USP37 prevents premature disassembly of stressed replisomes by TRAIP
Open accessPublished version of a preprint
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.
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Cites
Varadi, M., Bertoni, D., Magana, P., Paramval, U., Pidruchna, I., Radhakrishnan, M., Tsenkov, M., Nair, S., Mirdita, M., Yeo, J., et al. (2024) · Nucleic Acids Research · doi:10.1093/nar/gkad1011 · Cited by 2,052 · cited 1× · see citing works
“Average interface pLDDT values above 70 are generally considered con fi dent 68 .”
Improved prediction of protein-protein interactions using AlphaFold2
Bryant, P., Pozzati, G., & Elofsson, A. (2021) · doi:10.1101/2021.09.15.460468 · Cited by 1,025 · see citing works
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
Self-citationA conserved mechanism for regulating replisome disassembly in eukaryotes
Jenkyn-Bedford, M., Jones, M. L., Baris, Y., Labib, K. P. M., Cannone, G., Yeeles, J. T. P., & Deegan, T. D. (2021) · Nature · doi:10.1038/s41586-021-04145-3 · Cited by 116 · cited 4× · see citing works
“However, because CRL2 Lrr1 is thought to be recruited to CMGs that have completed DNA replication, this hyper-ubiquitylation is unlikely to be deleterious 8,9 .”
InfluentialIn silico protein interaction screening uncovers DONSON’s role in replication initiation
Lim, Y., Tamayo-Orrego, L., Schmid, E., Tarnauskaite, Z., Kochenova, O. V., Gruar, R., Muramatsu, S., Lynch, L., Schlie, A. V., Carroll, P. L., et al. (2023) · Science · doi:10.1126/science.adi3448 · Cited by 112 · see citing works
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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
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- 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., Alex Wu, R., Gueorguieva, N., Lam, S., 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
- Nature Communications
- Published
- 2025-06-18
- Volume
- 16
- Issue
- 1
- Pages
- 5333-5333
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC12177040
- OpenAlex
- W4411423758
- Cited by
- 6
- References
- 5
- Citations by year
- 2026: 5 · 2025: 1
- FWCI
- 1.80
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- University of Birmingham Research Portal (University of Birmingham) (acceptedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (HL098316)
- Howard Hughes Medical Institute
- Cancer Research UK (DRCPGM\100005, A:29580, C17183/A23303)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Keywords
- USP37, TRAIP, E3 ubiquitin ligase, CMG helicase, Cdc45, replication stress, topoisomerase inhibitors, genome stability, protein ubiquitylation, Xenopus egg extracts
- MeSH terms
- Animals, DNA Replication, HeLa Cells, Humans, Endopeptidases, Xenopus laevis, Cell Cycle Proteins, Genomic Instability, Ubiquitin Thiolesterase, Ubiquitin-Protein Ligases, Ubiquitination
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