USP37 prevents unscheduled replisome unloading through MCM complex deubiquitination
Abstract 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 describ...
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| Format: | Article |
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Nature Portfolio
2025-05-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-59770-7 |
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| author | Derek L. Bolhuis Dalia Fleifel Thomas Bonacci Xianxi Wang Brandon L. Mouery Jeanette Gowen Cook Nicholas G. Brown Michael J. Emanuele |
| author_facet | Derek L. Bolhuis Dalia Fleifel Thomas Bonacci Xianxi Wang Brandon L. Mouery Jeanette Gowen Cook Nicholas G. Brown Michael J. Emanuele |
| author_sort | Derek L. Bolhuis |
| collection | DOAJ |
| description | Abstract 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 biochemical assays revealed USP37 interacts with the CMG complex to deubiquitinate MCM7, 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. |
| format | Article |
| id | doaj-art-50ae1b57bb2b4e628ef52f3d9efc6248 |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-50ae1b57bb2b4e628ef52f3d9efc62482025-08-20T02:25:16ZengNature PortfolioNature Communications2041-17232025-05-0116111710.1038/s41467-025-59770-7USP37 prevents unscheduled replisome unloading through MCM complex deubiquitinationDerek L. Bolhuis0Dalia Fleifel1Thomas Bonacci2Xianxi Wang3Brandon L. Mouery4Jeanette Gowen Cook5Nicholas G. Brown6Michael J. Emanuele7Department of Biochemistry and Biophysics and Lineberger Comprehensive Cancer Center, University of North CarolinaDepartment of Biochemistry and Biophysics and Lineberger Comprehensive Cancer Center, University of North CarolinaDepartment of Pharmacology and Lineberger Comprehensive Cancer Center, University of North CarolinaDepartment of Pharmacology and Lineberger Comprehensive Cancer Center, University of North CarolinaCurriculum in Genetics and Molecular Biology, University of North CarolinaDepartment of Biochemistry and Biophysics and Lineberger Comprehensive Cancer Center, University of North CarolinaDepartment of Pharmacology and Lineberger Comprehensive Cancer Center, University of North CarolinaDepartment of Pharmacology and Lineberger Comprehensive Cancer Center, University of North CarolinaAbstract 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 biochemical assays revealed USP37 interacts with the CMG complex to deubiquitinate MCM7, 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.https://doi.org/10.1038/s41467-025-59770-7 |
| spellingShingle | Derek L. Bolhuis Dalia Fleifel Thomas Bonacci Xianxi Wang Brandon L. Mouery Jeanette Gowen Cook Nicholas G. Brown Michael J. Emanuele USP37 prevents unscheduled replisome unloading through MCM complex deubiquitination Nature Communications |
| title | USP37 prevents unscheduled replisome unloading through MCM complex deubiquitination |
| title_full | USP37 prevents unscheduled replisome unloading through MCM complex deubiquitination |
| title_fullStr | USP37 prevents unscheduled replisome unloading through MCM complex deubiquitination |
| title_full_unstemmed | USP37 prevents unscheduled replisome unloading through MCM complex deubiquitination |
| title_short | USP37 prevents unscheduled replisome unloading through MCM complex deubiquitination |
| title_sort | usp37 prevents unscheduled replisome unloading through mcm complex deubiquitination |
| url | https://doi.org/10.1038/s41467-025-59770-7 |
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