replisomes in S-phase and suggest USP37-targeting as a potential strategy for treating malignancies with defective DNA replication control.
Indexed as
CMGDNA replicationgenome integrityreplisomeubiquitin
Identifiers
PMID39282338
PMCPMC11398414
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