Laboratory for Cell Biology and Genetics, The Rockefeller University, New York, New York.
Mol Cancer Res. 2017 Nov;15(11):1579-1586. doi: 10.1158/1541-7786.MCR-17-0084. Epub 2017 Aug 15.
The mammalian nuclear envelope (NE) forms a stable physical barrier between the nucleus and the cytoplasm, normally breaking down only during mitosis. However, spontaneous transient NE rupture in interphase can occur when NE integrity is compromised, such as when the nucleus experiences mechanical stress. For instance, deficiencies in the nuclear lamins and their associated proteins can cause NE rupture that is promoted by forces exerted by actin filaments. NE rupture can allow cytoplasmic nucleases to access chromatin, potentially compromising genome integrity. Importantly, spontaneous NE rupture was noted in several human cancer cell lines, but the cause of this defect is not known. Here, we investigated the mechanistic contributions of two major tumor suppressors, p53 (TP53) and Rb (RB1), to the repression of NE rupture. NE rupture was induced in normal human epithelial RPE-1 cells upon impairment of either Rb or p53 achieved by shRNA knockdown and CRISPR/Cas9 gene editing. NE rupture did not involve diminished expression of NE components or greater cell motility. However, cells that underwent NE rupture displayed a larger nuclear projection area. In conclusion, the data indicate that NE rupture in cancer cells is likely due to loss of either the Rb or the p53 pathway. These findings imply that tumor suppression by Rb and p53 includes the ability to prevent NE rupture, thereby protecting against genome alterations. .
哺乳动物核膜（NE）在核和细胞质之间形成稳定的物理屏障，通常仅在有丝分裂期间分解。然而，当 NE 完整性受到损害时，如当细胞核经历机械应激时，间隙期会发生自发的瞬时 NE 破裂。例如，核纤层及其相关蛋白的缺陷会导致由肌动蛋白丝施加的力促进的 NE 破裂。NE 破裂可允许细胞质核酶接近染色质，从而可能损害基因组完整性。重要的是，在几种人类癌细胞系中观察到自发的 NE 破裂，但该缺陷的原因尚不清楚。在这里，我们研究了两个主要肿瘤抑制因子 p53（TP53）和 Rb（RB1）对抑制 NE 破裂的机制贡献。通过 shRNA 敲低和 CRISPR/Cas9 基因编辑来破坏 Rb 或 p53，在正常的人上皮 RPE-1 细胞中诱导 NE 破裂。NE 破裂不涉及 NE 成分表达减少或细胞迁移性增加。然而，经历了 NE 破裂的细胞显示出更大的核突出面积。总之，数据表明癌细胞中的 NE 破裂可能是由于 Rb 或 p53 通路的丧失所致。这些发现意味着 Rb 和 p53 的肿瘤抑制作用包括防止 NE 破裂的能力，从而防止基因组改变。
