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Identification of the elementary structural units of the DNA damage response

Author

Listed:
  • Francesco Natale

    (Technische Universität Darmstadt)

  • Alexander Rapp

    (Technische Universität Darmstadt)

  • Wei Yu

    (Technische Universität Darmstadt
    Present address: G5 Lymphocyte Development and Oncogenesis, Immunology Department, Pasteur Institute, 75724 Paris Cedex 15, France)

  • Andreas Maiser

    (Center for Integrated Protein Science Munich (CIPSM), LMU Munich)

  • Hartmann Harz

    (Center for Integrated Protein Science Munich (CIPSM), LMU Munich)

  • Annina Scholl

    (Technische Universität Darmstadt)

  • Stephan Grulich

    (Technische Universität Darmstadt)

  • Tobias Anton

    (Center for Integrated Protein Science Munich (CIPSM), LMU Munich)

  • David Hörl

    (Center for Integrated Protein Science Munich (CIPSM), LMU Munich)

  • Wei Chen

    (Max Delbrück Center for Molecular Medicine)

  • Marco Durante

    (GSI Helmholtzzentrum für Schwerionenforschung
    Present address: Trento Institute for Fundamental Physics and Application (TIFPA-INFN), via Sommarive 14, 38123 Trento, Italy)

  • Gisela Taucher-Scholz

    (GSI Helmholtzzentrum für Schwerionenforschung)

  • Heinrich Leonhardt

    (Center for Integrated Protein Science Munich (CIPSM), LMU Munich)

  • M. Cristina Cardoso

    (Technische Universität Darmstadt)

Abstract

Histone H2AX phosphorylation is an early signalling event triggered by DNA double-strand breaks (DSBs). To elucidate the elementary units of phospho-H2AX-labelled chromatin, we integrate super-resolution microscopy of phospho-H2AX during DNA repair in human cells with genome-wide sequencing analyses. Here we identify phospho-H2AX chromatin domains in the nanometre range with median length of ∼75 kb. Correlation analysis with over 60 genomic features shows a time-dependent euchromatin-to-heterochromatin repair trend. After X-ray or CRISPR-Cas9-mediated DSBs, phospho-H2AX-labelled heterochromatin exhibits DNA decondensation while retaining heterochromatic histone marks, indicating that chromatin structural and molecular determinants are uncoupled during repair. The phospho-H2AX nano-domains arrange into higher-order clustered structures of discontinuously phosphorylated chromatin, flanked by CTCF. CTCF knockdown impairs spreading of the phosphorylation throughout the 3D-looped nano-domains. Co-staining of phospho-H2AX with phospho-Ku70 and TUNEL reveals that clusters rather than nano-foci represent single DSBs. Hence, each chromatin loop is a nano-focus, whose clusters correspond to previously known phospho-H2AX foci.

Suggested Citation

  • Francesco Natale & Alexander Rapp & Wei Yu & Andreas Maiser & Hartmann Harz & Annina Scholl & Stephan Grulich & Tobias Anton & David Hörl & Wei Chen & Marco Durante & Gisela Taucher-Scholz & Heinrich , 2017. "Identification of the elementary structural units of the DNA damage response," Nature Communications, Nature, vol. 8(1), pages 1-18, August.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms15760
    DOI: 10.1038/ncomms15760
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    Cited by:

    1. Kim L. Luca & Pim M. J. Rullens & Magdalena A. Karpinska & Sandra S. Vries & Agnieszka Gacek-Matthews & Lőrinc S. Pongor & Gaëlle Legube & Joanna W. Jachowicz & A. Marieke Oudelaar & Jop Kind, 2024. "Genome-wide profiling of DNA repair proteins in single cells," Nature Communications, Nature, vol. 15(1), pages 1-16, December.

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