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A nucleotide resolution map of Top2-linked DNA breaks in the yeast and human genome

Author

Listed:
  • William H. Gittens

    (University of Sussex)

  • Dominic J. Johnson

    (University of Sussex)

  • Rachal M. Allison

    (University of Sussex)

  • Tim J. Cooper

    (University of Sussex)

  • Holly Thomas

    (University of Sussex)

  • Matthew J. Neale

    (University of Sussex)

Abstract

DNA topoisomerases are required to resolve DNA topological stress. Despite this essential role, abortive topoisomerase activity generates aberrant protein-linked DNA breaks, jeopardising genome stability. Here, to understand the genomic distribution and mechanisms underpinning topoisomerase-induced DNA breaks, we map Top2 DNA cleavage with strand-specific nucleotide resolution across the S. cerevisiae and human genomes—and use the meiotic Spo11 protein to validate the broad applicability of this method to explore the role of diverse topoisomerase family members. Our data characterises Mre11-dependent repair in yeast and defines two strikingly different fractions of Top2 activity in humans: tightly localised CTCF-proximal, and broadly distributed transcription-proximal, the latter correlated with gene length and expression. Moreover, single nucleotide accuracy reveals the influence primary DNA sequence has upon Top2 cleavage—distinguishing sites likely to form canonical DNA double-strand breaks (DSBs) from those predisposed to form strand-biased DNA single-strand breaks (SSBs) induced by etoposide (VP16) in vivo.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-12802-5
    DOI: 10.1038/s41467-019-12802-5
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    Cited by:

    1. 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.
    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. 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.

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