Chromatin compartmentalization regulates the response to DNA damage

Coline Arnould, Vincent Rocher, Florian Saur, Aldo S. Bader, Fernando Muzzopappa, Sarah Collins, Emma Lesage, Benjamin Bozec, Nadine Puget, Thomas Clouaire, Thomas Mangeat, Raphael Mourad, Nadav Ahituv, Daan Noordermeer, Fabian Erdel, Martin Bushell, Aline Marnef and Gaëlle Legube ()
Additional contact information
Coline Arnould: Université de Toulouse, UT3
Vincent Rocher: Université de Toulouse, UT3
Florian Saur: Université de Toulouse, UT3
Aldo S. Bader: Cancer Research UK Beatson Institute
Fernando Muzzopappa: Université de Toulouse, UT3
Sarah Collins: Université de Toulouse, UT3
Emma Lesage: Université de Toulouse, UT3
Benjamin Bozec: Université de Toulouse, UT3
Nadine Puget: Université de Toulouse, UT3
Thomas Clouaire: Université de Toulouse, UT3
Thomas Mangeat: Université de Toulouse, CNRS, UPS
Raphael Mourad: Université de Toulouse, UT3
Nadav Ahituv: University of California, San Francisco
Daan Noordermeer: Université Paris-Saclay, CEA, CNRS, Institute for Integrative Biology of the Cell (I2BC)
Fabian Erdel: Université de Toulouse, UT3
Martin Bushell: University of California, San Francisco
Aline Marnef: Université de Toulouse, UT3
Gaëlle Legube: Université de Toulouse, UT3

Nature, 2023, vol. 623, issue 7985, 183-192

Abstract: Abstract The DNA damage response is essential to safeguard genome integrity. Although the contribution of chromatin in DNA repair has been investigated1,2, the contribution of chromosome folding to these processes remains unclear3. Here we report that, after the production of double-stranded breaks (DSBs) in mammalian cells, ATM drives the formation of a new chromatin compartment (D compartment) through the clustering of damaged topologically associating domains, decorated with γH2AX and 53BP1. This compartment forms by a mechanism that is consistent with polymer–polymer phase separation rather than liquid–liquid phase separation. The D compartment arises mostly in G1 phase, is independent of cohesin and is enhanced after pharmacological inhibition of DNA-dependent protein kinase (DNA-PK) or R-loop accumulation. Importantly, R-loop-enriched DNA-damage-responsive genes physically localize to the D compartment, and this contributes to their optimal activation, providing a function for DSB clustering in the DNA damage response. However, DSB-induced chromosome reorganization comes at the expense of an increased rate of translocations, also observed in cancer genomes. Overall, we characterize how DSB-induced compartmentalization orchestrates the DNA damage response and highlight the critical impact of chromosome architecture in genomic instability.

Date: 2023
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DOI: 10.1038/s41586-023-06635-y

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