Spatiotemporal dynamics of DNA repair proteins between the Golgi and nucleus maintain genomic stability.

Abstract

The Golgi complex is a key organelle of the secretory pathway, but also serves as a critical hub for maintaining cellular homeostasis, orchestrating various signalling pathways and essential cellular processes such as membrane trafficking and post-translational modifications. Despite its central role, the communication between the Golgi and the cell nucleus has remained largely unexplored. To bridge this gap, we have analysed and siRNA-validated localisation data of the Human Protein Atlas, finding an unexpected and significant level of interconnectivity between the proteomes of the Golgi complex and nucleus, including an intriguing involvement in DNA repair processes. Here, we uncovered a cluster of DNA repair proteins present in distinct sub-Golgi localisations as well as in the nuclear compartment. In response to genotoxic stress these proteins redistribute dynamically between the Golgi complex and the nucleus, with the specific type of DNA injury influencing this distribution pattern. To probe this Golgi-nucleus link, we examined the Homologous Recombination (HR) regulator RAD51C and find that DNA damage triggers ATM-dependent release of a Giantin-tethered Golgi pool and Importin-{beta}-dependent nuclear import, where repair-associated nuclear foci form. Downregulation of Giantin prematurely releases RAD51C, producing RAD51C nuclear foci lacking key HR markers, reducing ATM activation, elevating genome instability, and accelerating cell proliferation. These findings support a timing-based pathway in which the Golgi acts as a spatiotemporal coordination node for HR regulators and other DDR factors. Our study sheds light on the dynamic interplay between the Golgi and the nucleus in safeguarding genomic stability while maintaining the delicate balance of cellular homeostasis.