The tumour suppressor CYLD regulates the p53 DNA damage response

Vanesa Fernández-Majada, Patrick-Simon Welz, Maria A. Ermolaeva, Michael Schell, Alexander Adam, Felix Dietlein, David Komander, Reinhard Büttner, Roman K. Thomas, Björn Schumacher and Manolis Pasparakis ()
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Vanesa Fernández-Majada: Institute for Genetics, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Centre for Molecular Medicine (CMMC)
Patrick-Simon Welz: Institute for Genetics, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Centre for Molecular Medicine (CMMC)
Maria A. Ermolaeva: Institute for Genetics, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Centre for Molecular Medicine (CMMC)
Michael Schell: Institute for Genetics, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Centre for Molecular Medicine (CMMC)
Alexander Adam: Institute of Pathology, University Hospital Cologne
Felix Dietlein: University Hospital of Cologne
David Komander: Medical Research Council Laboratory of Molecular Biology
Reinhard Büttner: Institute of Pathology, University Hospital Cologne
Roman K. Thomas: Center of Integrated Oncology Cologne-Bonn, Medical Faculty
Björn Schumacher: Institute for Genetics, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Centre for Molecular Medicine (CMMC)
Manolis Pasparakis: Institute for Genetics, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Centre for Molecular Medicine (CMMC)

Nature Communications, 2016, vol. 7, issue 1, 1-14

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms12508

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