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You are here: Home / Teams / RNA metabolism in immunity and infection (RMI2) - E. Ricci / Publications / Loop extrusion as a mechanism for formation of DNA damage repair foci.

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, Raphaël Mourad, James E Haber, Daan Noordermeer, and Gaëlle Legube (2021)

Nature, 590(7847):660-665.

The repair of DNA double-strand breaks (DSBs) is essential for safeguarding genomeintegrity. When a DSB forms, the PI3K-related ATM kinase rapidly triggers theestablishment of megabase-sized, chromatin domains decorated with phosphorylatedhistone H2AX (γH2AX), which act as seeds for the formation of DNA-damage responsefoci(1). It is unclear how these foci are rapidly assembled to establish a'repair-prone' environment within the nucleus. Topologically associating domains area key feature of 3D genome organization that compartmentalize transcription andreplication, but little is known about their contribution to DNA repairprocesses(2,3). Here we show that topologically associating domains are functionalunits of the DNA damage response, and are instrumental for the correct establishmentof γH2AX-53BP1 chromatin domains in a manner that involves one-sidedcohesin-mediated loop extrusion on both sides of the DSB. We propose a model inwhich H2AX-containing nucleosomes are rapidly phosphorylated as they actively passby DSB-anchored cohesin. Our work highlights the importance of chromosomeconformation in the maintenance of genome integrity and demonstrates theestablishment of a chromatin modification by loop extrusion.

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