中国科学院生物物理研究所生物大分子国家重点实验室,蛋白质与多肽药物所重点实验室,中国科学院大学,中国科学院生物物理研究所生物大分子国家重点实验室,蛋白质与多肽药物所重点实验室,中国科学院大学,中国科学院生物物理研究所生物大分子国家重点实验室,蛋白质与多肽药物所重点实验室,中国科学院大学,中国科学院生物物理研究所生物大分子国家重点实验室,蛋白质与多肽药物所重点实验室,中国科学院大学,中国科学院生物物理研究所生物大分子国家重点实验室,蛋白质与多肽药物所重点实验室,中国科学院生物物理研究所生物大分子国家重点实验室,蛋白质与多肽药物所重点实验室,中国科学院生物物理研究所生物大分子国家重点实验室,蛋白质与多肽药物所重点实验室,中国科学院生物物理研究所生物大分子国家重点实验室,蛋白质与多肽药物所重点实验室
国家自然科学基金资助项目(31370792, U1738112)
Key Laboratory for Protein and Peptide Pharmaceuticals, National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, University of Chinese Academy of Sciences,Key Laboratory for Protein and Peptide Pharmaceuticals, National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, University of Chinese Academy of Sciences,Key Laboratory for Protein and Peptide Pharmaceuticals, National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, University of Chinese Academy of Sciences,Key Laboratory for Protein and Peptide Pharmaceuticals, National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, University of Chinese Academy of Sciences,Key Laboratory for Protein and Peptide Pharmaceuticals, National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences,Key Laboratory for Protein and Peptide Pharmaceuticals, National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences,Key Laboratory for Protein and Peptide Pharmaceuticals, National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences,Key Laboratory for Protein and Peptide Pharmaceuticals, National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences
This work was supported by grants from The National Natural Science Foundation of China (31370792, U1738112)
Rad9是一种重要的细胞周期监控点调控蛋白.越来越多的证据显示,Rad9也可与多种DNA损伤修复通路中的蛋白质相互作用,并调节其功能,在DNA损伤修复中发挥重要作用.非同源末端连接修复是DNA双链断裂的一条重要修复途径.Ku70、Ku80和DNA依赖的蛋白激酶催化亚基(DNA-PKcs)共同组成DNA依赖的蛋白激酶复合物(DNA-PK),在非同源末端修复连接中起重要作用.本研究中,检测到Rad9与Ku70有直接的物理相互作用和功能相互作用.我们在不同的细胞模型中发现,Rad9基因敲除、Rad9蛋白去除或Rad9表达降低会导致非同源末端连接效率明显下降.已有的研究表明,DNA损伤可导致细胞中Ku70与染色质结合增加及DNA-PKcs激酶活性增强.我们的结果显示,与野生小鼠细胞相比,Rad9基因敲除的小鼠细胞中, DNA损伤诱导的上述效应均减弱.综上所述,我们的研究首次报道了Rad9与非同源末端连接修复蛋白Ku70间有相互作用,并提示Rad9可通过调节Ku70/Ku80/DNA-PKcs复合物功能参与非同源末端连接修复.
Rad9 plays roles in both cell cycle checkpoint control and DNA repair. It can interact with the components of multiple DNA repair pathways and regulate their functions. Non-homologous end-joining (NHEJ) repair pathway is predominantly used in vertebrates for the repair of DNA double strand break (DSB). Proper activation of DNA-dependent protein kinase (DNA-PK), composed of Ku70, Ku80, and DNA-dependent protein kinase catalytic subunit (DNA-PKcs), is essential for NHEJ repair. In this study, we found that Rad9 interacts with Ku70 physically and functionally. Deletion of Rad9 gene, knockdown of Rad9 expression or removal of Rad9 protein led to inefficient DNA end-joining repair. Furthermore, loss of Rad9 impaired the DNA damage-induced binding of Ku70 to the chromatin and attenuated the DNA damage-induced kinase activity of DNA-PKcs. Taken together, our data unveil a novel functional interplay between Rad9 and the NHEJ protein Ku70, indicating a role of Rad9 in NHEJ repair through modulating the activation of the DNA-PKcs/Ku70/Ku80 complex.
范英俊,刘宇恒,王玉兰,孔冰洁,赵云,叶琛,安莉莉,杭海英.细胞周期监控点蛋白Rad9与非同源末端连接修复蛋白Ku70的相互作用研究[J].生物化学与生物物理进展,2018,45(10):1054-1067
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