title: The tumour suppressor CYLD regulates the p53 DNA damage response.
abstract: The tumour suppressor CYLD is a deubiquitinase previously shown to inhibit NF-κB, 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.
authors: Institute for Genetics, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Centre for Molecular Medicine (CMMC), University of Cologne, Joseph-Stelzmann-Straβe 26, Cologne 50931, Germany.
authors: Vanesa
authors: V
authors: Fernández-Majada
authors: Institute for Genetics, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Centre for Molecular Medicine (CMMC), University of Cologne, Joseph-Stelzmann-Straβe 26, Cologne 50931, Germany.
authors: Patrick-Simon
authors: PS
authors: Welz
authors: Institute for Genetics, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Centre for Molecular Medicine (CMMC), University of Cologne, Joseph-Stelzmann-Straβe 26, Cologne 50931, Germany.|Institute for Genome Stability in Ageing and Disease, Cologne Excellence Cluster for Cellular Stress Responses in Ageing-Associated Diseases (CECAD) and Centre for Molecular Medicine (CMMC), University of Cologne, Joseph-Stelzmann-Straβe 26, Cologne 50931, Germany.
authors: Maria A
authors: MA
authors: Ermolaeva
authors: Institute for Genetics, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Centre for Molecular Medicine (CMMC), University of Cologne, Joseph-Stelzmann-Straβe 26, Cologne 50931, Germany.
authors: Michael
authors: M
authors: Schell
authors: Institute of Pathology, University Hospital Cologne, Kerpener Straβe 62, Cologne 50937, Germany.
authors: Alexander
authors: A
authors: Adam
authors: Department I of Internal Medicine, University Hospital of Cologne, Weyertal 115B, Cologne 50931, Germany.
authors: Felix
authors: F
authors: Dietlein
authors: Medical Research Council Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK.
authors: David
authors: D
authors: Komander
authors: Institute of Pathology, University Hospital Cologne, Kerpener Straβe 62, Cologne 50937, Germany.
authors: Reinhard
authors: R
authors: Büttner
authors: Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, Weyertal 115b, Cologne 50931, Germany.
authors: Roman K
authors: RK
authors: Thomas
authors: Institute for Genetics, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Centre for Molecular Medicine (CMMC), University of Cologne, Joseph-Stelzmann-Straβe 26, Cologne 50931, Germany.|Institute for Genome Stability in Ageing and Disease, Cologne Excellence Cluster for Cellular Stress Responses in Ageing-Associated Diseases (CECAD) and Centre for Molecular Medicine (CMMC), University of Cologne, Joseph-Stelzmann-Straβe 26, Cologne 50931, Germany.
authors: Björn
authors: B
authors: Schumacher
authors: Institute for Genetics, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Centre for Molecular Medicine (CMMC), University of Cologne, Joseph-Stelzmann-Straβe 26, Cologne 50931, Germany.
authors: Manolis
authors: 0000-0002-9870-0966
authors: M
authors: Pasparakis
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001397:Azoxymethane / Q000633:toxicity; D017173:Caenorhabditis elegans / Q000502:physiology; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism; D063646:Carcinogenesis / Q000235:genetics*; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage / Q000502:physiology; D004260:DNA Repair / Q000235:genetics*; D000074749:Deubiquitinating Enzyme CYLD; D005260:Female; D020022:Genetic Predisposition to Disease; D007414:Intestinal Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000473:pathology; D008239:Lysine / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D015398:Signal Transduction / Q000502:physiology; D012878:Skin Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D054875:Ubiquitination / Q000235:genetics
chemical_list: C438244:CEP-1 protein, C elegans; D029742:Caenorhabditis elegans Proteins; D016159:Tumor Suppressor Protein p53; C511601:CYLD protein, mouse; D000074749:Deubiquitinating Enzyme CYLD; D003546:Cysteine Endopeptidases; D008239:Lysine; D001397:Azoxymethane