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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Role For Proteasome Activator Pa200 And Postglutamyl Proteasome Activity In Genomic Stability
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Role For Proteasome Activator Pa200 And Postglutamyl Proteasome Activity In Genomic Stability

机译：蛋白酶体激活剂Pa200和后谷氨酰蛋白酶体活性在基因组稳定性中的作用

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摘要

Proteasome activator PA200 enhances proteasome-mediated cleavage after acidic residues in vitro; however, its role within cells is not known. Here, we show that, in response to ionizing radiation, PA200 forms hybrid proteasomes with 19S caps and 20S core proteasomes that accumulate on chromatin, leading to an increase in proteolytic activity. Unlike many other proteins that respond to DNA damage, the response of PA200 appears to be independent of Ataxia Telangiectasia Mutated and p53, but dependent on DNA-dependent protein kinase activity. Nonetheless, PA200 is critical because PA200-knockdown cells show genomic instability and reduced survival after exposure to ionizing radiation. This pheno-type is reproduced by specific inhibition of postglutamyl activity of proteasomes, but combined treatment with PA200 siRNA and postglutamyl inhibitor does not show additive effects on survival. Together, these data suggest a unique role for PA200 in genomic stability that is likely mediated through its ability to enhance postglutamyl cleavage by proteasomes.
机译：蛋白酶体激活剂PA200增强了体外酸性残基后蛋白酶体介导的裂解。然而，其在细胞内的作用尚不清楚。在这里，我们显示出，响应电离辐射，PA200形成带有在染色质上积累的19S帽和20S核心蛋白酶体的杂合蛋白酶体，从而导致蛋白水解活性的提高。与许多其他对DNA损伤有反应的蛋白质不同，PA200的反应似乎独立于共济失调毛细血管扩张症和p53，但取决于DNA依赖性蛋白激酶活性。尽管如此，PA200是至关重要的，因为击倒PA200的细胞在暴露于电离辐射后显示出基因组不稳定性并降低了存活率。该表型是通过特异性抑制蛋白酶体的谷氨酰后活性而再现的，但是用PA200 siRNA和谷氨酰后抑制剂的联合治疗并未显示出对生存的累加作用。总之，这些数据表明PA200在基因组稳定性中的独特作用很可能是通过其增强蛋白酶体的谷氨酰胺后裂解能力来介导的。

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