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首页> 外文期刊>Cell discovery. >SMG7 is a critical regulator of p53 stability and function in DNA damage stress response
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SMG7 is a critical regulator of p53 stability and function in DNA damage stress response

机译：SMG7是p53稳定性和DNA损伤应激反应功能的关键调节剂

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摘要

The p53 tumor suppressor functions as a transcription factor and plays a pivotal role in regulation of cellular response to DNA damage by activating various genes including those involved in cell cycle arrest. p53 stability is essential for its function during stress response; however, the molecular mechanism for DNA damage-induced stabilization of p53 is not fully understood. In our present study, we have identified SMG7 ( s uppressor with m orphological defects in g enitalia 7), also known as EST1C, as a novel p53-binding protein. SMG7 is an mRNA surveillance factor implicated in degradation of p53 mRNA-containing nonsense mutations, yet it is completely unknown whether SMG7 regulates p53 function. Here, we show that SMG7 has a crucial role in p53-mediated response to genotoxic stress by regulating p53 stability. Using somatic gene knockout, we found that deletion of SMG7 abrogates DNA damage-induced p53 stabilization, although it exhibits minimal effect on the basal levels of p53. Importantly, loss of SMG7 impairs p53-mediated activation of p21 and cell cycle arrest following DNA damage. Pharmacological inhibition of Mdm2, a major E3 ubiquitin ligase for p53, restored p53 stability in gamma-irradiated SMG7 -deficient cells. Furthermore, SMG7 physically interacts with Mdm2 and promotes ATM-mediated inhibitory phosphorylation of Mdm2 following ionizing radiation. Therefore, our present data demonstrate that SMG7 is critical for p53 function in DNA damage response, and reveal the SMG7-mediated phosphorylation of Mdm2 as a previously unknown mechanism for p53 regulation.
机译：p53肿瘤抑制物起转录因子的作用，并通过激活各种基因（包括参与细胞周期阻滞的基因）在调节细胞对DNA损伤的反应中起关键作用。 p53的稳定性对其在应激反应中的功能至关重要;然而，DNA损伤诱导的p53稳定化的分子机制尚不完全清楚。在我们目前的研究中，我们已经将SMG7（s抑制物在g italitalia 7中具有形态缺陷），也称为EST1C，作为一种新型的p53结合蛋白。 SMG7是一种mRNA监测因子，与包含p53 mRNA的无意义突变的降解有关，但SMG7是否调节p53功能尚不完全清楚。在这里，我们表明SMG7通过调节p53的稳定性在p53介导的对遗传毒性胁迫的反应中起着至关重要的作用。使用体细胞基因敲除，我们发现SMG7的缺失消除了DNA损伤诱导的p53稳定，尽管它对p53的基础水平显示出最小的影响。重要的是，SMG7的缺失会破坏p53介导的p21激活，并破坏DNA损伤后的细胞周期停滞。 Mdm2是p53的主要E3泛素连接酶，在药理学上具有抑制作用，可恢复经γ射线照射的SMG7缺陷细胞中p53的稳定性。此外，SMG7与Mdm2发生物理相互作用，并在电离辐射后促进ATM介导的Mdm2抑制性磷酸化。因此，我们目前的数据表明SMG7对于DNA损伤反应中的p53功能至关重要，并揭示了SMG7介导的Mdm2磷酸化作为p53调控的先前未知机制。

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