RRC ID 53324
Author Fernández-Majada V, Welz PS, Ermolaeva MA, Schell M, Adam A, Dietlein F, Komander D, Büttner R, Thomas RK, Schumacher B, Pasparakis M.
Title The tumour suppressor CYLD regulates the p53 DNA damage response.
Journal Nat Commun
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.
Volume 7
Pages 12508
Published 2016-8-26
DOI 10.1038/ncomms12508
PII ncomms12508
PMID 27561390
PMC PMC5007442
MeSH Animals Apoptosis / genetics Azoxymethane / toxicity Caenorhabditis elegans / physiology Caenorhabditis elegans Proteins / metabolism Carcinogenesis / genetics* Cysteine Endopeptidases / genetics Cysteine Endopeptidases / metabolism* DNA Damage / physiology DNA Repair / genetics* Female Genetic Predisposition to Disease Intestinal Neoplasms / chemically induced Intestinal Neoplasms / genetics Intestinal Neoplasms / pathology Lysine / metabolism Male Mice Mice, Transgenic Signal Transduction / physiology Skin Neoplasms / chemically induced Skin Neoplasms / genetics Skin Neoplasms / pathology Tumor Suppressor Protein p53 / genetics* Tumor Suppressor Protein p53 / metabolism Ubiquitination / genetics
IF 12.353