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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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