ATM regulates ATR chromatin loading in response to DNA double-strand breaks
ATM regulates ATR chromatin loading in response to DNA double-strand breaks
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DOI：
10.1084/jem.20051923
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发表时间：
2006-02-20
影响因子：
15.3
通讯作者：
Fernandez-Capetillo, O
中科院分区：
文献类型：
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作者：
Cuadrado, M;Martinez-Pastor, B;Fernandez-Capetillo, O
DNA 双链断裂 (DSB) 是挑战基因组完整性的最有害损伤之一。在修复断裂的同时，必须在病变部位协调快速信号级联，从而导致细胞周期检查点的激活和/或细胞凋亡。在这种情况下，共济失调毛细血管扩张突变 (ATM) 以及 ATM 和 Rad-3 相关 (ATR) 蛋白激酶是已知在损伤部位启动转导级联的最早信号分子。目前的模型将 ATM 和 ATR 置于不同的分子路径中，协调不同的检查点反应路径。 ATM 通过 Chk2 依赖性途径向电离辐射 (IR) 产生的 DSB 发出信号，而 ATR 在各种复制相关 DSB 中被激活，并以 Chk1 激酶依赖性方式导致检查点激活。然而，G2/M 检查点响应 IR 的激活逃脱了这一公认的范例，因为它依赖于 ATM 和 ATR，但独立于 Chk2。我们的数据对此观察结果提供了解释，并将 ATM 活性置于 ATR 募集至 IR 损伤染色质的上游。这些数据提供了 ATM 和 ATR 信号通路之间针对 DNA 损伤的活跃串扰的实验证据。
DNA double-strand breaks (DSBs) are among the most deleterious lesions that can challenge genomic integrity. Concomitant to the repair of the breaks, a rapid signaling cascade must be coordinated at the lesion site that leads to the activation of cell cycle checkpoints and/or apoptosis. In this context, ataxia telangiectasia mutated (ATM) and ATM and Rad-3-related (ATR) protein kinases are the earliest signaling molecules that are known to initiate the transduction cascade at damage sites. The current model places ATM and ATR in separate molecular routes that orchestrate distinct pathways of the checkpoint responses. Whereas ATM signals DSBs arising from ionizing radiation (IR) through a Chk2-dependent pathway, ATR is activated in a variety of replication-linked DSBs and leads to activation of the checkpoints in a Chk1 kinase-dependent manner. However, activation of the G2/M checkpoint in response to IR escapes this accepted paradigm because it is dependent on both ATM and ATR but independent of Chk2. Our data provides an explanation for this observation and places ATM activity upstream of ATR recruitment to IR-damaged chromatin. These data provide experimental evidence of an active cross talk between ATM and ATR signaling pathways in response to DNA damage.