The tumour suppressor CYLD regulates the p53 DNA damage response.
The tumour suppressor CYLD regulates the p53 DNA damage response.
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DOI：
10.1038/ncomms12508
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发表时间：
2016-08-26
影响因子：
16.6
通讯作者：
Pasparakis, Manolis
中科院分区：
文献类型：
--
作者：
Fernandez-Majada, Vanesa;Welz, Patrick-Simon;Ermolaeva, Maria A.;Schell, Michael;Adam, Alexander;Dietlein, Felix;Komander, David;Buettner, Reinhard;Thomas, Roman K.;Schumacher, Bjoern;Pasparakis, Manolis
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. CYLD is a deubiquitinase known to act as a tumour suppressor in different models of carcinogenesis. Here, the authors show that CYLD suppresses carcinogen-induced tumorigenesis by deubiquitinating p53 and promoting its stabilization and activation in response to DNA damage.
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