Journal Article

Chromatin compartmentalization regulates the response to DNA damage

Rocher, Vincent, Le Bozec, Benjamin, Ahituv, Nadav, Arnould, Coline, Muzzopappa, Fernando, Puget, Nadine, Mourad, Raphael, Noordermeer, Daan, Erdel, Fabian, Saur, Florian, Collins, Sarah, Clouaire, Thomas, Marnef, Aline, Bader, Aldo S., Bushell, Martin, Mangeat, Thomas, Lesage, Emma, Legube, Gaëlle

2023

Overview

The DNA damage response is essential to safeguard genome integrity. Although the contribution of chromatin in DNA repair has been investigated 1 , 2 , the contribution of chromosome folding to these processes remains unclear 3 . 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. After the production of double-stranded breaks in mammalian cells, ATM drives the formation of the D compartment, which regulates DNA damage-responsive genes, through the clustering of damaged topologically associating domains, with a mechanism that is consistent with polymer–polymer phase separation.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 14/63 / 38/32 / 38/77 / 38/91 / 45/15 / 45/23 / 631/337/1427 / 631/337/386 / Agreements / Animals / Ataxia Telangiectasia Mutated Proteins / Ataxia Telangiectasia Mutated Proteins - metabolism / Cell Compartmentation / Cell cycle / Cell Line / Chromatin / Chromatin - genetics / Chromatin - metabolism / Chromosomes / Clustering / Cohesin / Damage accumulation / Deoxyribonucleic acid / DNA / DNA Breaks, Double-Stranded / DNA Damage / DNA Repair / DNA-Activated Protein Kinase / DNA-Activated Protein Kinase - metabolism / DNA-dependent protein kinase / Double-strand break repair / G1 Phase / Genomes / Genomic instability / Histones / Histones - metabolism / Humanities and Social Sciences / Impact damage / Kinases / Life Sciences / Liquid phases / Mammalian cells / multidisciplinary / Neoplasms / Neoplasms - genetics / Phase separation / Polymers / Proteins / R-Loop Structures / RNA polymerase / Science / Science (multidisciplinary) / Tumor Suppressor p53-Binding Protein 1 / Tumor Suppressor p53-Binding Protein 1 - metabolism / Yeast