A kinome-targeted RNAi-based screen links FGF signaling to H2AX phosphorylation in response to radiation.
A kinome-targeted RNAi-based screen links FGF signaling to H2AX phosphorylation in response to radiation.
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DOI：
10.1007/s00018-015-1901-7
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发表时间：
2015-09
期刊：
影响因子：
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通讯作者：
Gidrol X
中科院分区：
文献类型：
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作者：
Benzina S;Pitaval A;Lemercier C;Lustremant C;Frouin V;Wu N;Papine A;Soussaline F;Romeo PH;Gidrol X
自20世纪90年代初以来，成纤维细胞生长因子（FGF）的一般辐射防护作用已被广泛描述;然而，所涉及的分子机制在很大程度上仍然未知。辐射诱导的DNA双链断裂（DSB）在真核细胞中导致一系列复杂的反应。最早的结果之一是组蛋白H2 AX的磷酸化，以在邻近DSB位点的染色质中形成磷酸化形式的H2 AX（γ H2 AX）的核灶，并启动DNA修复分子的募集。在DSB事件后，快速信号传导网络被激活以协调DNA修复与细胞周期检查点的诱导。迄今为止，三种激酶（ATM、ATR和DNA-PK）已显示响应于辐射而磷酸化组蛋白H2 AX。在这里，我们报告了一个激酶组靶向的小干扰RNA（siRNA）的屏幕来表征人类激酶参与H2 AX磷酸化。通过在单核水平上分析γ H2 AX焦点，我们鉴定了46种直接或间接参与人角质形成细胞对辐射的反应中H2 AX磷酸化的激酶。此外，我们证明，在响应辐射，FGFR 4信号级联促进JNK 1激活和直接H2 AX磷酸化，从而导致更有效的DNA修复。这至少可以部分解释FGF的辐射防护作用。本文的在线版本（doi：10.1007/s 00018 -015-1901-7）包含补充材料，可供授权用户使用。
A general radioprotective effect by fibroblast growth factor (FGF) has been extensively described since the early 1990s; however, the molecular mechanisms involved remain largely unknown. Radiation-induced DNA double-strand breaks (DSBs) lead to a complex set of responses in eukaryotic cells. One of the earliest consequences is phosphorylation of histone H2AX to form nuclear foci of the phosphorylated form of H2AX (γH2AX) in the chromatin adjacent to sites of DSBs and to initiate the recruitment of DNA-repair molecules. Upon a DSB event, a rapid signaling network is activated to coordinate DNA repair with the induction of cell-cycle checkpoints. To date, three kinases (ATM, ATR, and DNA-PK) have been shown to phosphorylate histone H2AX in response to irradiation. Here, we report a kinome-targeted small interfering RNA (siRNA) screen to characterize human kinases involved in H2AX phosphorylation. By analyzing γH2AX foci at a single-nucleus level, we identified 46 kinases involved either directly or indirectly in H2AX phosphorylation in response to irradiation in human keratinocytes. Furthermore, we demonstrate that in response to irradiation, the FGFR4 signaling cascade promotes JNK1 activation and direct H2AX phosphorylation leading, in turn, to more efficient DNA repair. This can explain, at least partially, the radioprotective effect of FGF. The online version of this article (doi:10.1007/s00018-015-1901-7) contains supplementary material, which is available to authorized users.