DNA 损伤通过 ATR 介导的核纤层蛋白 A/C 磷酸化诱导核膜破裂。
DNA damage induces nuclear envelope rupture through ATR-mediated phosphorylation of lamin A/C.
发表日期：2023 Oct 19
作者：
Marton Tibor Kovacs, Marie Vallette, Pauline Wiertsema, Florent Dingli, Damarys Loew, Guilherme Pedreira de Freitas Nader, Matthieu Piel, Raphael Ceccaldi
来源：
MOLECULAR CELL
摘要：
核膜（NE）的完整性对于维持细胞核的结构稳定性至关重要。在癌细胞中经常观察到 NE 的破裂，特别是在物理限制和迁移等机械挑战的情况下。然而，也有报道称，自发的 NE 破裂事件对细胞没有任何明显的物理挑战。这些自发的 NE 破裂事件的分子机制仍有待探索。在这里，我们证明 DNA 损伤和随后的 ATR 激活会导致 NE 破裂。 DNA 损伤后，核纤层蛋白 A/C 以 ATR 依赖性方式磷酸化，导致核纤层组装发生变化，最终导致 NE 破裂。此外，我们还发现，具有内在 DNA 修复缺陷的癌细胞经常经历 DNA 损伤诱导的 NE 破裂事件，这使得它们对进一步的 NE 扰动极其敏感。利用这种 NE 漏洞可以提供一个新的角度来补充传统的、基于 DNA 损伤的化疗。版权所有 © 2023 作者。由爱思唯尔公司出版。保留所有权利。
The integrity of the nuclear envelope (NE) is essential for maintaining 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, without any obvious physical challenges to the cell, have also been described. The molecular mechanism(s) of these spontaneous NE rupture events remain to be explored. Here, we show that DNA damage and subsequent ATR activation leads 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.Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.