Nuclear Envelope Rupture Is Enhanced by Loss of p53 or Rb.
Nuclear Envelope Rupture Is Enhanced by Loss of p53 or Rb.
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DOI：
10.1158/1541-7786.mcr-17-0084
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发表时间：
2017-11
期刊：
影响因子：
--
通讯作者：
de Lange T
中科院分区：
文献类型：
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作者：
Yang Z;Maciejowski J;de Lange T
哺乳动物核膜（NE）在细胞核和细胞质之间形成稳定的物理屏障，通常仅在有丝分裂的细胞周期阶段才会分解。然而，当 NE 完整性受到损害时，例如当细胞核经历机械应力时，可能会发生间期自发的短暂 NE 破裂。例如，核纤层蛋白及其相关蛋白的缺陷可能导致 NE 破裂，而肌动蛋白丝施加的力会促进 NE 破裂。 NE 破裂可使细胞质核酸酶进入染色质，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发现了自发的 NE 破裂，但这种缺陷的原因尚不清楚。在这里，我们研究了两种主要肿瘤抑制因子 p53 (TP53) 和 Rb (RB1) 对抑制 NE 破裂的机制贡献。通过 shRNA 敲低和 CRISPR/Cas9 基因编辑实现 Rb 或 p53 损伤，从而在正常人上皮 RPE-1 细胞中诱导 NE 破裂。 NE 破裂并不涉及 NE 成分表达的减少或细胞运动性的增强。然而，经历NE破裂的细胞显示出更大的核投影面积。总之，数据表明癌细胞中的 NE 破裂很可能是由于 Rb 或 p53 途径的丢失所致。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。
The mammalian nuclear envelope (NE) forms a stable physical barrier between the nucleus and the cytoplasm, normally breaking down only during the cell cycle phase of 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.