Biophysical mechanism and functional consequences of TopBP1 condensation – BioTop

Signaling by the master checkpoint kinase ATR is necessary for cells to overcome DNA replication obstacles and for organismal survival. TopBP1 is the main activator of ATR. Our results indicate that the nucleation of non-stoichiometrically defined TopBP1 biomolecular condensates, visualized as foci by immunofluorescence microscopy, switches on ATR signaling. We find that the self-assembly of TopBP1 condensates actuates DNA replication stress responses. In this interdisciplinary project, we will explore quantitatively the organization and the dynamics of TopBP1 proteins within condensates in physiological conditions. Our ambition is to reveal the underlying structure and the biophysical properties of TopBP1 condensates, and to understand how these properties contribute to TopBP1 functions in DNA replication stress responses. This knowledge will be crucial to develop modulators of TopBP1 condensation to control DNA damage responses and mitigate ageing-associated diseases.