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

Author

Listed:
  • Coline Arnould

    (Centre de Biologie Intégrative (CBI), UPS, CNRS)

  • Vincent Rocher

    (Centre de Biologie Intégrative (CBI), UPS, CNRS)

  • Anne-Laure Finoux

    (Centre de Biologie Intégrative (CBI), UPS, CNRS)

  • Thomas Clouaire

    (Centre de Biologie Intégrative (CBI), UPS, CNRS)

  • Kevin Li

    (Brandeis University)

  • Felix Zhou

    (Brandeis University)

  • Pierre Caron

    (Centre de Biologie Intégrative (CBI), UPS, CNRS)

  • Philippe. E. Mangeot

    (University of Lyon)

  • Emiliano P. Ricci

    (Université Claude Bernard Lyon 1)

  • Raphaël Mourad

    (Centre de Biologie Intégrative (CBI), UPS, CNRS)

  • James E. Haber

    (Brandeis University)

  • Daan Noordermeer

    (Université Paris-Saclay, CEA, CNRS, Institute for Integrative Biology of the Cell (I2BC))

  • Gaëlle Legube

    (Centre de Biologie Intégrative (CBI), UPS, CNRS)

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 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.

Suggested Citation

  • Coline Arnould & Vincent Rocher & Anne-Laure Finoux & Thomas Clouaire & Kevin Li & Felix Zhou & Pierre Caron & Philippe. E. Mangeot & Emiliano P. Ricci & Raphaël Mourad & James E. Haber & Daan Noorder, 2021. "Loop extrusion as a mechanism for formation of DNA damage repair foci," Nature, Nature, vol. 590(7847), pages 660-665, February.
  • Handle: RePEc:nat:nature:v:590:y:2021:i:7847:d:10.1038_s41586-021-03193-z
    DOI: 10.1038/s41586-021-03193-z
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    Cited by:

    1. Jin H. Yang & Hugo B. Brandão & Anders S. Hansen, 2023. "DNA double-strand break end synapsis by DNA loop extrusion," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    2. Li-Hsin Chang & Sourav Ghosh & Andrea Papale & Jennifer M. Luppino & Mélanie Miranda & Vincent Piras & Jéril Degrouard & Joanne Edouard & Mallory Poncelet & Nathan Lecouvreur & Sébastien Bloyer & Amél, 2023. "Multi-feature clustering of CTCF binding creates robustness for loop extrusion blocking and Topologically Associating Domain boundaries," Nature Communications, Nature, vol. 14(1), pages 1-19, December.

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