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| Item Type: | Article |
|---|---|
| Title: | Identification of the elementary structural units of the DNA damage response |
| Creators Name: | Natale, F., Rapp, A., Yu, W., Maiser, A., Harz, H., Scholl, A., Grulich, S., Anton, T., Hoerl, D., Chen, W., Durante, M., Taucher-Scholz, G., Leonhardt, H. and Cardoso, M.C. |
| 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. |
| Keywords: | DNA Damage and Repair, Histone Post-Translational Modifications, Super-Resolution Microscopy |
| Source: | Nature Communications |
| ISSN: | 2041-1723 |
| Publisher: | Nature Publishing Group |
| Volume: | 8 |
| Page Range: | 15760 |
| Date: | 12 June 2017 |
| Official Publication: | https://doi.org/10.1038/ncomms15760 |
| PubMed: | View item in PubMed |
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