A telomere-dependent DNA damage checkpoint induced by prolonged mitotic arrest
A telomere-dependent DNA damage checkpoint induced by prolonged mitotic arrest
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DOI：
10.1038/nsmb.2245
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发表时间：
2012-04-01
影响因子：
16.8
通讯作者：
Karlseder, Jan
中科院分区：
文献类型：
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作者：
Hayashi, Makoto T.;Cesare, Anthony J.;Karlseder, Jan
端粒缩短和端粒组分的破坏是诱导端粒去保护的途径。在这里，我们描述了另一种途径，其中延长有丝分裂停滞诱导人类细胞端粒损伤信号。暴露于微管药物，驱动蛋白抑制剂，蛋白酶体抑制剂或适当的染色体凝聚力的破坏导致在端粒损伤灶的形成。有丝分裂端粒脱保护的诱导与TRF 2从端粒上解离、端粒3 '-突出端降解和ATM活化一致，并且脱保护可以通过TRF 2过表达或Aurora B激酶的抑制来抑制。正常细胞从长期的有丝分裂停滞中逃脱，在随后的Cl期停止，而缺乏p53的细胞继续循环，成为非整倍体。我们提出了一个端粒依赖的有丝分裂持续时间监测系统，通过有丝分裂反应不当的进展。
Telomere shortening and disruption of telomeric components are pathways that induce telomere deprotection. Here we describe another pathway, in which prolonged mitotic arrest induces damage signals at telomeres in human cells. Exposure to microtubule drugs, kinesin inhibitors, proteasome inhibitors or the disruption of proper chromosome cohesion resulted in the formation of damage foci at telomeres. Induction of mitotic telomere deprotection coincided with dissociation of TRF2 from telomeres, telomeric 3'-overhang degradation and ATM activation, and deprotection could be suppressed by TRF2 overexpression or inhibition of Aurora B kinase. Normal cells that escaped from prolonged mitotic arrest halted in the following Cl phase, whereas cells lacking p53 continued to cycle and became aneuploid. We propose a telomere-dependent mitotic-duration monitoring system that reacts to improper progression through mitosis.