ATM/Wip1 activities at chromatin control Plk1 re-activation to determine G2 checkpoint duration
ATM/Wip1 activities at chromatin control Plk1 re-activation to determine G2 checkpoint duration
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DOI：
10.15252/embj.201696082
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发表时间：
2017-07-14
期刊：
影响因子：
11.4
通讯作者：
Lindqvist, Arne
中科院分区：
文献类型：
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作者：
Jaiswal, Himjyot;Benada, Jan;Lindqvist, Arne
DNA 损伤后，细胞周期被抑制以避免突变的传播。 G2 期的停滞是由 ATM/ATR 依赖性信号传导启动的，该信号传导抑制 Plk1 等有丝分裂促进激酶。同时，Plk1 可以抵消 ATR 依赖性信号传导，并且是细胞周期最终恢复所必需的。然而，是什么决定了 Plk1 活动何时可以恢复仍不清楚。在这里，我们使用基于 FRET 的报告基因显示 ATM 活性在染色质上的全球传播以及 ATM 靶标的磷酸化，包括 KAP1 控制 Plk1 重新激活。这些磷酸化被染色质结合磷酸酶 Wip1 迅速抵消，尽管 DNA 损伤处存在持续的 ATM 活性，但仍允许细胞周期重新启动。结合实验数据和数学模型，我们提出了一个如何控制细胞周期停滞最短持续时间的模型。我们的模型展示了细胞周期如何在 DNA 修复完成之前重新启动，并提出了人类细胞检查点适应的机制。
After DNA damage, the cell cycle is arrested to avoid propagation of mutations. Arrest in G2 phase is initiated by ATM-/ATR-dependent signaling that inhibits mitosis-promoting kinases such as Plk1. At the same time, Plk1 can counteract ATR-dependent signaling and is required for eventual resumption of the cell cycle. However, what determines when Plk1 activity can resume remains unclear. Here, we use FRET-based reporters to show that a global spread of ATM activity on chromatin and phosphorylation of ATM targets including KAP1 control Plk1 re-activation. These phosphorylations are rapidly counteracted by the chromatin-bound phosphatase Wip1, allowing cell cycle restart despite persistent ATM activity present at DNA lesions. Combining experimental data and mathematical modeling, we propose a model for how the minimal duration of cell cycle arrest is controlled. Our model shows how cell cycle restart can occur before completion of DNA repair and suggests a mechanism for checkpoint adaptation in human cells.