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DNA looping helps genome repair

Published in Nature on feb. 17, 2021

Following the appearance of a double-strand break in DNA, the chromatin that surrounds this damage is modified over a large domain of up to a megabase in size. This creates a repair focus which allows efficient processing of the break. By studying the 3D organization of chromatin using Chromosome Conformation Capture techniques, scientists have shown that interacting genomic domains called TADs are functional units of the response to DNA breaks. This work, published in Nature, shows that the process of establishing TADs by loop extrusion plays a major role in the rapid formation of these favorable foci for DNA repair.

Double-Strand Breaks (DSB) are an extremely toxic damage to the DNA, and its repair is therefore essential to preserve the integrity of chromosomes. In response to the appearance of a DSB in the genome, the ATM kinase phosphorylates the histone H2AX variant over a very large domain, in the order of one megabase (one million base pairs), in a few minutes, thus creating a focus for repair. However, how these foci are assembled so rapidly to establish a nuclear environment that is favorable to DNA repair remained largely unknown.

The human genome adopts a highly structured organization in three dimensions in the cell nucleus. Of particular importance are the TADs (Topologically Associating Domains), which are domains enriched in chromatin interactions, each corresponding to a key unit of this chromatin organization. It has been proposed that TADs emerge from a loop extrusion process. According to this model, once associated with chromatin, a ring of Cohesin molecules surrounds the DNA to form a loop, which gradually widens as Cohesin actively extrudes the DNA. This process ends when Cohesin encounters particular sequences called strong boundary elements that mark the boundaries of the TAD. These DNA loops are ubiquitous in the human genome and various studies have highlighted a functional role of the organization of DNA into TADs in processes such as transcription or replication. However, the role of TADs and their loop extrusion formation mechanism had not yet been implicated in DNA repair.

A collaboration between Gaëlle Legube’s team at the CBI in Toulouse, and the teams of Daan Noordermeer at the I2BC in Gif-sur-Yvette, James E. Haber at Brandeis University in Waltham (USA) and Emiliano P. Ricci at the ENS in Lyon, has made it possible to answer these questions. The researchers used chromosome conformation capture techniques, such as Hi-C and 4C-seq, which make it possible to know respectively the chromatin interactions of the entire genome or of a specific DNA locus with the rest of the genome. These technologies, combined with a cellular system in which it is possible to induce a constant number of DSBs at known and annotated positions of the genome (DIvA model), have made it possible to highlight a major role of 3D chromatin conformation by loop extrusion in the repair of DSBs. Indeed, the researchers showed that H2AX phosphorylation on a whole DSB is is achieved through a Cohesin-dependent chromatin loop extrusion process that takes place on either side of the DSB (see Figure). The authors thus propose a new model to explain, on the one hand, how the repair sites are assembled, and on the other hand, the speed of this assembly, and thus involving TADs as functional units of the cellular response to DNA damage.

(a) >(a) The loop extrusion phenomena, as performed by Cohesin, occurs continuously on the genome. The appearance of a DSB in DNA blocks this ongoing process, resulting in the accumulation of Cohesin at the DSBs. (b) Cohesins, blocked on one side by the DSB, provide a unidirectional loop extrusion process anchored to the DSB. The ATM kinase, which is only locally recruited to the DSB, phosphoryl H2AX to form γH2AX as the nucleosomes are extruded. (c) The same process occurs on each side of the DSBs, allowing unidirectional and divergent loop extrusion phenomena, and thus bi-directional establishment of γH2AX. (d) These loop extrusion processes stop when cohesins encounter strong boundary elements. Since the chromatin loop extrusion speed measured in vitro can reach 0.5-2 kb/sec, this mechanism could allow phosphorylating H2AX on a whole TAD ( 1-2 Mb) in 10-30 min, allowing the rapid establishment of repair foci. © Arnould et Legube



This work has shown the major role of chromosome conformation in maintaining genome integrity while highlighting for the first time an example of chromatin modification through the loop extrusion process.


Reference :
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, Raphael Mourad, James E. Haber, Daan Noordermeer and Gaëlle Legube

Nature (2021) https://www.nature.com/articles/s41586-021-03193-z
DOI : 10.1038/s41586-021-03193-z


This publication is also highlighted by a ’News and views’ paper in Nature


Contact I2BC :
Daan Noordermeer

par Communication - publié le