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@ARTICLE{Pal:298906,
      author       = {J. Pal and M. Riester and A. Ganner and A. Ghosh$^*$ and S.
                      Dhamija$^*$ and D. Mookherjee and C. Voss and I. J. Frew and
                      F. Kotsis and E. Neumann-Haefelin and A. Spang and S.
                      Diederichs$^*$},
      title        = {{N}onstop mutations cause loss of renal tumor suppressor
                      proteins {VHL} and {BAP}1 and affect multiple stages of
                      protein translation.},
      journal      = {Science advances},
      volume       = {11},
      number       = {7},
      issn         = {2375-2548},
      address      = {Washington, DC [u.a.]},
      publisher    = {Assoc.},
      reportid     = {DKFZ-2025-00345},
      pages        = {eadr6375},
      year         = {2025},
      abstract     = {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.},
      keywords     = {Von Hippel-Lindau Tumor Suppressor Protein: genetics / Von
                      Hippel-Lindau Tumor Suppressor Protein: metabolism / Tumor
                      Suppressor Proteins: genetics / Tumor Suppressor Proteins:
                      metabolism / Humans / Ubiquitin Thiolesterase: genetics /
                      Ubiquitin Thiolesterase: metabolism / Protein Biosynthesis /
                      Kidney Neoplasms: genetics / Kidney Neoplasms: metabolism /
                      Kidney Neoplasms: pathology / Mutation / Carcinoma, Renal
                      Cell: genetics / Carcinoma, Renal Cell: metabolism /
                      Carcinoma, Renal Cell: pathology / Proteasome Endopeptidase
                      Complex: metabolism / Proteasome Endopeptidase Complex:
                      genetics / Proteolysis / BAP1 protein, human (NLM Chemicals)
                      / Von Hippel-Lindau Tumor Suppressor Protein (NLM Chemicals)
                      / Tumor Suppressor Proteins (NLM Chemicals) / Ubiquitin
                      Thiolesterase (NLM Chemicals) / VHL protein, human (NLM
                      Chemicals) / Proteasome Endopeptidase Complex (NLM
                      Chemicals)},
      cin          = {FR01},
      ddc          = {500},
      cid          = {I:(DE-He78)FR01-20160331},
      pnm          = {899 - ohne Topic (POF4-899)},
      pid          = {G:(DE-HGF)POF4-899},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:39937911},
      doi          = {10.1126/sciadv.adr6375},
      url          = {https://inrepo02.dkfz.de/record/298906},
}