DNA damage-induced G2-M checkpoint activation by histone H2AX and 53BP1
DNA damage-induced G2-M checkpoint activation by histone H2AX and 53BP1
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DOI：
10.1038/ncb884
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发表时间：
2002-12-01
影响因子：
21.3
通讯作者：
Nussenzweig, A
中科院分区：
文献类型：
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作者：
Fernandez-Capetillo, O;Chen, HT;Nussenzweig, A
共济失调毛细血管扩张突变（ATM）激酶的激活触发对电离辐射（IR）的多种细胞反应，包括启动细胞周期检查点（1）。组蛋白H2 AX、p53结合蛋白1（53 BP 1）和Chk 2是ATM介导的磷酸化的靶点（2-5），但关于它们在DNA损伤存在的信号传导中的作用知之甚少。在这里，我们表明，缺乏H2 AX或53 BP 1但不缺乏Chk 2的小鼠在暴露于低剂量（但不是高剂量）IR后，表现出与ATM（-/-）细胞中观察到的接近的G2-M检查点缺陷。此外，H2 AX调节53 BP 1有效积聚到IR诱导的病灶中的能力。我们建议，在阈值水平的DNA损伤，H2 AX介导的浓度的53 BP 1在双链断裂是必不可少的信号，否则可能不足以防止进入受损的细胞进入有丝分裂的放大。
Activation of the ataxia telangiectasia mutated (ATM) kinase triggers diverse cellular responses to ionizing radiation (IR), including the initiation of cell cycle checkpoints(1). Histone H2AX, p53 binding-protein 1 (53BP1) and Chk2 are targets of ATM-mediated phosphorylation(2-5), but little is known about their roles in signalling the presence of DNA damage. Here, we show that mice lacking either H2AX or 53BP1, but not Chk2, manifest a G2-M checkpoint defect close to that observed in ATM(-/-) cells after exposure to low, but not high, doses of IR. Moreover, H2AX regulates the ability of 53BP1 to efficiently accumulate into IR-induced foci. We propose that at threshold levels of DNA damage, H2AX-mediated concentration of 53BP1 at double-strand breaks is essential for the amplification of signals that might otherwise be insufficient to prevent entry of damaged cells into mitosis.