Ataxia telangiectasia mutated (ATM) is essential for DNA-PKcs phosphorylations at the Thr-2609 cluster upon DNA double strand break
Ataxia telangiectasia mutated (ATM) is essential for DNA-PKcs phosphorylations at the Thr-2609 cluster upon DNA double strand break
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DOI：
10.1074/jbc.m611605200
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发表时间：
2007-03-02
影响因子：
4.8
通讯作者：
Chen, David J.
中科院分区：
文献类型：
--
作者：
Chen, Benjamin P. C.;Uematsu, Naoya;Chen, David J.
DNA依赖性蛋白激酶（DNA-PKcs）的催化亚基在电离辐射（IR）下在Thr-2609簇和Ser-2056处迅速磷酸化。此外，DNA-PKcs在两个区域的磷酸化对于其在DNA双链断裂（DSB）修复以及细胞对辐射的抗性中的作用至关重要。然而，IR诱导的DNA-PKcs在Thr-2609和Ser-2056的磷酸化表现出不同的动力学，表明它们受到差异调节。尽管IR后DNA-PKcs自身在Ser-2056处磷酸化，但我们在此报道ATM介导DNA-PKcs在Thr-2609以及Thr-2609簇内相邻（S/T）Q基序的磷酸化。此外，我们的数据表明，DNA-PKcs和ATM介导的DNA-PKcs磷酸化是合作的，并需要完全激活的DNA-PKcs和随后的DSB修复。在这两个区域的DNA-PKcs磷酸化的消除严重损害辐射抗性和DSB修复。最后，我们的结果提供了一个可能的机制，ATM直接参与非同源末端连接介导的DSB修复。
The catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) is rapidly phosphorylated at the Thr-2609 cluster and Ser-2056 upon ionizing radiation (IR). Furthermore, DNA-PKcs phosphorylation at both regions is critical for its role in DNA double strand break (DSB) repair as well as cellular resistance to radiation. IR-induced DNA-PKcs phosphorylation at Thr-2609 and Ser-2056, however, exhibits distinct kinetics indicating that they are differentially regulated. Although DNA-PKcs autophosphorylates itself at Ser-2056 after IR, we have reported here that ATM mediates DNA-PKcs phosphorylation at Thr-2609 as well as at the adjacent (S/T)Q motifs within the Thr-2609 cluster. In addition, our data suggest that DNA-PKcs and ATM-mediated DNA-PKcs phosphorylations are cooperative and required for the full activation of DNA-PKcs and the subsequent DSB repair. Elimination of DNA-PKcs phosphorylation at both regions severely compromises radioresistance and DSB repair. Finally, our result provides a possible mechanism for the direct involvement of ATM in non-homologous end joining-mediated DSB repair.