ATM-dependent formation of a novel chromatin compartment regulates the Response to DNA Double Strand Breaks and the biogenesis of translocations - Archive ouverte HAL Accéder directement au contenu
Pré-Publication, Document De Travail Année : 2022

ATM-dependent formation of a novel chromatin compartment regulates the Response to DNA Double Strand Breaks and the biogenesis of translocations

Coline Arnould
Vincent Rocher
Emma Lesage
Nadine Puget
Thomas Clouaire
Raphael Mourad
Gaëlle Legube

Résumé

DNA Double-Strand Breaks (DSBs) repair is essential to safeguard genome integrity but the contribution of chromosome folding into this process remains elusive. Here we unveiled basic principles of chromosome dynamics upon DSBs in mammalian cells, controlled by key kinases from the DNA Damage Response. We report that ATM is responsible for the reinforcement of topologically associating domains (TAD) that experience a DSB. ATM further drives the formation of a new chromatin sub-compartment (“D” compartment) upon clustering of damaged TADs decorated with γH2AX and 53BP1. “D” compartment formation mostly occurs in G1, is independent of cohesin and is enhanced upon DNA-PK pharmacological inhibition. Importantly, a subset of DNA damage responsive genes that are upregulated following DSBs also physically localize in the D sub-compartment and this ensures their optimal activation, providing a function for DSB clustering in activating the DNA Damage Response. However, these DSB-induced changes in genome organization also come at the expense of an increased translocations rate, which we could also detect on cancer genomes. Overall, our work provides a function for DSB-induced compartmentalization in orchestrating the DNA Damage Response and highlights the critical impact of chromosome architecture in genomic instability.
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hal-03818730 , version 1 (18-10-2022)

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Paternité - Pas d'utilisation commerciale - Pas de modification

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Coline Arnould, Vincent Rocher, Aldo S Bader, Emma Lesage, Nadine Puget, et al.. ATM-dependent formation of a novel chromatin compartment regulates the Response to DNA Double Strand Breaks and the biogenesis of translocations. 2022. ⟨hal-03818730⟩
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