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Identification of the elementary structural units of the DNA damage response.

Natale, Francesco ; Rapp, Alexander ; Yu, Wei ; Maiser, Andreas ; Harz, Hartmann ; Scholl, Annina ; Grulich, Stephan ; Anton, Tobias ; Hörl, David ; Chen, Wei ; Durante, Marco ; Taucher-Scholz, Gisela ; Leonhardt, Heinrich ; Cardoso, M. Cristina (2017):
Identification of the elementary structural units of the DNA damage response.
In: Nature communications, 8, p. 15760. ISSN 2041-1723,
[Article]

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.

Item Type: Article
Erschienen: 2017
Creators: Natale, Francesco ; Rapp, Alexander ; Yu, Wei ; Maiser, Andreas ; Harz, Hartmann ; Scholl, Annina ; Grulich, Stephan ; Anton, Tobias ; Hörl, David ; Chen, Wei ; Durante, Marco ; Taucher-Scholz, Gisela ; Leonhardt, Heinrich ; Cardoso, M. Cristina
Title: Identification of the elementary structural units of the DNA damage response.
Language: English
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.

Journal or Publication Title: Nature communications
Journal volume: 8
Divisions: 10 Department of Biology
10 Department of Biology > Cell Biology and Epigenetics
Date Deposited: 20 Jun 2017 06:40
Identification Number: pmid:28604675
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