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SIRT7-dependent deacetylation of NPM promotes p53 stabilization following UV-induced genotoxic stress

Significance We discovered that the histone/protein deacetylase SIRT7, which is the only member of the mammalian sirtuin family residing primarily in the nucleolus, stabilizes p53 in response to UV-induced DNA damage by enabling binding of deacetylated NPM to MDM2/HDM2. The study unveils a crucial mechanism by which the nucleolus controls cellular stress responses. Furthermore, it characterizes SIRT7 as a potent regulator of cellular stress and offers opportunities to manipulate cellular p53 levels, which is important for the development of antitumor therapies. 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.