IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v15y2024i1d10.1038_s41467-024-52250-4.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-024-52250-4
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-024-52250-4?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    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. 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.
    7. 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.
    8. 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.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. 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.
    2. Lonnie P. Swift & B. Christoffer Lagerholm & Lucy R. Henderson & Malitha Ratnaweera & Hannah T. Baddock & Blanka Sengerova & Sook Lee & Abimael Cruz-Migoni & Dominic Waithe & Christian Renz & Helle D., 2024. "SNM1A is crucial for efficient repair of complex DNA breaks in human cells," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    3. Pierre Azoulay & Joshua Krieger & Abhishek Nagaraj, 2024. "Old Moats for New Models: Openness, Control, and Competition in Generative AI," NBER Chapters, in: Entrepreneurship and Innovation Policy and the Economy, volume 4, National Bureau of Economic Research, Inc.
    4. Deyun Qiu & Jinxin V. Pei & James E. O. Rosling & Vandana Thathy & Dongdi Li & Yi Xue & John D. Tanner & Jocelyn Sietsma Penington & Yi Tong Vincent Aw & Jessica Yi Han Aw & Guoyue Xu & Abhai K. Tripa, 2022. "A G358S mutation in the Plasmodium falciparum Na+ pump PfATP4 confers clinically-relevant resistance to cipargamin," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    5. Shuo-Shuo Liu & Tian-Xia Jiang & Fan Bu & Ji-Lan Zhao & Guang-Fei Wang & Guo-Heng Yang & Jie-Yan Kong & Yun-Fan Qie & Pei Wen & Li-Bin Fan & Ning-Ning Li & Ning Gao & Xiao-Bo Qiu, 2024. "Molecular mechanisms underlying the BIRC6-mediated regulation of apoptosis and autophagy," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    6. Xiaoke Yang & Mingqi Zhu & Xue Lu & Yuxin Wang & Junyu Xiao, 2024. "Architecture and activation of human muscle phosphorylase kinase," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    7. Efren Garcia-Maldonado & Andrew D. Huber & Sergio C. Chai & Stanley Nithianantham & Yongtao Li & Jing Wu & Shyaron Poudel & Darcie J. Miller & Jayaraman Seetharaman & Taosheng Chen, 2024. "Chemical manipulation of an activation/inhibition switch in the nuclear receptor PXR," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    8. Kristy Rochon & Brianna L. Bauer & Nathaniel A. Roethler & Yuli Buckley & Chih-Chia Su & Wei Huang & Rajesh Ramachandran & Maria S. K. Stoll & Edward W. Yu & Derek J. Taylor & Jason A. Mears, 2024. "Structural basis for regulated assembly of the mitochondrial fission GTPase Drp1," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    9. Katherine A. Ray & Joshua D. Lutgens & Ramesh Bista & Jie Zhang & Ronak R. Desai & Melissa Hirsch & Takeshi Miyazawa & Antonio Cordova & Adrian T. Keatinge-Clay, 2024. "Assessing and harnessing updated polyketide synthase modules through combinatorial engineering," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    10. Fan Lu & Liang Zhu & Thomas Bromberger & Jun Yang & Qiannan Yang & Jianmin Liu & Edward F. Plow & Markus Moser & Jun Qin, 2022. "Mechanism of integrin activation by talin and its cooperation with kindlin," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    11. Zengyu Shao & Jiuwei Lu & Nelli Khudaverdyan & Jikui Song, 2024. "Multi-layered heterochromatin interaction as a switch for DIM2-mediated DNA methylation," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    12. Yudong Gao & Daichi Shonai & Matthew Trn & Jieqing Zhao & Erik J. Soderblom & S. Alexandra Garcia-Moreno & Charles A. Gersbach & William C. Wetsel & Geraldine Dawson & Dmitry Velmeshev & Yong-hui Jian, 2024. "Proximity analysis of native proteomes reveals phenotypic modifiers in a mouse model of autism and related neurodevelopmental conditions," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    13. Martin F. Peter & Christian Gebhardt & Rebecca Mächtel & Gabriel G. Moya Muñoz & Janin Glaenzer & Alessandra Narducci & Gavin H. Thomas & Thorben Cordes & Gregor Hagelueken, 2022. "Cross-validation of distance measurements in proteins by PELDOR/DEER and single-molecule FRET," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    14. Jutta Diessl & Jens Berndtsson & Filomena Broeskamp & Lukas Habernig & Verena Kohler & Carmela Vazquez-Calvo & Arpita Nandy & Carlotta Peselj & Sofia Drobysheva & Ludovic Pelosi & F.-Nora Vögtle & Fab, 2022. "Manganese-driven CoQ deficiency," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    15. Alexander Kroll & Sahasra Ranjan & Martin K. M. Engqvist & Martin J. Lercher, 2023. "A general model to predict small molecule substrates of enzymes based on machine and deep learning," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    16. Lisa-Marie Appel & Vedran Franke & Johannes Benedum & Irina Grishkovskaya & Xué Strobl & Anton Polyansky & Gregor Ammann & Sebastian Platzer & Andrea Neudolt & Anna Wunder & Lena Walch & Stefanie Kais, 2023. "The SPOC domain is a phosphoserine binding module that bridges transcription machinery with co- and post-transcriptional regulators," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
    17. Maciej K. Kocylowski & Hande Aypek & Wolfgang Bildl & Martin Helmstädter & Philipp Trachte & Bernhard Dumoulin & Sina Wittösch & Lukas Kühne & Ute Aukschun & Carolin Teetzen & Oliver Kretz & Botond Ga, 2022. "A slit-diaphragm-associated protein network for dynamic control of renal filtration," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    18. Marie C. Schoelmerich & Lynn Ly & Jacob West-Roberts & Ling-Dong Shi & Cong Shen & Nikhil S. Malvankar & Najwa Taib & Simonetta Gribaldo & Ben J. Woodcroft & Christopher W. Schadt & Basem Al-Shayeb & , 2024. "Borg extrachromosomal elements of methane-oxidizing archaea have conserved and expressed genetic repertoires," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    19. Michael A. Longo & Sunetra Roy & Yue Chen & Karl-Heinz Tomaszowski & Andrew S. Arvai & Jordan T. Pepper & Rebecca A. Boisvert & Selvi Kunnimalaiyaan & Caezanne Keshvani & David Schild & Albino Bacolla, 2023. "RAD51C-XRCC3 structure and cancer patient mutations define DNA replication roles," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    20. Zachary C. Drake & Justin T. Seffernick & Steffen Lindert, 2022. "Protein complex prediction using Rosetta, AlphaFold, and mass spectrometry covalent labeling," Nature Communications, Nature, vol. 13(1), pages 1-9, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-52250-4. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.