Fernández-Majada, VanesaWelz, Patrick-SimonErmolaeva, MariaSchell, MichaelAdam, AlexanderDietlein, FelixKomander, DavidBüttner, ReinhardThomas, Roman K.Schumacher, BjörnPasparakis, Manolis2022-11-092022-11-0920162041-1723https://hdl.handle.net/2445/190635The 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.14 p.application/pdfengcc-by (c) Fernández-Majada, Vanesa et al., 2016https://creativecommons.org/licenses/by/4.0/ApoptosiCarcinogènesiExperimentació animalApoptosisCarcinogenesisAnimal experimentationinfo:eu-repo/semantics/article7009972022-11-09info:eu-repo/semantics/openAccess27561390