Distinct spatiotemporal dynamics of mammalian checkpoint regulators induced by DNA damage
Distinct spatiotemporal dynamics of mammalian checkpoint regulators induced by DNA damage
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DOI：
10.1038/ncb945
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发表时间：
2003-03-01
影响因子：
21.3
通讯作者：
Lukas, J
中科院分区：
文献类型：
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作者：
Lukas, C;Falck, J;Lukas, J
细胞周期检查点是DNA损伤后激活的信号转导途径，以保护基因组完整性（1）。动态时空协调是这些检查点的一个重要方面，但了解甚少。在这里，我们提供了Chk 2与Nbs 1的显著不同行为的证据，Nbs 1是由DNA双链断裂（DSB）诱导的共济失调-毛细血管扩张症突变（ATM）控制的检查点通路的关键介质（1，2）。在DSB仅限于小亚核区域的活人类细胞中，Nbs 1被迅速募集到受损区域，并在DSB位点附近进行动态交换。与此相反，Chk 2继续在整个细胞核中快速移动，无论DNA损伤如何，包括无DSB区域。虽然ATM的Chk 2磷酸化只发生在DSB位点，迫使Chk 2固定在空间受限的，含DSB的核区域削弱了其对p53依赖性转录的刺激作用。这些结果揭示了Nbs 1与DSB病变相互作用的动态性质，并将Chk 2确定为检查点信号的候选发射器，从而允许对局灶性DNA损伤的协调泛核反应。
Cell cycle checkpoints are signal transduction pathways activated after DNA damage to protect genomic integrity(1). Dynamic spatiotemporal coordination is a vital, but poorly understood aspect, of these checkpoints. Here, we provide evidence for a strikingly different behaviour of Chk2 versus Nbs1, key mediators of the ataxia-telangiecatesia-mutated (ATM)-controlled checkpoint pathways induced by DNA double-strand breaks (DSBs)(1,2). In live human cells with DSBs restricted to small sub-nuclear areas, Nbs1 was rapidly recruited to the damaged regions and underwent a dynamic exchange in the close vicinity of the DSB sites. In contrast, Chk2 continued to rapidly move throughout the entire nucleus, irrespective of DNA damage and including the DSB-free areas. Although phosphorylation of Chk2 by ATM occurred exclusively at the DSB sites, forced immobilization of Chk2 to spatially restricted, DSB-containing nuclear areas impaired its stimulating effect on p53-dependent transcription. These results unravel a dynamic nature of Nbs1 interaction with DSB lesions and identify Chk2 as a candidate transmitter of the checkpoint signal, allowing for a coordinated pan-nuclear response to focal DNA damage.