Reference - Detail
| 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* 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 |
| IF | 12.121 |
| Times Cited | 9 |
| Altmetric score |
オルトメトリクス指標項目
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| The most frequently cited source | X(Twitter) |
| Total number of mentions | 9 |
| Altmetric score changes over past 6months | 0.0 |
| Resource | |
| C.elegans | tm3768 |