Cited by 341DNA Repair MechanismsGenomics and Chromatin DynamicsChromatin Remodeling and Cancer

Loop extrusion as a mechanism for formation of DNA damage repair foci

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Arnould, Coline, Rocher, Vincent, Finoux, Anne-Laure, Clouaire, Thomas, Li, Kevin, Zhou, Felix, Caron, Pierre, Mangeot, Philippe. E. +5 more·2021·Nature

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Abstract

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 foci 1. 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 processes 2,3. 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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Authors
Arnould, C., Rocher, V., Finoux, A.-L., Clouaire, T., Li, K., Zhou, F., Caron, P., Mangeot, P. E., Ricci, E. P., Mourad, R., Haber, J. E., Noordermeer, D., & Legube, G.
Affiliations
  • Centre National de la Recherche Scientifique (FR)
  • Brandeis University (US)
  • Lyon 1 Université (FR)
Corresponding author
Legube, Gaëlle
Venue
Nature
Published
2021-02-17
Volume
590
Issue
7847
Pages
660-665
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
OpenAlex
W3132847906
Cited by
341
References
56
Citations by year
2026: 43 · 2025: 64 · 2024: 66 · 2023: 67 · 2022: 62 · 2021: 33 · 2020: 5 · 2019: 1
FWCI
17.97
Type
journal article
Language
en
Open access
Locations
  • Nature (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • HAL (submittedVersion, other-oa)
  • HAL (submittedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
Funders
  • Fondation Innovations en Infectiologie
  • European Commission (ERC-2014, ERC-2014-CoG)
  • Agence Nationale de la Recherche (ANR18, ANR-11-LABX-0048, ANR-14-CE10-0002, ANR-13-BSV8-0013, ANR-18-CE12-0015)
  • Institut National Du Cancer
  • Université de Lyon (ANR-11-LABX-0048)
  • Laboratoire d'Excellence Ecofect (ANR-11-LABX-0048)
  • National Institutes of Health
  • National Institute of General Medical Sciences (T32GM007122, GM127029, R35GM127029)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
Keywords
loop extrusion, DNA double-strand break repair, topologically associating domains, cohesin, γH2AX, 53BP1, ATM kinase, chromatin domains, 3D genome organization, genome stability, H2AX phosphorylation
MeSH terms
Tumor Suppressor p53-Binding Protein 1, Cohesins, Cell Line, Chromosomal Proteins, Non-Histone, DNA, DNA Repair, Histones, Humans, Nucleic Acid Conformation, Nucleosomes, Phosphorylation, Saccharomyces cerevisiae, Genome, Cell Cycle Proteins, Saccharomyces cerevisiae Proteins, DNA Breaks, Double-Stranded

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