Abstract
Intra-organelle communication is essential for cellular homeostasis, but the coordination between nuclear processes and cytoplasmic compartments remains poorly understood. Here, we uncover a novel spatiotemporal regulatory pathway linking the Golgi complex to the nucleus upon DNA damage. We show key DNA repair proteins, including RAD51C, dynamically shuttle between these organelles in response to distinct types of DNA damage. Mechanistic analysis reveals that RAD51C is anchored at the Golgi by Giantin. Disrupting this interaction leads to premature RAD51C nuclear localization, impaired homologous recombination signaling, genomic instability, and increased cell proliferation. Our findings establish Golgi-nuclear communication as a critical regulator of DNA repair, offering new insights into genomic integrity maintenance with profound implications for cancer and aging-related genomic instability.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
This version of the manuscript has been significantly revised to incorporate expanded mechanistic detail on the recruitment of RAD51C at the Golgi and the roles played by ATM, NBN, and GMAP210 in this process. We now describe how ATM activity facilitates the localization of RAD51C at the Golgi, throught the action of NBN and GMAP210. In addition, we have further dissected the signaling impacts arising from dysregulation of these components. This includes evidence that impaired RAD51C recruitment can lead to altered DNA repair processes and compromised cellular responses to genomic stress. We have updated the corresponding figures to illustrate these new findings and have refined our methods to provide clarity on experimental approaches. We also revised the discussion section to integrate recent literature. These updates represent a substantive advance from our previous version, offering a deeper exploration of the molecular events governing RAD51C recruitment and how their dysregulation can affect overall cellular homeostasis. Minor typographical and formatting errors have also been corrected throughout.
