%0 Journal Article
%A Pal, Jagriti
%A Riester, Marisa
%A Ganner, Athina
%A Ghosh, Avantika
%A Dhamija, Sonam
%A Mookherjee, Debdatto
%A Voss, Christian
%A Frew, Ian J
%A Kotsis, Fruzsina
%A Neumann-Haefelin, Elke
%A Spang, Anne
%A Diederichs, Sven
%T Nonstop mutations cause loss of renal tumor suppressor proteins VHL and BAP1 and affect multiple stages of protein translation.
%J Science advances
%V 11
%N 7
%@ 2375-2548
%C Washington, DC [u.a.]
%I Assoc.
%M DKFZ-2025-00345
%P eadr6375
%D 2025
%X Nonstop extension or stop-loss mutations lead to the extension of a protein at its carboxyl terminus. Recently, nonstop mutations in the tumor suppressor SMAD Family Member 4 (SMAD4) have been discovered to lead to proteasomal SMAD4 degradation. However, this mutation type has not been studied in other cancer genes. Here, we explore somatic nonstop mutations in the tumor suppressor genes BRCA1 Associated Protein 1 (BAP1) and Von Hippel-Lindau (VHL) enriched in renal cell carcinoma. For BAP1, nonstop mutations generate an extremely long extension. Instead of proteasomal degradation, the extension decreases translation and depletes BAP1 messenger RNA from heavy polysomes. For VHL, the short extension leads to proteasomal degradation. Unexpectedly, the mutation alters the selection of the translational start site shifting VHL isoforms. We identify germline VHL nonstop mutations in patients leading to the early onset of severe disease manifestations. In summary, nonstop extension mutations inhibit the expression of renal tumor suppressor genes with pleiotropic effects on translation and protein stability.
%K Von Hippel-Lindau Tumor Suppressor Protein: genetics
%K Von Hippel-Lindau Tumor Suppressor Protein: metabolism
%K Tumor Suppressor Proteins: genetics
%K Tumor Suppressor Proteins: metabolism
%K Humans
%K Ubiquitin Thiolesterase: genetics
%K Ubiquitin Thiolesterase: metabolism
%K Protein Biosynthesis
%K Kidney Neoplasms: genetics
%K Kidney Neoplasms: metabolism
%K Kidney Neoplasms: pathology
%K Mutation
%K Carcinoma, Renal Cell: genetics
%K Carcinoma, Renal Cell: metabolism
%K Carcinoma, Renal Cell: pathology
%K Proteasome Endopeptidase Complex: metabolism
%K Proteasome Endopeptidase Complex: genetics
%K Proteolysis
%K BAP1 protein, human (NLM Chemicals)
%K Von Hippel-Lindau Tumor Suppressor Protein (NLM Chemicals)
%K Tumor Suppressor Proteins (NLM Chemicals)
%K Ubiquitin Thiolesterase (NLM Chemicals)
%K VHL protein, human (NLM Chemicals)
%K Proteasome Endopeptidase Complex (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:39937911
%R 10.1126/sciadv.adr6375
%U https://inrepo02.dkfz.de/record/298906