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

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 Noordermeer and Gaëlle Legube ()
Additional contact information
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

Nature, 2021, vol. 590, issue 7847, 660-665

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41586-021-03193-z

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