EDD mediates DNA damage-induced activation of CHK2
EDD mediates DNA damage-induced activation of CHK2
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DOI：
10.1074/jbc.m602818200
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发表时间：
2006-12-29
影响因子：
4.8
通讯作者：
Watts, Colin K. W.
中科院分区：
文献类型：
--
作者：
Henderson, Michelle J.;Munoz, Marcia A.;Watts, Colin K. W.
EDD是黑腹果蝇“增生盘”的人类直向同源物，在许多常见的人类癌症中过表达或突变。虽然EDD与DNA损伤信号有关，但其确切作用尚未得到证实。在这里，我们报告了EDD和DNA损伤检查点激酶CHK2之间的一种新的相互作用。EDD和CHK2通过磷酸依赖性相互作用相关联，涉及CHK2 Forkhead相关结构域和跨越许多推定的Forkhead相关结构域结合苏氨酸的EDD区域。使用RNA干扰，我们证明了EDD上游CHK2在DNA损伤信号通路中的关键作用。EDD对于CHK2响应于暴露于电离辐射或放射模拟物腐草霉素后的DNA损伤而有效激活磷酸化是必需的。消耗EDD的细胞显示CHK2激酶活性受损，并且不能对DNA损伤做出反应。这些结果确定EDD作为一种新的介质，通过CHK2的DNA损伤信号转导，并强调EDD在癌症中的潜在重要性。
EDD, the human orthologue of Drosophila melanogaster "hyperplastic discs," is overexpressed or mutated in a number of common human cancers. Although EDD has been implicated in DNA damage signaling, a definitive role has yet to be demonstrated. Here we report a novel interaction between EDD and the DNA damage checkpoint kinase CHK2. EDD and CHK2 associate through a phospho-dependent interaction involving the CHK2 Forkhead-associated domain and a region of EDD spanning a number of putative Forkhead-associated domain-binding threonines. Using RNA interference, we demonstrate a critical role for EDD upstream of CHK2 in the DNA damage signaling pathway. EDD is necessary for the efficient activating phosphorylation of CHK2 in response to DNA damage following exposure to ionizing radiation or the radiomimetic, phleomycin. Cells depleted of EDD display impaired CHK2 kinase activity and an inability to respond to DNA damage. These results identify EDD as a novel mediator in DNA damage signal transduction via CHK2 and emphasize the potential importance of EDD in cancer.