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bioRxiv · 10.1101/2025.01.17.633376

Nuclear Disruption as a Mechanism of the Chemotherapeutic Drug Paclitaxel in Interphase

Hale, T.·Hale, V. L.·Kolata, P.·dos Santos, A.·Allegretti, M.
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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.

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Hale, T., Hale, V. L., Kolata, P., dos Santos, A., Allegretti, M.. 2025-01-20. Nuclear Disruption as a Mechanism of the Chemotherapeutic Drug Paclitaxel in Interphase. https://doi.org/10.1101/2025.01.17.633376

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