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Nature封面故事: 有丝分裂停滞

摘要 : 本期Nature封面是一个经过调整的图像,它显示的是凝聚的有丝分裂染色体(蓝色)。端粒TTAGGG重复序列(绿色)之间的共定位(co-localization)和一个DNA损伤标记(红色)表明,端粒被当成是细胞中的损伤,这些细胞在危机期间会在有丝分裂过程中自发停滞。

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本期Nature封面是一个经过调整的图像,它显示的是凝聚的有丝分裂染色体(蓝色)。端粒TTAGGG重复序列(绿色)之间的共定位(co-localization)和一个DNA损伤标记(红色)表明,端粒被当成是细胞中的损伤,这些细胞在危机期间会在有丝分裂过程中自发停滞。形成一个肿瘤的细胞在癌变之前必须克服两个障碍。第一个障碍是衰老(senescence),第二个障碍是被称为危机的增生障碍(proliferative block)。躲过了衰老的细胞在危机过程中通常会屈服,但此前一直不清楚在这个阶段是什么触发细胞死亡的。现在,Jan Karlseder及同事显示,在没有p53的情况下绕过了衰老的细胞具有会发生融合(fusion)的缩短的端粒,这些融合过程会触发有丝分裂延迟。在有丝分裂停滞期间,端粒被进一步 “去保护”,并被DNA损伤机构检测到,这会导致细胞死亡。这些发现也许提供了一个临床机会,因为有丝分裂的端粒去保护的加重会使癌细胞对有丝分裂药物敏感,但有丝分裂停滞也已被发现与检查点受损的细胞中的基因组不稳定和肿瘤发生有关。(封面图示:Jamie Simon, The Salk Institute)


Cell death during crisis is mediated by mitotic telomere deprotection


Tumour formation is blocked by two barriers: replicative senescence and crisis1. Senescence is triggered by short telomeres and is bypassed by disruption of tumour-suppressive pathways. After senescence bypass, cells undergo crisis, during which almost all of the cells in the population die. Cells that escape crisis harbour unstable genomes and other parameters of transformation. The mechanism of cell death during crisis remains unexplained. Here we show that human cells in crisis undergo spontaneous mitotic arrest, resulting in death during mitosis or in the following cell cycle. This phenotype is induced by loss of p53 function, and is suppressed by telomerase overexpression. Telomere fusions triggered mitotic arrest in p53-compromised non-crisis cells, indicating that such fusions are the underlying cause of cell death. Exacerbation of mitotic telomere deprotection by partial TRF2 (also known as TERF2) knockdown increased the ratio of cells that died during mitotic arrest and sensitized cancer cells to mitotic poisons. We propose a crisis pathway wherin chromosome fusions induce mitotic arrest, resulting in mitotic telomere deprotection and cell death, thereby eliminating precancerous cells from the population.

来源: Nature 浏览次数:10


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