Permanent cell cycle exit in G2 phase after DNA damage in normal human fibroblasts
Permanent cell cycle exit in G2 phase after DNA damage in normal human fibroblasts
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DOI：
10.1093/emboj/cdg387
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发表时间：
2003-08-01
期刊：
影响因子：
11.4
通讯作者：
Dulic, V
中科院分区：
文献类型：
--
作者：
Baus, F;Gire, V;Dulic, V
虽然Cdk抑制剂p21（Waf 1/Cip 1）是p53的转录靶点之一，与DNA损伤后G（2）阻滞的维持有关，但其在细胞周期这一阶段的功能尚不清楚。在这里，我们表明，正常人成纤维细胞（NHF）暴露于遗传毒性剂引起细胞周期永久退出G（2）期，而小鼠胚胎成纤维细胞和转化的人细胞通过有丝分裂和G（1）停滞的进展，没有干预胞质分裂。p21（Waf 1/Cip 1）通过抑制控制G（2）/M进展的细胞周期蛋白B1-Cdk 1和细胞周期蛋白A-Cdk 1/2复合物以及通过阻断pRb家族蛋白的磷酸化，在驱动G（2）退出方面发挥关键作用。具有受损pRb蛋白的NHF仍然可以有效地停滞在G（2），但不能退出细胞周期，导致细胞死亡。我们的实验表明，在持续的遗传毒性应激下，正常细胞可以通过限制点逆转其有丝分裂进程的承诺，并且涉及p21（Waf 1/Cip 1）和口袋蛋白的机制可以诱导G（2）和G（1）退出。
Although the Cdk inhibitor p21(Waf1/Cip1), one of the transcriptional targets of p53, has been implicated in the maintenance of G(2) arrest after DNA damage, its function at this stage of the cell cycle is not really understood. Here, we show that the exposure of normal human fibroblasts (NHFs) to genotoxic agents provokes permanent cell cycle exit in G(2) phase, whereas mouse embryo fibroblasts and transformed human cells progress through mitosis and arrest in G(1) without intervening cytokinesis. p21(Waf1/Cip1) exerts a key role in driving this G(2) exit both by inhibiting cyclin B1-Cdk1 and cyclin A-Cdk1/2 complexes, which control G(2)/M progression, and by blocking the phosphorylation of pRb family proteins. NHFs with compromised pRb proteins could still efficiently arrest in G(2) but were unable to exit the cell cycle, resulting in cell death. Our experiments show that, when under continuous genotoxic stress, normal cells can reverse their commitment to mitotic progression due to passage through the restriction point and that mechanisms involving p21(Waf1/Cip1) and pocket proteins can induce exit in G(2) and G(1).