Open AccessLoop extrusion as a mechanism for formation of DNA damage repair foci
Author(s) -
Coline Arnould,
Vincent Rocher,
Anne-Laure Finoux,
Thomas Clouaire,
Kevin Li,
Felix Zhou,
Pierre Caron,
Philippe Mangeot,
Emiliano P. Ricci,
Raphaël Mourad,
James E. Haber,
Daan Noordermeer,
Gaëlle Legube
Publication year - 2021
Publication title -
nature
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 15.993
H-Index - 1226
eISSN - 1476-4687
pISSN - 0028-0836
DOI - 10.1038/s41586-021-03193-z
Subject(s) - cohesin , chromatin , histone , dna damage , microbiology and biotechnology , dna repair , biology , dna , nucleosome , dna replication , genome , genetics , chemistry , computational biology , gene
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.