Paclitaxel compromises nuclear integrity in interphase through SUN2-mediated cytoskeletal coupling

Abstract Regulation of Lamin A/C levels and distribution is crucial for nuclear integrity and mechanotransduction via the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex. Dysregulation of Lamin A/C correlates with poor cancer prognosis, and its levels determine sensitivity to the microtubule-stabilising drug paclitaxel. Paclitaxel is well-known for disrupting mitosis, yet it also reduces tumour size in slow-dividing tumours, indicating an additional, poorly characterised interphase mechanism. Here, we reveal that paclitaxel induces nuclear aberrations in interphase through SUN2-dependent Lamin A/C disruption. Using advanced optical imaging and electron cryo-tomography, we show the formation of aberrant microtubule-vimentin bundles during paclitaxel treatment, which coincides with nuclear deformation and altered Lamin A/C protein levels and organisation at the nuclear envelope. SUN2 is required for Lamin A/C reduction in paclitaxel and is in turn regulated by polyubiquitination. Furthermore, Lamin A/C expression levels determine not only cell survival during treatment but also recovery after drug removal. Our findings support a model in which paclitaxel acts through both defective mitosis and interphase nuclear-cytoskeletal disruption, providing additional mechanistic insights into a widely used anticancer drug.