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Loop extrusion as a mechanism for formation of DNA damage repair foci
Open accessPublished version of a preprint
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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“The cohesin complex is an important architectural protein that organizes the 3D genome and is also important in DSB repair”
From Neuronal DNA double-strand breaks lead to genome structural variations and 3D genome disruption in neurodegeneration (2023) · cites this paper as [32]
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“A recent study proposed that DSBs can act as roadblocks to loop extrusion32.”
From Neuronal DNA double-strand breaks lead to genome structural variations and 3D genome disruption in neurodegeneration (2023) · cites this paper as [32]
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Metadata
- 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
- ORCID
- Venue
- Nature
- Published
- 2021-02-17
- Volume
- 590
- Issue
- 7847
- Pages
- 660-665
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC7116834
- OpenAlex
- W3132847906
- Cited by
- 341
- References
- 56
- Citations by year
- 2026: 43 · 2025: 64 · 2024: 66 · 2023: 67 · 2022: 62 · 2021: 33
- FWCI
- 17.97
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- 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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