Identification of the elementary structural units of the DNA damage response

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 Leonhardt and M. Cristina Cardoso ()
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Francesco Natale: Technische Universität Darmstadt
Alexander Rapp: Technische Universität Darmstadt
Wei Yu: Technische Universität Darmstadt
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
Gisela Taucher-Scholz: GSI Helmholtzzentrum für Schwerionenforschung
Heinrich Leonhardt: Center for Integrated Protein Science Munich (CIPSM), LMU Munich
M. Cristina Cardoso: Technische Universität Darmstadt

Nature Communications, 2017, vol. 8, issue 1, 1-18

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms15760

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