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Updated: Jun 13, 2025
10:11
Author Spotlight: Investigating the Motion Dynamics of the Eukaryotic Replisome Components at the Single-Molecule Level
Published on: July 26, 2024
979
USP37 prevents unscheduled replisome unloading through MCM complex deubiquitination
Derek L Bolhuis1,2, Dalia Fleifel1, Thomas Bonacci2
1Department of Biochemistry and Biophysics and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
Biorxiv : the Preprint Server for Biology
|September 16, 2024
Summary
Human USP37 prevents premature replisome disassembly by deubiquitinating the CMG helicase. This safeguards genome stability and normal cell cycle progression, offering a potential cancer treatment target.
Area of Science:
- Molecular Biology
- Cell Biology
- Genetics
Background:
- Eukaryotic DNA replication relies on the CMG helicase (CDC45-MCM2-7-GINS) within replisomes.
- Replisome assembly and disassembly are critical for genome stability and cell cycle control.
- Factors preventing premature CMG helicase unloading are not well understood.
Purpose of the Study:
- To identify factors that prevent premature CMG helicase unloading and replisome disassembly.
- To investigate the role of deubiquitinases (DUBs) in maintaining replisome integrity.
- To characterize the function of human USP37 in DNA replication and cell cycle progression.
Main Methods:
- Targeted loss-of-function genetic screen in human cells.
- Quantitative single-cell analysis of replisome dynamics.
- Proteomics and enzymatic assays to identify protein interactions and functions.
- Analysis of USP37's role in response to replication stress.
Main Results:
- Human USP37 was identified as a key DUB preventing replisome disassembly.
- USP37 maintains active replisomes on S-phase chromatin and promotes cell cycle progression.
- USP37 directly interacts with the CMG complex to deubiquitinate MCM7, antagonizing disassembly.
- USP37 protects normal cells from oncoprotein-induced replication stress.
Conclusions:
- USP37 is essential for maintaining active replisomes during S-phase.
- USP37 deubiquitination of MCM7 prevents premature CMG unloading and replisome disassembly.
- Targeting USP37 may offer a therapeutic strategy for cancers with impaired DNA replication control.
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