The tumour suppressor CYLD regulates the p53 DNA damage response

Nat Commun. 2016 Aug 26;7:12508. doi: 10.1038/ncomms12508.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*
  • Deubiquitinating Enzyme CYLD
  • 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

Substances

  • CEP-1 protein, C elegans
  • Caenorhabditis elegans Proteins
  • Tumor Suppressor Protein p53
  • CYLD protein, mouse
  • Deubiquitinating Enzyme CYLD
  • Cysteine Endopeptidases
  • Lysine
  • Azoxymethane