A Pan-cancer Analysis Reveals Nonstop Extension Mutations Causing SMAD4 Tumour Suppressor Degradation

Overview

Journal Nat Cell Biol

Specialty Cell Biology

Date 2020 Jul 29

PMID 32719554

Citations 10

Authors

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

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

Nonstop mutations cause loss of renal tumor suppressor proteins and and affect multiple stages of protein translation.

Pal J, Riester M, Ganner A, Ghosh A, Dhamija S, Mookherjee D Sci Adv. 2025; 11(7):eadr6375.

PMID: 39937911 PMC: 11817944. DOI: 10.1126/sciadv.adr6375.

Suppressive cancer nonstop extension mutations increase C-terminal hydrophobicity and disrupt evolutionarily conserved amino acid patterns.

Ghosh A, Riester M, Pal J, Lainde K, Tangermann C, Wanninger A Nat Commun. 2024; 15(1):9209.

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