IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v15y2024i1d10.1038_s41467-024-52779-4.html
   My bibliography  Save this article

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

Author

Listed:
  • Avantika Ghosh

    (Faculty of Medicine
    a partnership between DKFZ and University Medical Center Freiburg)

  • Marisa Riester

    (Faculty of Medicine)

  • Jagriti Pal

    (Faculty of Medicine)

  • Kadri-Ann Lainde

    (Faculty of Medicine)

  • Carla Tangermann

    (Faculty of Medicine
    a partnership between DKFZ and University Medical Center Freiburg)

  • Angela Wanninger

    (Faculty of Medicine
    a partnership between DKFZ and University Medical Center Freiburg)

  • Ursula K. Dueren

    (Faculty of Medicine)

  • Sonam Dhamija

    (Faculty of Medicine
    a partnership between DKFZ and University Medical Center Freiburg
    CSIR-Institute of Genomics and Integrative Biology
    Academy of Scientific and Innovative Research (AcSIR))

  • Sven Diederichs

    (Faculty of Medicine
    a partnership between DKFZ and University Medical Center Freiburg)

Abstract

Nonstop extension mutations, a.k.a. stop-lost or stop-loss mutations, convert a stop codon into a sense codon resulting in translation into the 3’ untranslated region until the next in-frame stop codon, thereby extending the C-terminus of a protein. In cancer, only nonstop mutations in SMAD4 have been functionally characterized, while the impact of other nonstop mutations remain unknown. Here, we exploit our pan-cancer NonStopDB dataset and test all 2335 C-terminal extensions arising from somatic nonstop mutations in cancer for their impact on protein expression. In a high-throughput screen, 56.1% of the extensions effectively reduce protein abundance. Extensions of multiple tumor suppressor genes like PTEN, APC, B2M, CASP8, CDKN1B and MLH1 are effective and validated for their suppressive impact. Importantly, the effective extensions possess a higher hydrophobicity than the neutral extensions linking C-terminal hydrophobicity with protein destabilization. Analyzing the proteomes of eleven different species reveals conserved patterns of amino acid distribution in the C-terminal regions of all proteins compared to the proteomes like an enrichment of lysine and arginine and a depletion of glycine, leucine, valine and isoleucine across species and kingdoms. These evolutionary selection patterns are disrupted in the cancer-derived effective nonstop extensions.

Suggested Citation

  • Avantika Ghosh & Marisa Riester & Jagriti Pal & Kadri-Ann Lainde & Carla Tangermann & Angela Wanninger & Ursula K. Dueren & Sonam Dhamija & Sven Diederichs, 2024. "Suppressive cancer nonstop extension mutations increase C-terminal hydrophobicity and disrupt evolutionarily conserved amino acid patterns," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-52779-4
    DOI: 10.1038/s41467-024-52779-4
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-024-52779-4
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-024-52779-4?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Ruben Vidal & Blas Frangione & Agueda Rostagno & Simon Mead & Tamas Révész & Gordon Plant & Jorge Ghiso, 1999. "A stop-codon mutation in the BRI gene associated with familial British dementia," Nature, Nature, vol. 399(6738), pages 776-781, June.
    2. Jordan S. Kesner & Ziheng Chen & Peiguo Shi & Alexis O. Aparicio & Michael R. Murphy & Yang Guo & Aditi Trehan & Jessica E. Lipponen & Yocelyn Recinos & Natura Myeku & Xuebing Wu, 2023. "Noncoding translation mitigation," Nature, Nature, vol. 617(7960), pages 395-402, May.
    3. Alice H. Berger & Alfred G. Knudson & Pier Paolo Pandolfi, 2011. "A continuum model for tumour suppression," Nature, Nature, vol. 476(7359), pages 163-169, August.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Solip Park & Fran Supek & Ben Lehner, 2021. "Higher order genetic interactions switch cancer genes from two-hit to one-hit drivers," Nature Communications, Nature, vol. 12(1), pages 1-10, December.
    2. Haiwang Yang & Qianru Li & Emily K. Stroup & Sheng Wang & Zhe Ji, 2024. "Widespread stable noncanonical peptides identified by integrated analyses of ribosome profiling and ORF features," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    3. Janine H. Ree & Karthik B. Jeganathan & Raul O. Fierro Velasco & Cheng Zhang & Ismail Can & Masakazu Hamada & Hu Li & Darren J. Baker & Jan M. Deursen, 2023. "Hyperphosphorylated PTEN exerts oncogenic properties," Nature Communications, Nature, vol. 14(1), pages 1-17, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-52779-4. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.