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SPRTN protease and checkpoint kinase 1 cross-activation loop safeguards DNA replication

Author

Listed:
  • Swagata Halder

    (University of Oxford)

  • Ignacio Torrecilla

    (University of Oxford)

  • Martin D. Burkhalter

    (Ulm University
    University of Tübingen)

  • Marta Popović

    (University of Oxford
    Institute Ruder Boškovic, Bijenička Cesta 54)

  • John Fielden

    (University of Oxford)

  • Bruno Vaz

    (University of Oxford)

  • Judith Oehler

    (University of Oxford)

  • Domenic Pilger

    (University of Oxford)

  • Davor Lessel

    (University Medical Center Hamburg-Eppendorf)

  • Katherine Wiseman

    (University of Oxford)

  • Abhay Narayan Singh

    (University of Oxford)

  • Iolanda Vendrell

    (University of Oxford
    University of Oxford)

  • Roman Fischer

    (University of Oxford)

  • Melanie Philipp

    (Ulm University
    University of Tübingen)

  • Kristijan Ramadan

    (University of Oxford)

Abstract

The SPRTN metalloprotease is essential for DNA-protein crosslink (DPC) repair and DNA replication in vertebrate cells. Cells deficient in SPRTN protease exhibit DPC-induced replication stress and genome instability, manifesting as premature ageing and liver cancer. Here, we provide a body of evidence suggesting that SPRTN activates the ATR-CHK1 phosphorylation signalling cascade during physiological DNA replication by proteolysis-dependent eviction of CHK1 from replicative chromatin. During this process, SPRTN proteolyses the C-terminal/inhibitory part of CHK1, liberating N-terminal CHK1 kinase active fragments. Simultaneously, CHK1 full length and its N-terminal fragments phosphorylate SPRTN at the C-terminal regulatory domain, which stimulates SPRTN recruitment to chromatin to promote unperturbed DNA replication fork progression and DPC repair. Our data suggest that a SPRTN-CHK1 cross-activation loop plays a part in DNA replication and protection from DNA replication stress. Finally, our results with purified components of this pathway further support the proposed model of a SPRTN-CHK1 cross-activation loop.

Suggested Citation

  • Swagata Halder & Ignacio Torrecilla & Martin D. Burkhalter & Marta Popović & John Fielden & Bruno Vaz & Judith Oehler & Domenic Pilger & Davor Lessel & Katherine Wiseman & Abhay Narayan Singh & Ioland, 2019. "SPRTN protease and checkpoint kinase 1 cross-activation loop safeguards DNA replication," Nature Communications, Nature, vol. 10(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-11095-y
    DOI: 10.1038/s41467-019-11095-y
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    Cited by:

    1. Kate E. Coleman & Yandong Yin & Sarah Kit Leng Lui & Sarah Keegan & David Fenyo & Duncan J. Smith & Eli Rothenberg & Tony T. Huang, 2022. "USP1-trapping lesions as a source of DNA replication stress and genomic instability," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    2. Samuel Hume & Claudia P. Grou & Pauline Lascaux & Vincenzo D’Angiolella & Arnaud J. Legrand & Kristijan Ramadan & Grigory L. Dianov, 2021. "The NUCKS1-SKP2-p21/p27 axis controls S phase entry," Nature Communications, Nature, vol. 12(1), pages 1-14, December.

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