UV-induced reorganization of 3D genome mediates DNA damage response

Abstract While it is well-established that UV radiation threatens genomic integrity, the precise mechanisms by which cells orchestrate DNA damage response and repair within the context of 3D genome architecture remain unclear. Here, we address this gap by investigating the UV-induced reorganization of the 3D genome and its critical role in mediating damage response. Employing temporal maps of contact matrices and transcriptional profiles, we illustrate the immediate and holistic changes in genome architecture post-irradiation, emphasizing the significance of this reconfiguration for effective DNA repair processes. We demonstrate that UV radiation triggers a comprehensive restructuring of the 3D genome organization at all levels, including loops, topologically associating domains and compartments. Through the analysis of DNA damage and excision repair maps, we uncover a correlation between genome folding, gene regulation, damage formation probability, and repair efficacy. We show that adaptive reorganization of the 3D genome is a key mediator of the damage response, providing new insights into the complex interplay of genomic structure and cellular defense mechanisms against UV-induced damage, thereby advancing our understanding of cellular resilience.