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TopBP1 assembles nuclear condensates to switch on ATR signalling

Abstract : ATR checkpoint signalling is crucial for cellular responses to DNA replication impediments. Using an optogenetic platform, we show that TopBP1, the main activator of ATR, selfassembles extensively to yield micron-sized condensates. These opto-TopBP1 condensates are functional entities organized in tightly packed clusters of spherical nano-particles. TopBP1 condensates are reversible, occasionally fuse and co-localise with TopBP1 partner proteins. We provide evidence that TopBP1 condensation is a molecular switch that amplifies ATR activity to phosphorylate checkpoint kinase 1 (Chk1) and slowdown replication forks. Single amino acid substitutions of key residues in the intrinsically disordered ATR-activation domain disrupt TopBP1 condensation and, consequently, ATR/Chk1 signalling. In physiologic salt concentration and pH, purified TopBP1 undergoes liquid-liquid phase separation in vitro. We propose that the actuation mechanism of ATR signalling is the assembly of TopBP1 condensates driven by highly regulated multivalent and cooperative interactions.
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https://www.hal.inserm.fr/inserm-03252517
Contributor : Angelos Constantinou <>
Submitted on : Monday, June 7, 2021 - 4:59:28 PM
Last modification on : Monday, July 5, 2021 - 4:42:04 PM

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Camilla Frattini, Alexy Promonet, Emile Alghoul, Sophie Vidal-Eychenie, Marie Lamarque, et al.. TopBP1 assembles nuclear condensates to switch on ATR signalling. Molecular Cell, Elsevier, 2021, 81 (6), pp.1231-1245.e8. ⟨10.1016/j.molcel.2020.12.049⟩. ⟨inserm-03252517⟩

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