Universität zu Köln

Ianni, Alessandro ORCID: 0000-0001-7398-589X, Kumari, Poonam, Tarighi, Shahriar ORCID: 0000-0003-3807-9212, Simonet, Nicolas G., Popescu, Daniela, Guenther, Stefan, Holper, Soraya, Schmidt, Andreas, Smolka, Christian ORCID: 0000-0003-2341-2406, Yue, Shijing, Kruger, Marcus, Fiorillo, Claudia, Vaquero, Alejandro, Bober, Eva and Braun, Thomas ORCID: 0000-0002-6165-4804 (2021). SIRT7-dependent deacetylation of NPM promotes p53 stabilization following UV-induced genotoxic stress. Proc. Natl. Acad. Sci. U. S. A., 118 (5). WASHINGTON: NATL ACAD SCIENCES. ISSN 0027-8424

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Abstract

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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Ianni, Alessandro UNSPECIFIED orcid.org/0000-0001-7398-589X UNSPECIFIED Kumari, Poonam UNSPECIFIED UNSPECIFIED UNSPECIFIED Tarighi, Shahriar UNSPECIFIED orcid.org/0000-0003-3807-9212 UNSPECIFIED Simonet, Nicolas G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Popescu, Daniela UNSPECIFIED UNSPECIFIED UNSPECIFIED Guenther, Stefan UNSPECIFIED UNSPECIFIED UNSPECIFIED Holper, Soraya UNSPECIFIED UNSPECIFIED UNSPECIFIED Schmidt, Andreas UNSPECIFIED UNSPECIFIED UNSPECIFIED Smolka, Christian UNSPECIFIED orcid.org/0000-0003-2341-2406 UNSPECIFIED Yue, Shijing UNSPECIFIED UNSPECIFIED UNSPECIFIED Kruger, Marcus UNSPECIFIED UNSPECIFIED UNSPECIFIED Fiorillo, Claudia UNSPECIFIED UNSPECIFIED UNSPECIFIED Vaquero, Alejandro UNSPECIFIED UNSPECIFIED UNSPECIFIED Bober, Eva UNSPECIFIED UNSPECIFIED UNSPECIFIED Braun, Thomas UNSPECIFIED orcid.org/0000-0002-6165-4804 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-596372
DOI:	10.1073/pnas.2015339118
Journal or Publication Title:	Proc. Natl. Acad. Sci. U. S. A.
Volume:	118
Number:	5
Date:	2021
Publisher:	NATL ACAD SCIENCES
Place of Publication:	WASHINGTON
ISSN:	0027-8424
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language RNA-POLYMERASE-I; RIBOSOMAL-RNA; SIRT7; INHIBITION; ACTIVATION; NUCLEOLUS; APOPTOSIS; KINASE; DAMAGE; CELLS Multiple languages Multidisciplinary Sciences Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/59637