USP37 prevents premature disassembly of stressed replisomes by TRAIP
Open accessPreprint — published as 10.1038/s41467-025-60139-z · Paper page
Abstract
The E3 ubiquitin ligase TRAIP associates with the replisome and helps this molecular machine deal with replication stress. Thus, TRAIP promotes DNA inter-strand crosslink repair by triggering the disassembly of CDC45-MCM2-7-GINS (CMG) helicases that have converged on these lesions. However, disassembly of single CMGs that have stalled temporarily would be deleterious, suggesting that TRAIP must be carefully regulated. Here, we demonstrate that human cells lacking the de-ubiquitylating enzyme USP37 are hypersensitive to topoisomerase poisons and other replication stress-inducing agents. We further show that 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. In conclusion, we propose that USP37 protects genome stability by preventing TRAIP-dependent CMG unloading when replication stress impedes timely termination.
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Predictomes, a classifier-curated database of AlphaFold-modeled protein-protein interactions
Schmid, E. W., & Walter, J. C. (2025) · Molecular Cell · doi:10.1016/j.molcel.2025.01.034 · Cited by 120 · see citing works
“Another example is USP37-CDC45, which is consistent with our finding that CDC45 recruits USP37 to the replisome 56 .”
Self-citationProteome-wide in silico screening for human protein-protein interactionsPreprint
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Self-citationUSP37 protects mammalian cells during DNA replication stress by counteracting CUL2LRR1 and TRAIP.
Villa, F., Ainsworth, J., & Labib, K. P. M. (2025) · Cell Reports · doi:10.1016/j.celrep.2025.115739 · Cited by 3 · see citing works
- Authors
- 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., Wu, R. A., Gueorguieva, N., Stewart, G. S., Walter, J. C., & Jackson, S. P.
- Affiliations
- Howard Hughes Medical Institute (US)
- Cancer Research UK (GB)
- University of Cambridge (GB)
- Harvard University (US)
- University of Birmingham (GB)
- Corresponding author
- Walter, Johannes C.
- Jackson, Stephen P.
- ORCID
- Venue
- bioRxiv (Cold Spring Harbor Laboratory)
- Publisher
- openRxiv
- Published
- 2024-09-04
- PMC
- PMC11398331
- OpenAlex
- W4402285827
- Cited by
- 3
- References
- 67
- Citations by year
- 2025: 3
- Type
- posted content
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion, cc-by-nc-nd)
- Apollo (University of Cambridge) (submittedVersion, cc-by)
- Funders
- Cancer Research UK (DRCPGM\100005, C17183/A23303, 29580)
- European Commission (800924, HORIZON2020)
- Associazione Italiana per la Ricerca sul Cancro (800924)
- National Institutes of Health
- Cancer Research UK Cambridge Institute, University of Cambridge
- National Heart, Lung, and Blood Institute (R01HL098316)
- H2020 European Research Council (855741)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Keywords
- USP37, TRAIP, replication stress, CMG helicase, Cdc45, topoisomerase inhibitors, genome stability, topological stress, Xenopus egg extracts
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