The repair of DNA double-strand breaks (DSBs) is essential for safeguarding genome integrity. When a DSB forms, the PI3K-related ATM kinase rapidly triggers the establishment of megabase-sized, chromatin domains decorated with phosphorylated histone H2AX (γH2AX), which act as seeds for the formation of DNA-damage response foci1. It is unclear how these foci are rapidly assembled to establish a ‘repair-prone’ environment within the nucleus. Topologically associating domains are a key feature of 3D genome organization that compartmentalize transcription and replication, but little is known about their contribution to DNA repair processes2,3. Here we show that topologically associating domains are functional units of the DNA damage response, and are instrumental for the correct establishment of γH2AX–53BP1 chromatin domains in a manner that involves one-sided cohesin-mediated loop extrusion on both sides of the DSB. We propose a model in which H2AX-containing nucleosomes are rapidly phosphorylated as they actively pass by DSB-anchored cohesin. Our work highlights the importance of chromosome conformation in the maintenance of genome integrity and demonstrates the establishment of a chromatin modification by loop extrusion.
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A graph neural network-based interpretable framework reveals a novel DNA fragility–associated chromatin structural unit
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Nature Communications Open Access 06 April 2023
Nature Structural & Molecular Biology Open Access 06 March 2023
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All high-throughput sequencing data (Hi-C, ChIP–seq, 4C–seq) have been deposited to Array Express (https://www.ebi.ac.uk/arrayexpress/) under accession number E-MTAB-8851. ChIP–chip data have been deposited to Array Express under accession number E-MTAB-8793. Uncropped blots are shown in Supplementary Fig. 1. Other data (ChIP–qPCR and raw microscopy data) are available upon request.
Source codes are available from https://github.com/LegubeDNAREPAIR/LoopExtrusion.
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We thank the genomics core facility of EMBL for high-throughput sequencing; the high-throughput sequencing core facility of the I2BC (Centre de Recherche de Gif) for facilities and expertise; F. Beckouet for advice on yeast work; J. Rispal and N. Firmin for occasional experimental help; and C. Normand for discussions. Work in the Haber laboratory was funded by grant R35 GM127029 from the US National Institutes of Health. F.Z. was supported by the National Institute of General Medical Sciences Training Grant TM32GM007122. E.R. is supported by Labex Ecofect (ANR-11-LABX-0048) of the Université de Lyon, Fondation FINOVI and by the European Research Council (ERC-StG-LS6-805500) under the European Union’s Horizon 2020 research and innovation programmes. Funding in the Legube laboratory was provided by grants from the European Research Council (ERC-2014-CoG 647344), the Agence Nationale pour la Recherche (ANR-14-CE10-0002-01 and ANR-18-CE12-0015), the Institut National Contre le Cancer (INCA), and the Ligue Nationale Contre le Cancer (LNCC). This work was supported by the Fondation pour la Recherche Médicale, grant number FDT201904007941, to C.A.
The authors declare no competing interests.
Peer review information Nature thanks Leonid Mirny and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Peer reviewer reports are available.
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Extended data figures and tables
a, 4C–seq tracks before DSB induction obtained for three independent biological replicates and γH2AX ChIP–seq track after DSB induction for different viewpoints (red arrows) localized at three AsiSI sites (black arrows). ChIP–seq data were smoothed using 100-kb span and 4C–seq data using a 50-kb span. b, Example of the Hi-C pattern obtained on chromosome 1 at a 500-kb resolution (left) together with a magnification at a 10-kb resolution (right). c, CTCF and calibrated-SCC1 ChIP–seq tracks. d, Average profile of CTCF ChIP–seq around all loop anchors on the genome (determined using this Hi-C dataset, Methods), validating both CTCF ChIP–seq and Hi-C datasets. e, γH2AX ChIP–seq after DSB induction. 4C–seq and CTCF ChIP–seq peak position before DSB induction are shown (peaks in blue contain a CTCF motif in the forward orientation and peaks in red a CTCF motif in the reverse orientation). f, Box plot showing γH2AX (top), 53BP1 (middle) and MDC1 (bottom) ChIP–seq quantification within the damaged TAD and neighbouring TADs for the best cleaved DSBs in DIvA cells (Methods). Centre line, median; box limits, first and third quartiles; whiskers, maximum and minimum without outliers; points, outliers (n = 153). g, γH2AX tracks around a DSB induced by CRISPR–Cas9 (top, ChIP–chip, expressed as log2[sample/input], smoothed using 100-probe windows) and by AsiSI at the same position (bottom, ChIP–seq, 50-kb smoothed). h, Top, immunofluorescence experiment showing γH2AX and DAPI staining before and after DSB induction with or without ATM inhibitor as indicated (scale bars, 10 μm). Bottom, quantification of γH2AX intensity (expressed in arbitrary units (A.U.)) in the above conditions. One representative experiment is shown (out of n = 3 biological replicates). Box plots as in f. –DSB, n = 117 nuclei; +DSB, n = 97 nuclei; +DSB + ATMi, n = 95 nuclei. i, Validation of ATR inhibitor efficiency. Western blot showing the effect of ATRi on the phosphorylation of CHK1 following treatment with hydroxyurea (HU) (n = 2). For gel source data, see Supplementary Fig. 1. j, γH2AX ChIP–seq tracks after DSB induction in untreated cells or in cells treated with an inhibitor of ATM or ATR at two DSB sites (20-kb smoothed). The differential γH2AX signal obtained after DSB induction (expressed as the log2 ratio ATMi/untreated or ATRi/untreated, grey tracks) is also shown (n = 1). k, Average profile of pATM (S1981) (left) and γH2AX (right) ChIP–seq on a 2-Mb window around the 80 best-cleaved DSBs in DIvA cells.
a, Calibrated SCC1 ChIP–seq tracks before (grey) and after (black) DSB induction (n = 1). SCC1 enrichment at DSB site is indicated by a red arrow. b, Average profile of SCC1 ChIP–seq signal centred on the 80 best-induced DSBs (left) or centred on all CTCF peaks of the genome (right) on a 10-kb window. c, Calibrated ChIP–qPCR of SCC1 in the indicated conditions at three DSB sites or a negative control region. Insets, western blots validating depletion of the proteins NIPBL (n = 1) and MRE11 (n = 2) by the corresponding siRNAs. For gel source data, see Supplementary Fig. 1. Mean ± s.e.m. for technical replicates (n = 4) of a representative experiment (out of n = 2 biological replicates). d, Averaged Hi-C matrix before (−DSB) and after DSB induction (+DSB) (observed/expected) and of the log2 ratio between damaged and undamaged cells centred on the 80 best-induced DSBs (top) or centred on eighty random TAD borders (bottom) (50-kb resolution, 5-Mb window; combined replicates). e, Averaged Hi-C contact matrix of log2[+DSB/−DSB] centred on the eighty best-induced DSBs in the two independent biological replicates. f, APA plot on a 200-kb window (10-kb resolution) before (−DSB) and after DSB induction (+DSB) in biological replicate no. 2 (replicate no. 1 shown in Fig. 2c). APAs are calculated between the DSBs and loop anchors (n = 552 pairs). The fold change between the signal (central pixel) and the background (upper left corner 5 × 5 pixels) is indicated. g, For comparison with f, APA plot on a 200-kb window (10-kb resolution) before DSB induction computed between classical loop anchors that are near DSB sites (<500 kb; n = 674 pairs for replicate 1 and n = 737 pairs for replicate 2). The fold change between the signal (central pixel) and the background (upper left corner 5 × 5 pixels) is indicated. The loop strength (quantified by the fold change between signal and background on the APA plot) is higher at loop anchors (g, replicate 1 fold-change = 5.4; replicate 2 fold-change = 5.8) than the loop strength observed at DSBs after break induction (Fig. 2c, replicate 1, fold-change = 2; f, replicate 2, fold-change = 2.3).
a, 4C–seq tracks (10-kb smoothed) before and after DSB induction, obtained for three biological replicates using viewpoints localized at three DSB sites (arrows). b, 4C–seq tracks before (blue) and after (purple) DSB induction, at two DSB viewpoints. Differential 4C–seq (log2[+DSB/−DSB]) is also shown (black). c, Differential 4C–seq (log2[+DSB/−DSB]) for three viewpoints located at DSB sites and on a control region as indicated. d, Differential 4C–seq signal (log2[+DSB/−DSB]) computed on 1 Mb around four independent viewpoints located at DSBs (DSBs viewpoints, n = 11) and one control region (control viewpoint, n = 3), across four independent biological experiments (Methods). Two-sided Wilcoxon test; mean ± s.e.m. e, Western blot showing depletion of SCC1 by siRNA (n = 3). For gel source data, see Supplementary Fig. 1. f, Differential (log2) 4C–seq track in siSCC1-treated cells versus control siRNA-treated cells (in undamaged conditions) for three viewpoints. g, Genomics tracks showing 4C–seq signals before and after DSB induction in control siRNA- or siSCC1-treated cells and the differential 4C–seq signal in control siRNA- or siSCC1-treated cells (log2[+DSB/−DSB]; 10-kb smoothed). h, Average log2[+DSB/−DSB] 4C–seq, on 1 Mb around four DSB viewpoints (two biological experiments) upon treatment with control siRNA or siSCC1 (Methods) (n = 8). Two-sided Wilcoxon test. Centre line, median; box limits, first and third quartiles; whiskers, maximum and minimum without outliers; points, outliers.
a, Hi-C maps before DSB induction of a region of chromosome 17 in control and SCC1-depleted cells. Left, 100-kb resolution; right, 25-kb resolution. b, Genomic tracks of 4C–seq before and after DSB induction in untreated or ATM-inhibitor-treated cells and of differential 4C–seq signal (log2[+DSB/−DSB] or log2[+DSB + ATMi/−DSB]; 10-kb smoothed). c, Cis interactions computed as in Extended Data Fig. 3h for four DSB viewpoints across three biological experiments, in control condition or upon ATM inhibition. Two-sided Wilcoxon test. Centre line, median; box limits, first and third quartiles; whiskers, maximum and minimum without outliers; points, outliers (n = 8).
a, Quantification of γH2AX intensity after DSB induction (OHT, 4 h) and upon ATM inhibition followed by different times after ATMi release (0 min, n = 172 nuclei; 5 min, n = 183 nuclei; 15 min, n = 171 nuclei; 30 min, n = 197 nuclei; 1 h, n = 189 nuclei). Treatment with OHT for 4 h without ATMi is also shown (n = 182 nuclei). One representative experiment is shown (out of n = 2 biological replicates). Centre line, median; box limits, first and third quartiles; whiskers, maximum and minimum without outliers. b, Spread of γH2AX (in bp) at the indicated time points after release from ATMi around the best cleaved DSBs (n = 71). Centre line, median; box limits, first and third quartiles; whiskers, maximum and minimum without outliers; points, outliers. c, Black, 4C–seq track before DSB induction using a DSB viewpoint. Purple, differential γH2AX signal obtained after DSB induction by ChIP–chip in SCC1-depleted versus control cells (expressed as γH2AX log2[siSCC1/siCtrl]). Light blue, differential 4C–seq signal obtained in SCC1-depleted versus control cells before DSB induction (log2[siSCC1/siCtrl]). d, Genomic tracks of γH2AX ChIP–seq signal after DSB induction in control (red) or SCC1-depleted (pink) cells and of the differential γH2AX signal obtained after DSB induction (log2[siSCC1/siCtrl], purple) at two DSB sites. e, Western blot validating the effect of the siRNA targeting WAPL on the WAPL protein level (n = 2). For gel source data, see Supplementary Fig. 1. f, Genomics tracks of γH2AX ChIP–seq after DSB induction in control or WAPL-depleted cells and of the differential γH2AX signal obtained after DSB induction (log2[siWAPL/siCtrl]) at two DSB sites and one control (no DSB) genomic locus (20-kb smoothed). g, Genomics tracks of the differential γH2A ChIP–seq signal (log2[+DSB/−DSB]) before (no IAA) or after PDS5 degradation (IAA) at two DSB sites (HO sites) in S. cerevisiae (SacCer3, coordinates in bp) (n = 1).
Extended Data Fig. 6 Increased genome-wide, DSB-induced, cohesin binding is enhanced within damaged TADs.
a, Top, contact matrix (5-kb resolution) showing log2[observed/expected] before or after DSB induction on a region showing a loop on chromosome 20 and devoid of AsiSI site (no DSB). Loops anchors are circled and indicated by red and blue bars. Bottom, genome browser screenshot showing the SCC1-calibrated ChIP–seq on the same region before and after DSB induction. Cohesin enrichment at the loop anchors (blue and red bars) is increased after DSB (black arrows) compared to before DSB (grey arrows), in agreement with increased loop strength (grey and black circles, top). b, Violin plots showing SCC1 enrichment at cohesin peaks (n = 46,194) before and after DSB induction. Paired one-sided Wilcoxon test. c, Genomic tracks of γH2AX (red) and SCC1 ChIP–seq signal before (blue) and after (purple) DSB induction. The ratio between before and after DSB induction (grey) is also shown (log2[+DSB/−DSB]; 10-kb smoothed). d, Quantification of SCC1 recruitment on loop anchors at different distances from DSB sites as indicated (from left to right, n = 1,610, 3,161, 1,930, 3,232, 4,786, 25,263, 114,461). Centre line, median; box limits, first and third quartiles; whiskers, maximum and minimum; points, outliers. e, γH2AX ChIP–seq signal and Hi-C signal at different distances from a damaged TAD on chromosome 1 before (−DSB) and after DSB induction (+DSB). Green circles, chromatin loops. f, APA plot on a 200-kb window (10-kb resolution) before (−DSB) and after DSB induction (+DSB) calculated for all loop anchors, in damaged and undamaged TADs. The fold change between the signal (central pixel) and the background (lower left corner 5 × 5 pixels) is indicated. g, Differential loop strengths in undamaged or damaged TADs (Methods), computed from Hi-C data obtained before and after DSB, from replicates 1 and 2. P values between before and after DSB are indicated (Wilcoxon test, μ = 0). The increased loop strength following DSB is significantly higher in damaged TADs than in undamaged TADs (paired two-sided Wilcoxon test) in both Hi-C replicate experiments. Replicate 1: undamaged, n = 2,936; damaged, n = 264. Replicate 2: undamaged, n = 3,181; damaged, n = 302. Box plots as in d.
a, Genomic tracks showing γH2AX, pSMC3 S1083 and pSMC1 S966 ChIP–chip signals expressed as log2[sample/input] after DSB induction. Two damaged genomic locations are shown. b, Average profile of pSMC3 S1083 (expressed as log2([+DSB/−DSB] ChIP–seq signal) around the 80 best-induced DSBs on a 4-Mb window. c, Quantification of pSMC3 S1083 signal on loop anchors in damaged or undamaged TADs. P values between before and after DSB are indicated (paired two-sided Wilcoxon test). The increased pSMC3 S1083 enrichment on loop anchors following DSB is significantly higher in damaged TADs than in undamaged TADs (two-sided Wilcoxon test). Undamaged, n = 9,040; damaged, n = 1,626. Centre line, median; box limits, first and third quartiles; whiskers, maximum and minimum without outliers; points, outliers.
Supplementary Figure 1: Uncropped versions of the cropped Western blots presented in Extended Data Fig. 1i, 2c, 3e and 5e, with size marker indications. For each uncropped scan, the figure to which they refer is indicated above the scan. The red squares indicate which crop was used in the Extended Data figures.
Supplementary Table 1: Peak calling results (bed file) of the CTCF ChIP-seq performed before DSB induction in the DIvA cells and using MACS2. The MACS2 output “summits” is provided.
Supplementary Table 2: Peak calling results (bed file) of the SCC1 ChIP-seq performed before DSB induction in the DIvA cells and using MACS2. The MACS2 output “summits” is provided.
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Arnould, C., Rocher, V., Finoux, AL. et al. Loop extrusion as a mechanism for formation of DNA damage repair foci. Nature 590, 660–665 (2021). https://doi.org/10.1038/s41586-021-03193-z
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