A pan-cancer analysis reveals nonstop extension mutations causing SMAD4 tumour suppressor degradation
| Autor: | Mahmoud Abdelkarim, Sonam Dhamija, Sven Diederichs, Jeanette Seiler, Jochen Maurer, Yogita Sharma, Marisa Riester, Angela Wieland, Chul Min Yang, Maïwen Caudron-Herger, Ksenia Myacheva, Matthias Groß |
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| Rok vydání: | 2020 |
| Předmět: |
Untranslated region
Mutant Biology NonStop medicine.disease_cause law.invention Sense Codon 03 medical and health sciences 0302 clinical medicine law Cell Line Tumor Neoplasms Databases Genetic medicine Humans Codon Smad4 Protein 030304 developmental biology Genetics 0303 health sciences Mutation Cell Biology Stop codon Cell biology HEK293 Cells 030220 oncology & carcinogenesis Proteolysis Suppressor Degron |
| Zdroj: | Nature Cell Biology. 22:999-1010 |
| ISSN: | 1476-4679 1465-7392 |
| Popis: | Nonstop or stop-loss mutations convert a stop into a sense codon, resulting in translation into the 3′ untranslated region as a nonstop extension mutation to the next in-frame stop codon or as a readthrough mutation into the poly-A tail. Nonstop mutations have been characterized in hereditary diseases, but not in cancer genetics. In a pan-cancer analysis, we curated and analysed 3,412 nonstop mutations from 62 tumour entities, generating a comprehensive database at http://NonStopDB.dkfz.de. Six different nonstop extension mutations affected the tumour suppressor SMAD4, extending its carboxy terminus by 40 amino acids. These caused rapid degradation of the SMAD4 mutants via the ubiquitin–proteasome system. A hydrophobic degron signal sequence of ten amino acids within the carboxy-terminal extension was required to induce complete loss of the SMAD4 protein. Thus, we discovered that nonstop mutations can be functionally important in cancer and characterize their loss-of-function impact on the tumour suppressor SMAD4. Dhamija et al. profile 3,412 nonstop mutations from 62 tumour entities and as proof of concept demonstrate that six such mutations cause degradation and loss of the tumour suppressor SMAD4. |
| Databáze: | OpenAIRE |
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