USP37 prevents premature disassembly of stressed replisomes by TRAIP

Olga V. Kochenova; Giuseppina D’Alessandro; Domenic Pilger; Ernst Schmid; Sean L. Richards; Marcos Rios Garcia; Satpal S. Jhujh; Andrea Voigt; Vipul Gupta; Christopher J. Carnie; R. Alex Wu; Nadia Gueorguieva; Simon Lam; Grant S. Stewart; Johannes C. Walter; Stephen P. Jackson

doi:10.1038/s41467-025-60139-z

USP37 prevents premature disassembly of stressed replisomes by TRAIP

Olga V. Kochenova, Giuseppina D’Alessandro, Domenic Pilger, Ernst Schmid, Sean L. Richards, Marcos Rios Garcia, Satpal S. Jhujh, Andrea Voigt, Vipul Gupta, Christopher J. Carnie, R. Alex Wu, Nadia Gueorguieva, Simon Lam, Grant S. Stewart, Johannes C. Walter^*, Stephen P. Jackson^*

^*Corresponding author for this work

Cancer and Genomic Sciences

Research output: Contribution to journal › Article › peer-review

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Abstract

The eukaryotic replisome, which consists of the CDC45-MCM2-7-GINS (CMG) helicase, replicative polymerases, and several accessory factors, sometimes encounters proteinaceous obstacles that threaten genome integrity. These obstacles are targeted for removal or proteolysis by the E3 ubiquitin ligase TRAIP, which associates with the replisome. However, TRAIP must be carefully regulated to avoid inappropriate ubiquitylation and disassembly of the replisome. Here, we demonstrate that human cells lacking the de-ubiquitylating enzyme USP37 are hypersensitive to topoisomerase poisons and other replication stress-inducing agents. Furthermore, TRAIP loss rescues the hypersensitivity of USP37 knockout cells to topoisomerase inhibitors. In Xenopus egg extracts depleted of USP37, TRAIP promotes premature CMG ubiquitylation and disassembly when converging replisomes stall. Finally, guided by AlphaFold-Multimer, we discovered that binding to CDC45 mediates USP37’s response to topological stress. We propose that USP37 protects genome stability by preventing TRAIP-dependent CMG unloading when replication stress impedes timely termination.

Original language	English
Article number	5333
Number of pages	17
Journal	Nature Communications
Volume	16
Issue number	1
Early online date	18 Jun 2025
DOIs	https://doi.org/10.1038/s41467-025-60139-z
Publication status	Published - Dec 2025

Bibliographical note

Publisher Copyright:
© The Author(s) 2025.

ASJC Scopus subject areas

General Chemistry
General Biochemistry,Genetics and Molecular Biology
General Physics and Astronomy

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KochenovaO2025USP37Final published version, 3.97 MBLicence: Creative Commons: Attribution (CC BY)

Characterising novel regulators of the PI-3-kinase-like kinase-dependent DNA damage response and their role in preventing human disease and cancer
Stewart, G. (Principal Investigator)
Cancer Research UK
1/09/17 → 31/05/25
Project: Research

Cite this

Kochenova, O. V., D’Alessandro, G., Pilger, D., Schmid, E., Richards, S. L., Garcia, M. R., Jhujh, S. S., Voigt, A., Gupta, V., Carnie, C. J., Alex Wu, R., Gueorguieva, N., Lam, S., Stewart, G. S., Walter, J. C., & Jackson, S. P. (2025). USP37 prevents premature disassembly of stressed replisomes by TRAIP. Nature Communications, 16(1), Article 5333. https://doi.org/10.1038/s41467-025-60139-z

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title = "USP37 prevents premature disassembly of stressed replisomes by TRAIP",

abstract = "The eukaryotic replisome, which consists of the CDC45-MCM2-7-GINS (CMG) helicase, replicative polymerases, and several accessory factors, sometimes encounters proteinaceous obstacles that threaten genome integrity. These obstacles are targeted for removal or proteolysis by the E3 ubiquitin ligase TRAIP, which associates with the replisome. However, TRAIP must be carefully regulated to avoid inappropriate ubiquitylation and disassembly of the replisome. Here, we demonstrate that human cells lacking the de-ubiquitylating enzyme USP37 are hypersensitive to topoisomerase poisons and other replication stress-inducing agents. Furthermore, TRAIP loss rescues the hypersensitivity of USP37 knockout cells to topoisomerase inhibitors. In Xenopus egg extracts depleted of USP37, TRAIP promotes premature CMG ubiquitylation and disassembly when converging replisomes stall. Finally, guided by AlphaFold-Multimer, we discovered that binding to CDC45 mediates USP37{\textquoteright}s response to topological stress. We propose that USP37 protects genome stability by preventing TRAIP-dependent CMG unloading when replication stress impedes timely termination.",

author = "Kochenova, \{Olga V.\} and Giuseppina D{\textquoteright}Alessandro and Domenic Pilger and Ernst Schmid and Richards, \{Sean L.\} and Garcia, \{Marcos Rios\} and Jhujh, \{Satpal S.\} and Andrea Voigt and Vipul Gupta and Carnie, \{Christopher J.\} and \{Alex Wu\}, R. and Nadia Gueorguieva and Simon Lam and Stewart, \{Grant S.\} and Walter, \{Johannes C.\} and Jackson, \{Stephen P.\}",

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doi = "10.1038/s41467-025-60139-z",

language = "English",

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AU - Kochenova, Olga V.

AU - D’Alessandro, Giuseppina

AU - Pilger, Domenic

AU - Schmid, Ernst

AU - Richards, Sean L.

AU - Garcia, Marcos Rios

AU - Jhujh, Satpal S.

AU - Voigt, Andrea

AU - Gupta, Vipul

AU - Carnie, Christopher J.

AU - Alex Wu, R.

AU - Gueorguieva, Nadia

AU - Lam, Simon

AU - Stewart, Grant S.

AU - Walter, Johannes C.

AU - Jackson, Stephen P.

PY - 2025/12

Y1 - 2025/12

N2 - The eukaryotic replisome, which consists of the CDC45-MCM2-7-GINS (CMG) helicase, replicative polymerases, and several accessory factors, sometimes encounters proteinaceous obstacles that threaten genome integrity. These obstacles are targeted for removal or proteolysis by the E3 ubiquitin ligase TRAIP, which associates with the replisome. However, TRAIP must be carefully regulated to avoid inappropriate ubiquitylation and disassembly of the replisome. Here, we demonstrate that human cells lacking the de-ubiquitylating enzyme USP37 are hypersensitive to topoisomerase poisons and other replication stress-inducing agents. Furthermore, TRAIP loss rescues the hypersensitivity of USP37 knockout cells to topoisomerase inhibitors. In Xenopus egg extracts depleted of USP37, TRAIP promotes premature CMG ubiquitylation and disassembly when converging replisomes stall. Finally, guided by AlphaFold-Multimer, we discovered that binding to CDC45 mediates USP37’s response to topological stress. We propose that USP37 protects genome stability by preventing TRAIP-dependent CMG unloading when replication stress impedes timely termination.

AB - The eukaryotic replisome, which consists of the CDC45-MCM2-7-GINS (CMG) helicase, replicative polymerases, and several accessory factors, sometimes encounters proteinaceous obstacles that threaten genome integrity. These obstacles are targeted for removal or proteolysis by the E3 ubiquitin ligase TRAIP, which associates with the replisome. However, TRAIP must be carefully regulated to avoid inappropriate ubiquitylation and disassembly of the replisome. Here, we demonstrate that human cells lacking the de-ubiquitylating enzyme USP37 are hypersensitive to topoisomerase poisons and other replication stress-inducing agents. Furthermore, TRAIP loss rescues the hypersensitivity of USP37 knockout cells to topoisomerase inhibitors. In Xenopus egg extracts depleted of USP37, TRAIP promotes premature CMG ubiquitylation and disassembly when converging replisomes stall. Finally, guided by AlphaFold-Multimer, we discovered that binding to CDC45 mediates USP37’s response to topological stress. We propose that USP37 protects genome stability by preventing TRAIP-dependent CMG unloading when replication stress impedes timely termination.

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USP37 prevents premature disassembly of stressed replisomes by TRAIP

Abstract

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Characterising novel regulators of the PI-3-kinase-like kinase-dependent DNA damage response and their role in preventing human disease and cancer

Cite this