Inhibiting DNA-PKcs in a non-homologous end-joining pathway in response to DNA double-strand breaks.
Inhibiting DNA-PKcs in a non-homologous end-joining pathway in response to DNA double-strand breaks.
复制标题
响应 DNA 双链断裂，抑制非同源末端连接途径中的 DNA-PKc。
DOI：
10.18632/oncotarget.15153
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发表时间：
2017-04-04
期刊：
影响因子：
--
通讯作者：
Wen B
中科院分区：
文献类型：
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作者：
Dong J;Zhang T;Ren Y;Wang Z;Ling CC;He F;Li GC;Wang C;Wen B
DNA依赖蛋白激酶催化亚单位(DNA-PKcs)是参与DNA双链断裂(DSB)修复的非同源末端连接(NHEJ)途径中的一个独特因子。我们检测了DSB NHEJ修复途径中的关键蛋白与细胞周期调控之间的串扰，发现DNA-PKcs或Ku70缺陷的小鼠胚胎成纤维细胞(MEF)比野生型细胞更容易受到电离辐射(IR)的影响，DSB修复延迟。γ-H_2AX与磷酸化共济失调-毛细血管扩张突变激酶(Ser1987)和磷酸化检查点效应蛋白激酶1(Ser345)结合，使细胞周期停滞于G2/M期。DNA-PKcs的抑制延长了IR诱导的G2/M期停滞，因为细胞周期检查点的顺序激活。在鼻咽癌SUNE-1细胞中引入DSB，并在暴露于IR后招募细胞周期检查点。NU7441通过干扰DSB修复增敏MEF细胞和SUNE-1细胞综上所述，这些结果揭示了DSB修复与细胞周期偶联使NHEJ修复缺陷细胞辐射增敏的机制，为进一步开发DNA-PK抑制剂用于癌症治疗提供了依据。
DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is a distinct factor in the non-homologous end-joining (NHEJ) pathway involved in DNA double-strand break (DSB) repair. We examined the crosstalk between key proteins in the DSB NHEJ repair pathway and cell cycle regulation and found that mouse embryonic fibroblast (MEF) cells deficient in DNA-PKcs or Ku70 were more vulnerable to ionizing radiation (IR) compared with wild-type cells and that DSB repair was delayed. γH2AX was associated with phospho-Ataxia-telangiectasia mutated kinase (Ser1987) and phospho-checkpoint effector kinase 1 (Ser345) foci for the arrest of cell cycle through the G2/M phase. Inhibition of DNA-PKcs prolonged IR-induced G2/M phase arrest because of sequential activation of cell cycle checkpoints. DSBs were introduced, and cell cycle checkpoints were recruited after exposure to IR in nasopharyngeal carcinoma SUNE-1 cells. NU7441 radiosensitized MEF cells and SUNE-1 cells by interfering with DSB repair. Together, these results reveal a mechanism in which coupling of DSB repair with the cell cycle radiosensitizes NHEJ repair-deficient cells, justifying further development of DNA-PK inhibitors in cancer therapy.