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TAp73 contributes to the oxidative stress response by regulating protein synthesis [Cell Biology]
Proceedings of the National Academy of Sciences of the United States of America ( IF 9.4 ) Pub Date : 2018-06-12 , DOI: 10.1073/pnas.1718531115
Alberto Marini 1 , Barak Rotblat 1, 2 , Thomas Sbarrato 1 , Maria Victoria Niklison-Chirou 1, 3 , John R P Knight 1 , Kate Dudek 1 , Carolyn Jones 1 , Martin Bushell 1 , Richard A Knight 1 , Ivano Amelio 1 , Anne E Willis 4 , Gerry Melino 4, 5
Affiliation  

TAp73 is a transcription factor that plays key roles in brain development, aging, and cancer. At the cellular level, TAp73 is a critical homeostasis-maintaining factor, particularly following oxidative stress. Although major studies focused on TAp73 transcriptional activities have indicated a contribution of TAp73 to cellular metabolism, the mechanisms underlying its role in redox homeostasis have not been completely elucidated. Here we show that TAp73 contributes to the oxidative stress response by participating in the control of protein synthesis. Regulation of mRNA translation occupies a central position in cellular homeostasis during the stress response, often by reducing global rates of protein synthesis and promoting translation of specific mRNAs. TAp73 depletion results in aberrant ribosomal RNA (rRNA) processing and impaired protein synthesis. In particular, polysomal profiles show that TAp73 promotes the integration of mRNAs that encode rRNA-processing factors in polysomes, supporting their translation. Concurrently, TAp73 depletion causes increased sensitivity to oxidative stress that correlates with reduced ATP levels, hyperactivation of AMPK, and translational defects. TAp73 is important for maintaining active translation of mitochondrial transcripts in response to oxidative stress, thus promoting mitochondrial activity. Our results indicate that TAp73 contributes to redox homeostasis by affecting the translational machinery, facilitating the translation of specific mitochondrial transcripts. This study identifies a mechanism by which TAp73 contributes to the oxidative stress response and describes a completely unexpected role for TAp73 in regulating protein synthesis.



中文翻译:


TAp73 通过调节蛋白质合成促进氧化应激反应 [细胞生物学]



TAp73 是一种转录因子,在大脑发育、衰老和癌症中发挥着关键作用。在细胞水平上,TAp73 是一种关键的体内平衡维持因子,特别是在氧化应激后。尽管针对 TAp73 转录活性的主要研究表明 TAp73 对细胞代谢的贡献,但其在氧化还原稳态中作用的机制尚未完全阐明。在这里,我们表明 TAp73 通过参与蛋白质合成的控制来促进氧化应激反应。 mRNA 翻译的调节在应激反应期间的细胞稳态中占据着核心地位,通常是通过降低蛋白质合成的整体速率并促进特定 mRNA 的翻译来实现的。 TAp73 缺失会导致核糖体 RNA (rRNA) 加工异常和蛋白质合成受损。特别是,多核糖体谱显示 TAp73 促进编码 rRNA 加工因子的 mRNA 在多核糖体中的整合,支持它们的翻译。同时,TAp73 耗竭会导致对氧化应激的敏感性增加,这与 ATP 水平降低、AMPK 过度激活和翻译缺陷相关。 TAp73 对于维持线粒体转录物响应氧化应激的活跃翻译非常重要,从而促进线粒体活性。我们的结果表明,TAp73 通过影响翻译机制来促进氧化还原稳态,促进特定线粒体转录本的翻译。这项研究确定了 TAp73 促进氧化应激反应的机制,并描述了 TAp73 在调节蛋白质合成中完全出乎意料的作用。

更新日期:2018-06-13
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