p53肿瘤抑制因子作为转录因子起作用,并通过激活各种基因(包括与细胞周期停滞有关的基因)在调节细胞对DNA损伤的反应中起关键作用。p53的稳定性对于其在应激反应过程中的功能至关重要;然而,DNA损伤诱导p53稳定的分子机制尚不完全清楚。在我们目前的研究中,我们已经确定了SMG7(生殖器形态缺陷的抑制器7),也称为EST1C,作为一种新的p53结合蛋白。SMG7是一种mRNA监测因子,涉及p53含mRNA的无义突变的降解,然而,目前尚不清楚SMG7是否调节p53功能。这里,我们发现SMG7通过调节p53的稳定性在p53介导的基因毒性应激反应中起关键作用。利用体细胞基因敲除,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的基础水平影响很小。重要的是,SMG7的缺失会损害p53介导的p21激活和DNA损伤后的细胞周期停滞。对p53的主要E3泛素连接酶Mdm2的药理学抑制恢复了p53在γ辐射的SMG7缺陷细胞中的稳定性。此外,SMG7与Mdm2物理相互作用,并促进ATM介导的电离辐射后Mdm2的抑制性磷酸化。因此,我们目前的数据表明,SMG7在DNA损伤反应中对p53功能至关重要,并揭示了SMG7介导的Mdm2磷酸化是以前未知的p53调控机制。
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 (suppressor with morphological defects in genitalia 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.