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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 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.


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

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PMID: 32719554

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