DNA damage induces nuclear envelope rupture through ATR-mediated phosphorylation of Lamin A/C

The integrity of the nuclear envelope (NE) is essential to maintain the structural stability of the nucleus. Rupture of the NE has been frequently observed in cancer cells, especially in the context of mechanical challenges, such as physical confinement and migration. However, spontaneous NE rupture events have also been described, without any obvious physical challenges to the cell. The molecular mechanism(s) of these spontaneous NE rupture events remain to be explored. Here, we show that DNA damage and subsequent ATR activation can lead to NE rupture. Upon DNA damage, Lamin A/C is phosphorylated in an ATR-dependent manner, leading to changes in lamina assembly and, ultimately, NE rupture. In addition, we show that cancer cells with intrinsic DNA repair defects undergo frequent events of DNA damage-induced NE rupture, which renders them extremely sensitive to further NE perturbations. Exploiting this NE vulnerability could provide a new angle to complement traditional, DNA damage-based chemotherapy.

核被膜（nuclear envelope, NE）的完整性对于维持细胞核的结构稳定性至关重要。核被膜破裂现象在癌细胞中频繁被观测到，尤其在细胞面临机械应激的情境下，如物理约束与细胞迁移过程中。不过，无需细胞受到明显物理应激的自发性核被膜破裂事件也已有相关报道，此类事件的分子机制仍有待探索。本研究证实，DNA损伤及其后续的ATR激活可诱发核被膜破裂。当细胞发生DNA损伤时，核纤层蛋白A/C（Lamin A/C）会以ATR依赖的方式发生磷酸化，进而引发核纤层组装异常，最终导致核被膜破裂。此外，本研究发现，存在固有DNA修复缺陷的癌细胞会频繁发生DNA损伤诱导的核被膜破裂事件，这使得这类癌细胞对进一步的核被膜扰动极为敏感。利用这一核被膜脆弱性，可为传统的基于DNA损伤的化疗提供全新的补充思路。