Optimal function of the DNA repair enzyme TDP1 requires its phosphorylation by ATM and/or DNA-PK
Optimal function of the DNA repair enzyme TDP1 requires its phosphorylation by ATM and/or DNA-PK
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DOI：
10.1038/emboj.2009.302
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发表时间：
2009-12-02
期刊：
影响因子：
11.4
通讯作者：
Pommier, Yves
中科院分区：
文献类型：
--
作者：
Das, Benu Brata;Antony, Smitha;Pommier, Yves
人酪氨酰-DNA磷酸二酯酶（TDP 1）水解连接到酪氨酰部分的DNA 3'端的磷酸二酯键。在停滞的拓扑异构酶I（Top1）-DNA共价复合物中发现了这种类型的连接，并且TDP 1已经涉及这种复合物的修复。在这里，我们表明，Top1相关的DNA双链断裂（DSBs）诱导磷酸化的TDP 1在S81。这种磷酸化是由蛋白激酶介导的：共济失调-毛细血管扩张突变（ATM）和DNA依赖性蛋白激酶（DNA-PK）。磷酸化TDP 1形成与磷酸化组蛋白H2 AX（gamma H2 AX）共定位的核灶。Top1诱导的复制和转录介导的DNA损伤均诱导TDP 1磷酸化。此外，我们表明，S81磷酸化稳定TDP 1，诱导XRCC 1（X射线交叉互补组1）-TDP 1复合物的形成，并增强TDP 1的DNA损伤位点的动员。最后，我们提供的证据表明，TDP 1-S81磷酸化促进细胞存活和DNA修复响应CPT诱导的DSB。总之，我们的研究结果提供了一个新的机制，TDP 1的翻译后调节ATM和DNA-PK。The EMBO Journal（2009）28，3667-3680. doi：10.1038/doj.2009.302; 2009年10月22日在线发布
Human tyrosyl-DNA phosphodiesterase (TDP1) hydrolyzes the phosphodiester bond at a DNA 3' end linked to a tyrosyl moiety. This type of linkage is found at stalled topoisomerase I (Top1)-DNA covalent complexes, and TDP1 has been implicated in the repair of such complexes. Here we show that Top1-associated DNA double-stranded breaks (DSBs) induce the phosphorylation of TDP1 at S81. This phosphorylation is mediated by the protein kinases: ataxia-telangiectasia-mutated (ATM) and DNA-dependent protein kinase (DNA-PK). Phosphorylated TDP1 forms nuclear foci that co-localize with those of phosphorylated histone H2AX (gamma H2AX). Both Top1-induced replication-and transcription-mediated DNA damages induce TDP1 phosphorylation. Furthermore, we show that S81 phosphorylation stabilizes TDP1, induces the formation of XRCC1 (X-ray cross-complementing group 1)-TDP1 complexes and enhances the mobilization of TDP1 to DNA damage sites. Finally, we provide evidence that TDP1-S81 phosphorylation promotes cell survival and DNA repair in response to CPT-induced DSBs. Together; our findings provide a new mechanism for TDP1 post-translational regulation by ATM and DNA-PK. The EMBO Journal (2009) 28, 3667-3680. doi: 10.1038/emboj.2009.302; Published online 22 October 2009