A pan-cancer analysis reveals nonstop extension mutations causing SMAD4 tumour suppressor degradation.

Nature cell biology 2020 Aug

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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.

Citation

Sonam Dhamija, Chul Min Yang, Jeanette Seiler, Ksenia Myacheva, Maiwen Caudron-Herger, Angela Wieland, Mahmoud Abdelkarim, Yogita Sharma, Marisa Riester, Matthias Groß, Jochen Maurer, Sven Diederichs. A pan-cancer analysis reveals nonstop extension mutations causing SMAD4 tumour suppressor degradation. Nature cell biology. 2020 Aug;22(8):999-1010