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Loop extrusion as a mechanism for formation of DNA damage repair foci
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Journal Article
Loop extrusion as a mechanism for formation of DNA damage repair foci
2021
Overview
The repair of DNA double-strand breaks (DSBs) is essential for safeguarding genome integrity. When a DSB forms, the PI3K-related ATM kinase rapidly triggers the establishment of megabase-sized, chromatin domains decorated with phosphorylated histone H2AX (γH2AX), which act as seeds for the formation of DNA-damage response foci
1
. It is unclear how these foci are rapidly assembled to establish a ‘repair-prone’ environment within the nucleus. Topologically associating domains 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 show that topologically associating domains are functional units of the DNA damage response, and are 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 in which H2AX-containing nucleosomes are rapidly phosphorylated as they actively pass by DSB-anchored cohesin. Our work highlights the importance of chromosome conformation in the maintenance of genome integrity and demonstrates the establishment of a chromatin modification by loop extrusion.
During the repair of double-stranded DNA breaks, cohesin mediates the extrusion of loops of DNA along which phosphorylated H2AX spreads to establish a repair zone.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
1-Phosphatidylinositol 3-kinase
/ 45/15
/ 45/23
/ 45/61
/ 45/71
/ 45/77
/ Analysis
/ Cell Cycle Proteins - metabolism
/ Chromosomal Proteins, Non-Histone - metabolism
/ Cohesin
/ Cohesins
/ Damage
/ DNA
/ Domains
/ Genomes
/ Humanities and Social Sciences
/ Humans
/ Kinases
/ Methods
/ Repair
/ Saccharomyces cerevisiae - cytology
/ Saccharomyces cerevisiae - genetics
/ Saccharomyces cerevisiae Proteins - metabolism
/ Science
/ Seeds
