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USP37 prevents premature disassembly of stressed replisomes by TRAIP

Author

Listed:
  • Olga V. Kochenova

    (Blavatnik Institute
    Howard Hughes Medical Institute)

  • Giuseppina D’Alessandro

    (Robinson Way
    The AIRC Institute of Molecular Oncology)

  • Domenic Pilger

    (University of Cambridge)

  • Ernst Schmid

    (Blavatnik Institute)

  • Sean L. Richards

    (Robinson Way)

  • Marcos Rios Garcia

    (University of Birmingham)

  • Satpal S. Jhujh

    (University of Birmingham)

  • Andrea Voigt

    (Robinson Way)

  • Vipul Gupta

    (Robinson Way)

  • Christopher J. Carnie

    (Robinson Way)

  • R. Alex Wu

    (Blavatnik Institute)

  • Nadia Gueorguieva

    (Robinson Way)

  • Simon Lam

    (Robinson Way)

  • Grant S. Stewart

    (University of Birmingham)

  • Johannes C. Walter

    (Blavatnik Institute
    Howard Hughes Medical Institute)

  • Stephen P. Jackson

    (Robinson Way)

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.

Suggested Citation

  • 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 , 2025. "USP37 prevents premature disassembly of stressed replisomes by TRAIP," Nature Communications, Nature, vol. 16(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-60139-z
    DOI: 10.1038/s41467-025-60139-z
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    References listed on IDEAS

    as
    1. R. Alex Wu & Daniel R. Semlow & Ashley N. Kamimae-Lanning & Olga V. Kochenova & Gheorghe Chistol & Michael R. Hodskinson & Ravindra Amunugama & Justin L. Sparks & Meng Wang & Lin Deng & Claudia A. Mim, 2019. "TRAIP is a master regulator of DNA interstrand crosslink repair," Nature, Nature, vol. 567(7747), pages 267-272, March.
    2. Derek L. Bolhuis & Dalia Fleifel & Thomas Bonacci & Xianxi Wang & Brandon L. Mouery & Jeanette Gowen Cook & Nicholas G. Brown & Michael J. Emanuele, 2025. "USP37 prevents unscheduled replisome unloading through MCM complex deubiquitination," Nature Communications, Nature, vol. 16(1), pages 1-17, December.
    3. Olga V. Kochenova & Sirisha Mukkavalli & Malavika Raman & Johannes C. Walter, 2022. "Cooperative assembly of p97 complexes involved in replication termination," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    4. Patrick Bryant & Gabriele Pozzati & Arne Elofsson, 2022. "Author Correction: Improved prediction of protein-protein interactions using AlphaFold2," Nature Communications, Nature, vol. 13(1), pages 1-1, December.
    5. Shaun Scaramuzza & Rebecca M. Jones & Martina Muste Sadurni & Alicja Reynolds-Winczura & Divyasree Poovathumkadavil & Abigail Farrell & Toyoaki Natsume & Patricia Rojas & Cyntia Fernandez Cuesta & Mas, 2023. "TRAIP resolves DNA replication-transcription conflicts during the S-phase of unperturbed cells," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    6. Patrick Bryant & Gabriele Pozzati & Arne Elofsson, 2022. "Improved prediction of protein-protein interactions using AlphaFold2," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    7. Michael Jenkyn-Bedford & Morgan L. Jones & Yasemin Baris & Karim P. M. Labib & Giuseppe Cannone & Joseph T. P. Yeeles & Tom D. Deegan, 2021. "A conserved mechanism for regulating replisome disassembly in eukaryotes," Nature, Nature, vol. 600(7890), pages 743-747, December.
    8. James M. Dewar & Magda Budzowska & Johannes C. Walter, 2015. "The mechanism of DNA replication termination in vertebrates," Nature, Nature, vol. 525(7569), pages 345-350, September.
    Full references (including those not matched with items on IDEAS)

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