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.
Highlights
The tumour suppressor CYLD is a deubiquitinase previously shown to inhibit NF-kB, MAP kinase and Wnt signalling
The R932X mutation in mouse CYLD is equivalent to the R936X mutation in human CYLD, which truncates subdomain III of the Histidine box that is essential for CYLD catalytic activity[8] and was found to cause cylindromas[1] (Supplementary Fig. 1a)
In contrast to the suggestion by Zhang et al.[16] that CYLD deficiency in macrophages was responsible for the increased AOM/dextran sulphate sodium (DSS)-induced colon carcinogenesis in Cyld À / À mice to AOM/DSS-induced colon cancer, loss of CYLD catalytic activity in myeloid cells did not sensitize mice to AOM/DSS-induced inflammation and tumour development
Summary
The tumour suppressor CYLD is a deubiquitinase previously shown to inhibit NF-kB, MAP kinase and Wnt signalling. 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. In this study the authors suggested that increased activation of JNK and not NF-kB was responsible for the enhanced tumorigenesis caused by the expression of catalytically inactive CYLD. It appears that CYLD may suppress tumour development by different mechanisms acting either in a cell intrinsic manner in premalignant epithelial cells or by regulating the tumour microenvironment by acting in myeloid cells. In response to cellular stress, HAUSP and a number of other deubiquitinating enzymes, including Otub[1], USP10, USP29 and USP42 remove ubiquitin chains from p53 and other proteins regulating p53 ubiquitination including Mdm[2], inducing p53 stabilization (refs 23,24)
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