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

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  • 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
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    References listed on IDEAS

    as
    1. 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.
    2. 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.
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