Universität zu Köln

Fernandez-Majada, Vanesa, Welz, Patrick-Simon ORCID: 0000-0001-8370-625X, Ermolaeva, Maria A., Schell, Michael, Adam, Alexander, Dietlein, Felix, Komander, David, Buettner, Reinhard, Thomas, Roman K., Schumacher, Bjoern and Pasparakis, Manolis ORCID: 0000-0002-9870-0966 (2016). The tumour suppressor CYLD regulates the p53 DNA damage response. Nat. Commun., 7. LONDON: NATURE PUBLISHING GROUP. ISSN 2041-1723

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Abstract

The tumour suppressor CYLD is a deubiquitinase previously shown to inhibit NF-kappa B, MAP kinase and Wnt signalling. However, the tumour suppressing mechanisms of CYLD remain poorly understood. Here we show that loss of CYLD catalytic activity causes impaired DNA damage-induced p53 stabilization and activation in epithelial cells and sensitizes mice to chemical carcinogen-induced intestinal and skin tumorigenesis. Mechanistically, CYLD interacts with and deubiquitinates p53 facilitating its stabilization in response to genotoxic stress. Ubiquitin chain-restriction analysis provides evidence that CYLD removes K48 ubiquitin chains from p53 indirectly by cleaving K63 linkages, suggesting that p53 is decorated with complex K48/K63 chains. Moreover, CYLD deficiency also diminishes CEP-1/p53-dependent DNA damage-induced germ cell apoptosis in the nematode Caenorhabditis elegans. Collectively, our results identify CYLD as a deubiquitinase facilitating DNA damage-induced p53 activation and suggest that regulation of p53 responses to genotoxic stress contributes to the tumour suppressor function of CYLD.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Fernandez-Majada, Vanesa UNSPECIFIED UNSPECIFIED UNSPECIFIED Welz, Patrick-Simon UNSPECIFIED orcid.org/0000-0001-8370-625X UNSPECIFIED Ermolaeva, Maria A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Schell, Michael UNSPECIFIED UNSPECIFIED UNSPECIFIED Adam, Alexander UNSPECIFIED UNSPECIFIED UNSPECIFIED Dietlein, Felix UNSPECIFIED UNSPECIFIED UNSPECIFIED Komander, David UNSPECIFIED UNSPECIFIED UNSPECIFIED Buettner, Reinhard UNSPECIFIED UNSPECIFIED UNSPECIFIED Thomas, Roman K. UNSPECIFIED UNSPECIFIED UNSPECIFIED Schumacher, Bjoern UNSPECIFIED UNSPECIFIED UNSPECIFIED Pasparakis, Manolis UNSPECIFIED orcid.org/0000-0002-9870-0966 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-269067
DOI:	10.1038/ncomms12508
Journal or Publication Title:	Nat. Commun.
Volume:	7
Date:	2016
Publisher:	NATURE PUBLISHING GROUP
Place of Publication:	LONDON
ISSN:	2041-1723
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Faculty of Mathematics and Natural Sciences > Department of Biology > Institute for Genetics
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language NF-KAPPA-B; DEUBIQUITINATING ENZYME; ELEGANS P53; MOUSE MODEL; IN-VIVO; CELL; APOPTOSIS; ACTIVATION; PATHWAY; MICE Multiple languages Multidisciplinary Sciences Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/26906