TY  - JOUR
AU  - Pal, Jagriti
AU  - Riester, Marisa
AU  - Ganner, Athina
AU  - Ghosh, Avantika
AU  - Dhamija, Sonam
AU  - Mookherjee, Debdatto
AU  - Voss, Christian
AU  - Frew, Ian J
AU  - Kotsis, Fruzsina
AU  - Neumann-Haefelin, Elke
AU  - Spang, Anne
AU  - Diederichs, Sven
TI  - Nonstop mutations cause loss of renal tumor suppressor proteins VHL and BAP1 and affect multiple stages of protein translation.
JO  - Science advances
VL  - 11
IS  - 7
SN  - 2375-2548
CY  - Washington, DC [u.a.]
PB  - Assoc.
M1  - DKFZ-2025-00345
SP  - eadr6375
PY  - 2025
AB  - 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.
KW  - Von Hippel-Lindau Tumor Suppressor Protein: genetics
KW  - Von Hippel-Lindau Tumor Suppressor Protein: metabolism
KW  - Tumor Suppressor Proteins: genetics
KW  - Tumor Suppressor Proteins: metabolism
KW  - Humans
KW  - Ubiquitin Thiolesterase: genetics
KW  - Ubiquitin Thiolesterase: metabolism
KW  - Protein Biosynthesis
KW  - Kidney Neoplasms: genetics
KW  - Kidney Neoplasms: metabolism
KW  - Kidney Neoplasms: pathology
KW  - Mutation
KW  - Carcinoma, Renal Cell: genetics
KW  - Carcinoma, Renal Cell: metabolism
KW  - Carcinoma, Renal Cell: pathology
KW  - Proteasome Endopeptidase Complex: metabolism
KW  - Proteasome Endopeptidase Complex: genetics
KW  - Proteolysis
KW  - BAP1 protein, human (NLM Chemicals)
KW  - Von Hippel-Lindau Tumor Suppressor Protein (NLM Chemicals)
KW  - Tumor Suppressor Proteins (NLM Chemicals)
KW  - Ubiquitin Thiolesterase (NLM Chemicals)
KW  - VHL protein, human (NLM Chemicals)
KW  - Proteasome Endopeptidase Complex (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:39937911
DO  - DOI:10.1126/sciadv.adr6375
UR  - https://inrepo02.dkfz.de/record/298906
ER  -