Chromatin adaptors and TOPBP1 condensates cooperate to organize ATM signaling

Abstract

DNA damage response proteins frequently accumulate in biomolecular condensates, yet how these structures cooperate with classical adaptor-mediated recruitment mechanisms to organize DNA damage signaling remains poorly understood. Here, we identify Treacle and the ATM adaptor NBS1 as prominent components of TOPBP1 condensates and show that these structures activate ATM signaling in the absence of DNA damage. At rDNA breaks, Treacle recruits NBS1 and TOPBP1 through genetically separable interaction modules. Acute protein degradation further revealed that Treacle is required for condensate assembly, whereas TOPBP1 remains continuously required for condensate maintenance. Finally, we show that efficient ATM accumulation at IR-induced DNA double-strand breaks similarly depends on both NBS1 and TOPBP1, indicating that this two-component mechanism is not restricted to nucleolar DNA damage. Together, our findings support a two-component model in which adaptor proteins provide molecular specificity, whereas TOPBP1 condensates create the spatial organization required for robust ATM signaling.