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USP50 suppresses alternative RecQ helicase use and deleterious DNA2 activity during replication

Author

Listed:
  • Hannah L. Mackay

    (University of Birmingham)

  • Helen R. Stone

    (University of Birmingham
    University of Birmingham)

  • George E. Ronson

    (University of Birmingham)

  • Katherine Ellis

    (University of Birmingham
    University of Sheffield)

  • Alexander Lanz

    (University of Birmingham)

  • Yara Aghabi

    (University of Birmingham)

  • Alexandra K. Walker

    (University of Birmingham)

  • Katarzyna Starowicz

    (University of Birmingham
    Lyndon House)

  • Alexander J. Garvin

    (University of Birmingham
    University of Leeds)

  • Patrick Van Eijk

    (Hinxton
    Heath Park)

  • Stefan A. Koestler

    (University of Birmingham)

  • Elizabeth J. Anthony

    (University of Birmingham)

  • Ann Liza Piberger

    (University of Birmingham)

  • Anoop S. Chauhan

    (University of Birmingham)

  • Poppy Conway-Thomas

    (University of Birmingham)

  • Alina Vaitsiankova

    (Falmer
    Columbia University Irving Medical Center)

  • Sobana Vijayendran

    (University of Birmingham
    Mindelsohn Way)

  • James F. Beesley

    (University of Birmingham)

  • Eva Petermann

    (University of Birmingham)

  • Eric J. Brown

    (University of Pennsylvania)

  • Ruth M. Densham

    (University of Birmingham)

  • Simon H. Reed

    (Hinxton
    Heath Park)

  • Felix Dobbs

    (Hinxton
    Heath Park)

  • Marco Saponaro

    (University of Birmingham)

  • Joanna R. Morris

    (University of Birmingham)

Abstract

Mammalian DNA replication relies on various DNA helicase and nuclease activities to ensure accurate genetic duplication, but how different helicase and nuclease activities are properly directed remains unclear. Here, we identify the ubiquitin-specific protease, USP50, as a chromatin-associated protein required to promote ongoing replication, fork restart, telomere maintenance, cellular survival following hydroxyurea or pyridostatin treatment, and suppression of DNA breaks near GC-rich sequences. We find that USP50 supports proper WRN-FEN1 localisation at or near stalled replication forks. Nascent DNA in cells lacking USP50 shows increased association of the DNA2 nuclease and RECQL4 and RECQL5 helicases and replication defects in cells lacking USP50, or FEN1 are driven by these proteins. Consequently, suppression of DNA2 or RECQL4/5 improves USP50-depleted cell resistance to agents inducing replicative stress and restores telomere stability. These data define an unexpected regulatory protein that promotes the balance of helicase and nuclease use at ongoing and stalled replication forks.

Suggested Citation

  • Hannah L. Mackay & Helen R. Stone & George E. Ronson & Katherine Ellis & Alexander Lanz & Yara Aghabi & Alexandra K. Walker & Katarzyna Starowicz & Alexander J. Garvin & Patrick Van Eijk & Stefan A. K, 2024. "USP50 suppresses alternative RecQ helicase use and deleterious DNA2 activity during replication," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-52250-4
    DOI: 10.1038/s41467-024-52250-4
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    References listed on IDEAS

    as
    1. Tanay Thakar & Wendy Leung & Claudia M. Nicolae & Kristen E. Clements & Binghui Shen & Anja-Katrin Bielinsky & George-Lucian Moldovan, 2020. "Ubiquitinated-PCNA protects replication forks from DNA2-mediated degradation by regulating Okazaki fragment maturation and chromatin assembly," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
    2. Kathryn Tunyasuvunakool & Jonas Adler & Zachary Wu & Tim Green & Michal Zielinski & Augustin Žídek & Alex Bridgland & Andrew Cowie & Clemens Meyer & Agata Laydon & Sameer Velankar & Gerard J. Kleywegt, 2021. "Highly accurate protein structure prediction for the human proteome," Nature, Nature, vol. 596(7873), pages 590-596, August.
    3. Arindam Datta & Kajal Biswas & Joshua A. Sommers & Haley Thompson & Sanket Awate & Claudia M. Nicolae & Tanay Thakar & George-Lucian Moldovan & Robert H. Shoemaker & Shyam K. Sharan & Robert M. Brosh, 2021. "WRN helicase safeguards deprotected replication forks in BRCA2-mutated cancer cells," Nature Communications, Nature, vol. 12(1), pages 1-22, December.
    4. Niek van Wietmarschen & Sriram Sridharan & William J. Nathan & Anthony Tubbs & Edmond M. Chan & Elsa Callen & Wei Wu & Frida Belinky & Veenu Tripathi & Nancy Wong & Kyla Foster & Javad Noorbakhsh & Ki, 2020. "Repeat expansions confer WRN dependence in microsatellite-unstable cancers," Nature, Nature, vol. 586(7828), pages 292-298, October.
    5. Fiona M. Behan & Francesco Iorio & Gabriele Picco & Emanuel Gonçalves & Charlotte M. Beaver & Giorgia Migliardi & Rita Santos & Yanhua Rao & Francesco Sassi & Marika Pinnelli & Rizwan Ansari & Sarah H, 2019. "Prioritization of cancer therapeutic targets using CRISPR–Cas9 screens," Nature, Nature, vol. 568(7753), pages 511-516, April.
    6. Felix M. Dobbs & Patrick Eijk & Mick D. Fellows & Luisa Loiacono & Roberto Nitsch & Simon H. Reed, 2022. "Precision digital mapping of endogenous and induced genomic DNA breaks by INDUCE-seq," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    7. Chirantani Mukherjee & Vivek Tripathi & Eleni Maria Manolika & Anne Margriet Heijink & Giulia Ricci & Sarra Merzouk & H. Rudolf Boer & Jeroen Demmers & Marcel A. T. M. Vugt & Arnab Ray Chaudhuri, 2019. "RIF1 promotes replication fork protection and efficient restart to maintain genome stability," Nature Communications, Nature, vol. 10(1), pages 1-16, December.
    8. John Jumper & Richard Evans & Alexander Pritzel & Tim Green & Michael Figurnov & Olaf Ronneberger & Kathryn Tunyasuvunakool & Russ Bates & Augustin Žídek & Anna Potapenko & Alex Bridgland & Clemens Me, 2021. "Highly accurate protein structure prediction with AlphaFold," Nature, Nature, vol. 596(7873), pages 583-589, August.
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