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在非同源末端连接途径中抑制DNA依赖蛋白激酶催化亚基以应对DNA双链断裂。

Inhibiting DNA-PKcs in a non-homologous end-joining pathway in response to DNA double-strand breaks.

作者信息

Dong Jun, Zhang Tian, Ren Yufeng, Wang Zhenyu, Ling Clifton C, He Fuqiu, Li Gloria C, Wang Chengtao, Wen Bixiu

机构信息

Department of Radiation Oncology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China.

Department of Medical Physics and Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York 10021, USA.

出版信息

Oncotarget. 2017 Apr 4;8(14):22662-22673. doi: 10.18632/oncotarget.15153.

DOI:10.18632/oncotarget.15153
PMID:28186989
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5410253/
Abstract

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.

摘要

DNA依赖蛋白激酶催化亚基（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。我们研究了DSB NHEJ修复途径中的关键蛋白与细胞周期调控之间的相互作用，发现与野生型细胞相比，DNA-PKcs或Ku70缺陷的小鼠胚胎成纤维细胞（MEF）对电离辐射（IR）更敏感，并且DSB修复延迟。γH2AX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激酶1（Ser345）焦点相关，通过G2/M期阻止细胞周期。抑制DNA-PKcs会延长IR诱导的G2/M期阻滞，这是由于细胞周期检查点的顺序激活。在鼻咽癌SUNE-1细胞中，暴露于IR后会引入DSB，并募集细胞周期检查点。NU7441通过干扰DSB修复使MEF细胞和SUNE-1细胞对辐射敏感。总之，这些结果揭示了一种机制，即DSB修复与细胞周期的耦合使NHEJ修复缺陷细胞对辐射敏感，这为癌症治疗中DNA-PK抑制剂的进一步开发提供了依据。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bacf/5410253/58775dce7aca/oncotarget-08-22662-g008.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bacf/5410253/e8a2d25bd4f4/oncotarget-08-22662-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bacf/5410253/e3000736fdcf/oncotarget-08-22662-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bacf/5410253/58775dce7aca/oncotarget-08-22662-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bacf/5410253/bd714d2b67cf/oncotarget-08-22662-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bacf/5410253/60872c9abfb6/oncotarget-08-22662-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bacf/5410253/a096d5754047/oncotarget-08-22662-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bacf/5410253/33ab0f8bdae3/oncotarget-08-22662-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bacf/5410253/bbdcc4b403b4/oncotarget-08-22662-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bacf/5410253/e8a2d25bd4f4/oncotarget-08-22662-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bacf/5410253/e3000736fdcf/oncotarget-08-22662-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bacf/5410253/58775dce7aca/oncotarget-08-22662-g008.jpg

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