Ataxia-telangiectasia-mutated dependent phosphorylation of Artemis in response to DNA damage
Ataxia-telangiectasia-mutated dependent phosphorylation of Artemis in response to DNA damage
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DOI：
10.1111/j.1349-7006.2005.00019.x
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发表时间：
2005-02-01
期刊：
影响因子：
5.7
通讯作者：
Mizutani, S
中科院分区：
文献类型：
--
作者：
Chen, L;Morio, T;Mizutani, S
在脱氧核糖核酸（DNA）依赖蛋白（DNA- pkcs）亚基存在的情况下，Artemis在抗原受体VDJ基因重组的发夹打开步骤中起着至关重要的作用。阿尔忒弥斯的缺陷导致人类联合免疫缺陷。来自artemis缺陷和小鼠的细胞表现出增加的染色体不稳定性，但该因子在DNA损伤反应中的确切功能仍有待阐明。在这项研究中，我们发现Artemis在电离辐射（IR）下以ataxia -毛细血管扩张突变（ATM）和Nijmegen断裂综合征1 （Nbs1）依赖的方式过度磷酸化，并且S645是一个SQ/TQ位点，有助于Artemis在IR下的移动迟缓。在ATM-和nbs1缺失的细胞中，Artemis的过度磷酸化明显降低。重新引入野生型ATM或Nbs1分别在ATM-或Nbs1缺陷细胞中重建了Artemis过度磷酸化。为了支持这一功能联系，研究人员发现，在红外诱导的DNA双链断裂（DSB）中，过度磷酸化的Artemis以atm依赖的方式与Mre11/Rad50/Nbs1复合物发生物理关联。由于缺乏DNA-Pkcs或ATM都会导致ir诱导的DSB修复缺陷，因此我们的发现将Artemis置于ir诱导的DSB修复中DNA-Pkcs和ATM下游的信号传导十字路口。
Artemis plays a crucial role in the hairpin-opening step of antigen receptor VDJ gene recombination in the presence of subunit of deoxyribonucleic acid (DNA)-dependent protein (DNA-PKcs). A defect in Artemis causes human combined immunodeficiency. Cells from Artemis-deficient and mice display increased chromosomal instability, but the precise function of this factor in the response to DNA damage remains to be elucidate. In this study, we show that Artemis is hyperphosphorylated in an Ataxia-telangiectasia-mutated (ATM)- and Nijmegen breakage syndrome 1 (Nbs1)-dependent manner in response to ionizing radiation (IR), and that S645 is an SQ/TQ site that contributes to retarded mobility of Artemis upon IR. The hyperphosphorylation of Artemis is markedly reduced in ATM- and Nbs1-null cells. Reintroduction of wild-type ATM or Nbs1 reconstituted Artemis hyperphosphorylation in ATM- or Nbs1-deficient cells, respectively. in support of this functional link, hyperphosphorylated Artemis was found to physically associate with the Mre11/Rad50/Nbs1 complex in an ATM-dependent manner in response to IR-induced DNA double strand breaks (DSB). Since deficiency of either DNA-Pkcs or ATM leads to defective repair of IR-induced DSB, our finding places Artemis at the signaling crossroads downstream of DNA-PKcs and ATM in IR-induced DSB repair.