IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v15y2024i1d10.1038_s41467-024-49816-7.html
   My bibliography  Save this article

Inhibition of topoisomerase 2 catalytic activity impacts the integrity of heterochromatin and repetitive DNA and leads to interlinks between clustered repeats

Author

Listed:
  • Michalis Amoiridis

    (University of Sussex
    Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC)
    Institut National de la Santé et de la Recherche Médicale (INSERM)
    Centre National de Recherche Scientifique (CNRS))

  • John Verigos

    (University of Sussex)

  • Karen Meaburn

    (University of Sussex)

  • William H. Gittens

    (University of Sussex)

  • Tao Ye

    (Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC)
    Institut National de la Santé et de la Recherche Médicale (INSERM)
    Centre National de Recherche Scientifique (CNRS)
    Université de Strasbourg)

  • Matthew J. Neale

    (University of Sussex)

  • Evi Soutoglou

    (University of Sussex)

Abstract

DNA replication and transcription generate DNA supercoiling, which can cause topological stress and intertwining of daughter chromatin fibers, posing challenges to the completion of DNA replication and chromosome segregation. Type II topoisomerases (Top2s) are enzymes that relieve DNA supercoiling and decatenate braided sister chromatids. How Top2 complexes deal with the topological challenges in different chromatin contexts, and whether all chromosomal contexts are subjected equally to torsional stress and require Top2 activity is unknown. Here we show that catalytic inhibition of the Top2 complex in interphase has a profound effect on the stability of heterochromatin and repetitive DNA elements. Mechanistically, we find that catalytically inactive Top2 is trapped around heterochromatin leading to DNA breaks and unresolved catenates, which necessitate the recruitment of the structure specific endonuclease, Ercc1-XPF, in an SLX4- and SUMO-dependent manner. Our data are consistent with a model in which Top2 complex resolves not only catenates between sister chromatids but also inter-chromosomal catenates between clustered repetitive elements.

Suggested Citation

  • Michalis Amoiridis & John Verigos & Karen Meaburn & William H. Gittens & Tao Ye & Matthew J. Neale & Evi Soutoglou, 2024. "Inhibition of topoisomerase 2 catalytic activity impacts the integrity of heterochromatin and repetitive DNA and leads to interlinks between clustered repeats," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-49816-7
    DOI: 10.1038/s41467-024-49816-7
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-024-49816-7
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-024-49816-7?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. William H. Gittens & Dominic J. Johnson & Rachal M. Allison & Tim J. Cooper & Holly Thomas & Matthew J. Neale, 2019. "A nucleotide resolution map of Top2-linked DNA breaks in the yeast and human genome," Nature Communications, Nature, vol. 10(1), pages 1-16, December.
    2. Duygu Yilmaz & Audrey Furst & Karen Meaburn & Aleksandra Lezaja & Yanlin Wen & Matthias Altmeyer & Bernardo Reina-San-Martin & Evi Soutoglou, 2021. "Activation of homologous recombination in G1 preserves centromeric integrity," Nature, Nature, vol. 600(7890), pages 748-753, 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. Zhen Teng & Lu Yang & Qian Zhang & Yujue Chen & Xianfeng Wang & Yiran Zheng & Aiguo Tian & Di Tian & Zhen Lin & Wu-Min Deng & Hong Liu, 2024. "Topoisomerase I is an evolutionarily conserved key regulator for satellite DNA transcription," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    2. Aurélie Diman & Gaël Panis & Cédric Castrogiovanni & Julien Prados & Bastien Baechler & Michel Strubin, 2024. "Human Smc5/6 recognises transcription-generated positive DNA supercoils," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    3. Albert Stuart Reece & Gary Kenneth Hulse, 2022. "Cannabis- and Substance-Related Epidemiological Patterns of Chromosomal Congenital Anomalies in Europe: Geospatiotemporal and Causal Inferential Study," IJERPH, MDPI, vol. 19(18), pages 1-51, September.
    4. Albert Stuart Reece & Gary Kenneth Hulse, 2022. "Epigenomic and Other Evidence for Cannabis-Induced Aging Contextualized in a Synthetic Epidemiologic Overview of Cannabinoid-Related Teratogenesis and Cannabinoid-Related Carcinogenesis," IJERPH, MDPI, vol. 19(24), pages 1-57, December.
    5. Ashish Kumar Singh & Tamás Schauer & Lena Pfaller & Tobias Straub & Felix Mueller-Planitz, 2021. "The biogenesis and function of nucleosome arrays," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    6. Albert Stuart Reece & Gary Kenneth Hulse, 2023. "Clinical Epigenomic Explanation of the Epidemiology of Cannabinoid Genotoxicity Manifesting as Transgenerational Teratogenesis, Cancerogenesis and Aging Acceleration," IJERPH, MDPI, vol. 20(4), pages 1-24, February.

    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_s41467-024-49816-7. 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.