IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v7y2016i1d10.1038_ncomms10615.html
   My bibliography  Save this article

Cancer-associated SF3B1 mutations affect alternative splicing by promoting alternative branchpoint usage

Author

Listed:
  • Samar Alsafadi

    (INSERM U830, Institut Curie, PSL Research University)

  • Alexandre Houy

    (INSERM U830, Institut Curie, PSL Research University)

  • Aude Battistella

    (INSERM U830, Institut Curie, PSL Research University)

  • Tatiana Popova

    (INSERM U830, Institut Curie, PSL Research University)

  • Michel Wassef

    (Depatment of Developmental Biology and Genetics, CNRS UMR 3215/INSERM U934, Institut Curie, PSL Research University)

  • Emilie Henry

    (Institut Curie, PSL Research University)

  • Franck Tirode

    (INSERM U830, Institut Curie, PSL Research University)

  • Angelos Constantinou

    (CNRS UPR 1142, IGH-Institute of Human Genetics)

  • Sophie Piperno-Neumann

    (Institut Curie)

  • Sergio Roman-Roman

    (Institut Curie, PSL Research University)

  • Martin Dutertre

    (CNRS UMR 3348, Institut Curie, PSL Research University)

  • Marc-Henri Stern

    (INSERM U830, Institut Curie, PSL Research University)

Abstract

Hotspot mutations in the spliceosome gene SF3B1 are reported in ∼20% of uveal melanomas. SF3B1 is involved in 3′-splice site (3′ss) recognition during RNA splicing; however, the molecular mechanisms of its mutation have remained unclear. Here we show, using RNA-Seq analyses of uveal melanoma, that the SF3B1R625/K666 mutation results in deregulated splicing at a subset of junctions, mostly by the use of alternative 3′ss. Modelling the differential junctions in SF3B1WT and SF3B1R625/K666 cell lines demonstrates that the deregulated splice pattern strictly depends on SF3B1 status and on the 3’ss-sequence context. SF3B1WT knockdown or overexpression do not reproduce the SF3B1R625/K666 splice pattern, qualifying SF3B1R625/K666 as change-of-function mutants. Mutagenesis of predicted branchpoints reveals that the SF3B1R625/K666-promoted splice pattern is a direct result of alternative branchpoint usage. Altogether, this study provides a better understanding of the mechanisms underlying splicing alterations induced by mutant SF3B1 in cancer, and reveals a role for alternative branchpoints in disease.

Suggested Citation

  • Samar Alsafadi & Alexandre Houy & Aude Battistella & Tatiana Popova & Michel Wassef & Emilie Henry & Franck Tirode & Angelos Constantinou & Sophie Piperno-Neumann & Sergio Roman-Roman & Martin Dutertr, 2016. "Cancer-associated SF3B1 mutations affect alternative splicing by promoting alternative branchpoint usage," Nature Communications, Nature, vol. 7(1), pages 1-12, April.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms10615
    DOI: 10.1038/ncomms10615
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/ncomms10615
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/ncomms10615?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
    ---><---

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. David Rombaut & Carine Lefèvre & Tony Rached & Sabrina Bondu & Anne Letessier & Raphael M. Mangione & Batoul Farhat & Auriane Lesieur-Pasquier & Daisy Castillo-Guzman & Ismael Boussaid & Chloé Friedri, 2024. "Accelerated DNA replication fork speed due to loss of R-loops in myelodysplastic syndromes with SF3B1 mutation," Nature Communications, Nature, vol. 15(1), pages 1-20, 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:7:y:2016:i:1:d:10.1038_ncomms10615. 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.

    We have no bibliographic references for this item. You can help adding them by using 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.