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

Full text not available from this repository.

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:
CreatorsEmailORCIDORCID Put Code
Fernandez-Majada, VanesaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Welz, Patrick-SimonUNSPECIFIEDorcid.org/0000-0001-8370-625XUNSPECIFIED
Ermolaeva, Maria A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schell, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Adam, AlexanderUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dietlein, FelixUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Komander, DavidUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Buettner, ReinhardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thomas, Roman K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schumacher, BjoernUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pasparakis, ManolisUNSPECIFIEDorcid.org/0000-0002-9870-0966UNSPECIFIED
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:
KeywordsLanguage
NF-KAPPA-B; DEUBIQUITINATING ENZYME; ELEGANS P53; MOUSE MODEL; IN-VIVO; CELL; APOPTOSIS; ACTIVATION; PATHWAY; MICEMultiple languages
Multidisciplinary SciencesMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/26906

Downloads

Downloads per month over past year

Altmetric

Export

Actions (login required)

View Item View Item