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

## TL;DR

Paclitaxel causes nuclear damage in non-dividing cells by disrupting lamin A/C through SUN2, revealing a new mechanism beyond its known effects on cell division.

## Contribution

The study reveals a novel interphase mechanism of paclitaxel action involving SUN2 and lamin A/C disruption.

## Key findings

- Paclitaxel causes nuclear deformation and disrupts lamin A/C during interphase.
- SUN2 is essential for lamin A/C reduction and is regulated by polyubiquitylation during paclitaxel treatment.
- Lamin A/C levels affect cell survival and recovery after paclitaxel exposure.

## 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 upon paclitaxel treatment and is in turn regulated by polyubiquitylation. 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.

Summary: Paclitaxel induces nuclear aberrations in interphase through SUN2-dependent lamin A/C disruption, revealing mechanisms of action beyond mitotic arrest.