DNA damage activates a spatially distinct late cytoplasmic cell-cycle checkpoint network controlled by MK2-mediated RNA stabilization.
DNA damage activates a spatially distinct late cytoplasmic cell-cycle checkpoint network controlled by MK2-mediated RNA stabilization.
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DOI：
10.1016/j.molcel.2010.09.018
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发表时间：
2010-10-08
期刊：
影响因子：
16
通讯作者：
Yaffe MB
中科院分区：
文献类型：
--
作者：
Reinhardt HC;Hasskamp P;Schmedding I;Morandell S;van Vugt MA;Wang X;Linding R;Ong SE;Weaver D;Carr SA;Yaffe MB
在基因毒性应激后，细胞激活一个复杂的基于激酶的信号网络，以阻止细胞周期并启动DNA修复。P53缺陷的肿瘤细胞重新连接它们的检查点反应，并在DNA损伤后依赖p38/MK2途径生存，尽管ATR-Chk1途径起作用。我们使用功能遗传学分析了Chk1和MK2对检查点控制的贡献。我们表明，核Chk1活性是建立G2/M检查点所必需的，而细胞质MK2活性是通过转录后mRNA稳定过程延长检查点维持的关键。在DNA损伤后，p38/MK2复合体从细胞核重新定位到细胞质，在那里MK2磷酸化hnRNPA0，以稳定GADD45TIAR m RNA，而p38磷酸化并释放翻译抑制物TIAR。此外，MK2还能磷酸化PARN，阻断GADD45α基因的降解。Gadd45DNA在正反馈环路中发挥作用，维持依赖于α的细胞质隔离，在存在未修复的DNA损伤的情况下阻止有丝分裂进入。我们的发现表明，作为DNA损伤反应的一部分，MK2通路在转录后调控基因表达方面发挥了关键作用。
Following genotoxic stress, cells activate a complex kinase-based signaling network to arrest the cell cycle and initiate DNA repair. p53-defective tumor cells rewire their checkpoint response and become dependent on the p38/MK2 pathway for survival after DNA damage, despite a functional ATR-Chk1 pathway. We used functional genetics to dissect the contributions of Chk1 and MK2 to checkpoint control. We show that nuclear Chk1 activity is essential to establish a G2/M checkpoint, while cytoplasmic MK2 activity is critical for prolonged checkpoint maintenance through a process of post-transcriptional mRNA stabilization. Following DNA damage, the p38/MK2 complex relocalizes from nucleus to cytoplasm where MK2, phosphorylates hnRNPA0, to stabilize Gadd45α mRNA, while p38 phosphorylates and releases the translational inhibitor TIAR. In addition, MK2 phosphorylates PARN, blocking Gadd45α mRNA degradation. Gadd45α functions within a positive feedback loop, sustaining the MK2-dependent cytoplasmic sequestration of Cdc25B/C to block mitotic entry in the presence of unrepaired DNA damage. Our findings demonstrate a critical role for the MK2 pathway in the post-transcriptional regulation of gene expression as part of the DNA damage response in cancer cells.
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影响因子：
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作者：
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