Adaptation to different forms of environmental stress is crucial for maintaining essential cellular functions and survival. The nucleolus plays a decisive role as a signaling hub for coordinating cellular responses to various extrinsic and intrinsic cues. p53 levels are normally kept low in unstressed cells, mainly due to E3 ubiquitin ligase MDM2-mediated degradation. Under stress, nucleophosmin (NPM) relocates from the nucleolus to the nucleoplasm and binds MDM2, thereby preventing degradation of p53 and allowing cell-cycle arrest and DNA repair. Here, we demonstrate that the mammalian sirtuin SIRT7 is an essential component for the regulation of p53 stability during stress responses induced by ultraviolet (UV) irradiation. The catalytic activity of SIRT7 is substantially increased upon UV irradiation through ataxia telangiectasia mutated and Rad3 related (ATR)-mediated phosphorylation, which promotes efficient deacetylation of the SIRT7 target NPM. Deacetylation is required for stress-dependent relocation of NPM into the nucleoplasm and MDM2 binding, thereby preventing ubiquitination and degradation of p53. In the absence of SIRT7, stress-dependent stabilization of p53 is abrogated, both in vitro and in vivo, impairing cellular stress responses. The study uncovers an essential SIRT7-dependent mechanism for stabilization of the tumor suppressor p53 in response to genotoxic stress.

适应不同形式的环境压力对于维持必要的细胞功能和生存至关重要。核仁作为协调各种外在和内在线索的细胞反应的信号枢纽起着决定性的作用。通常，在非应激细胞中p53水平通常保持较低水平，这主要是由于E3泛素连接酶MDM2介导的降解。在压力下，核磷素（NPM）从核仁重新定位到核质并结合MDM2，从而防止p53降解并允许细胞周期停滞和DNA修复。在这里，我们证明了哺乳动物的sirtuin SIRT7是紫外线（UV）诱导的应激反应过程中调节p53稳定性的重要组成部分。在通过共济失调的毛细血管扩张突变和Rad3相关的（ATR）介导的磷酸化作用的紫外线照射下，SIRT7的催化活性大大提高，从而促进了SIRT7目标NPM的高效脱乙酰化。脱乙酰作用是NPM进入核质和MDM2结合的应力依赖性重定位所必需的，从而防止p53泛素化和降解。在缺少SIRT7的情况下，在体内和体外都消除了p53的应激依赖性稳定作用，从而削弱了细胞应激反应。这项研究发现了一种重要的依赖SIRT7的机制，该机制可稳定对基因毒性应激的抑癌基因p53。脱乙酰作用是NPM进入核质和MDM2结合的应力依赖性重定位所必需的，从而防止p53泛素化和降解。在缺少SIRT7的情况下，在体内和体外都消除了p53的应激依赖性稳定作用，从而削弱了细胞应激反应。这项研究发现了一种重要的依赖SIRT7的机制，该机制可稳定对基因毒性应激的抑癌基因p53。脱乙酰作用是NPM进入核质和MDM2结合的应力依赖性重定位所必需的，从而防止p53泛素化和降解。在缺少SIRT7的情况下，在体内和体外都消除了p53的应激依赖性稳定作用，从而削弱了细胞应激反应。这项研究发现了一种重要的依赖SIRT7的机制，该机制可稳定对基因毒性应激的抑癌基因p53。