Loop extrusion as a mechanism for formation of DNA damage repair foci

Abstract

DNA Double-Strand Break (DSB) repair is essential to safeguard genome integrity. Upon DSBs, the ATM PI3K kinase rapidly triggers the establishment of megabase-sized, γH2AX-decorated chromatin domains which further act as seeds for the formation of DNA Damage Response (DDR) foci 1 . How these foci are rapidly assembled in order to establish a “repair-prone” environment within the nucleus is yet unclear. Topologically Associating Domains (TADs) 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 found that TADs are functional units of the DDR, 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 whereby H2AX-containing nucleosomes are rapidly phosphorylated as they actively pass by DSB-anchored cohesin. Our work highlights the critical impact of chromosome conformation in the maintenance of genome integrity and provides the first example of a chromatin modification established by loop extrusion.

Untangling the crosstalk between BRCA1 and R-loops during DNA repair

“…As a first step in DSB repair, H2AX is rapidly phosphorylated at ser139 (γH2AX). This phosphorylation appears immediately after damage induction and spreads to both sides of the break in an asymmetric way ( 3 , 4 ). The spreading of γH2AX acts as a DDR recruitment platform by engaging downstream factors involved in signalling and repair.…”

Chromosome Organization in Early Meiotic Prophase

“…One well known ATM dependent-chromatin modification that is observed also away from DSB sites (50 Kb in yeast, a few Mb in mammals) is the phosphorylation of the H2A variant H2AX, named as gH2AX ( Mahadevaiah et al, 2001 ). As reported in somatic cells upon DSB induction, gH2AX spreads over large domains around the DSB sites, but its spreading is constrained at TADs in a process that requires cohesin-mediated loop extrusion ( Caron et al, 2012 ; Arnould et al, 2021 ).…”

“…Both REC8 and RAD21L could participate in loop extrusion, and loop boarders could be potentially defined by CTCF sites and sites of meiotic DSBs. Indeed, DSBs in vegetative cells are enriched in cohesins ( Strom et al, 2004 ; Unal et al, 2004 ) and DSBs have recently been shown to anchor cohesins at loop bases both in human cells ( Arnould et al, 2021 ) and S. cerevisiae ( Piazza et al, 2020 ).…”

MYC-Induced Replicative Stress: A Double-Edged Sword for Cancer Development and Treatment

“…The control of the 3D architecture of DNA replication and possibly chromatin looping [100] are likely key factors in preventing RS. In this regard, cohesins, by their coordinated control of DNA repair [101], DNA synthesis [102] and transcription [103], may play a relevant role. Indeed, silencing of the cohesin complex component RAD21 affected MYC-dependent transcription and altered replication forks [104].…”