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rbFOX1/MBNL1 competition for CCUG RNA repeats binding contributes to myotonic dystrophy type 1/type 2 differences

Author

Listed:
  • Chantal Sellier

    (University of Strasbourg)

  • Estefanía Cerro-Herreros

    (Interdisciplinary Research Structure for Biotechnology and Biomedicine BIOTECMED, University of Valencia
    INCLIVA Health Research Institute)

  • Markus Blatter

    (Swiss Federal Institute of Technology (ETH) Zurich)

  • Fernande Freyermuth

    (University of Strasbourg)

  • Angeline Gaucherot

    (University of Strasbourg)

  • Frank Ruffenach

    (University of Strasbourg)

  • Partha Sarkar

    (University of Texas Medical Branch)

  • Jack Puymirat

    (Laval University, CHUQ, Ste-Foy)

  • Bjarne Udd

    (Tampere University Hospital
    Helsinki University
    Vasa Central Hospital)

  • John W. Day

    (Stanford University)

  • Giovanni Meola

    (University of Milan
    IRCCS Policlinico San Donato, San Donato Milanese)

  • Guillaume Bassez

    (Center of Research in Myology)

  • Harutoshi Fujimura

    (Toneyama National Hospital)

  • Masanori P. Takahashi

    (Osaka University Graduate School of Medicine)

  • Benedikt Schoser

    (Ludwig Maximilian University)

  • Denis Furling

    (Center of Research in Myology)

  • Ruben Artero

    (Interdisciplinary Research Structure for Biotechnology and Biomedicine BIOTECMED, University of Valencia
    INCLIVA Health Research Institute)

  • Frédéric H. T. Allain

    (Swiss Federal Institute of Technology (ETH) Zurich)

  • Beatriz Llamusi

    (Interdisciplinary Research Structure for Biotechnology and Biomedicine BIOTECMED, University of Valencia
    INCLIVA Health Research Institute)

  • Nicolas Charlet-Berguerand

    (University of Strasbourg
    Centre National de la Recherche Scientifique
    Institut National de la Santé et de la Recherche Médicale, U964
    Université de Strasbourg)

Abstract

Myotonic dystrophy type 1 and type 2 (DM1, DM2) are caused by expansions of CTG and CCTG repeats, respectively. RNAs containing expanded CUG or CCUG repeats interfere with the metabolism of other RNAs through titration of the Muscleblind-like (MBNL) RNA binding proteins. DM2 follows a more favorable clinical course than DM1, suggesting that specific modifiers may modulate DM severity. Here, we report that the rbFOX1 RNA binding protein binds to expanded CCUG RNA repeats, but not to expanded CUG RNA repeats. Interestingly, rbFOX1 competes with MBNL1 for binding to CCUG expanded repeats and overexpression of rbFOX1 partly releases MBNL1 from sequestration within CCUG RNA foci in DM2 muscle cells. Furthermore, expression of rbFOX1 corrects alternative splicing alterations and rescues muscle atrophy, climbing and flying defects caused by expression of expanded CCUG repeats in a Drosophila model of DM2.

Suggested Citation

  • Chantal Sellier & Estefanía Cerro-Herreros & Markus Blatter & Fernande Freyermuth & Angeline Gaucherot & Frank Ruffenach & Partha Sarkar & Jack Puymirat & Bjarne Udd & John W. Day & Giovanni Meola & G, 2018. "rbFOX1/MBNL1 competition for CCUG RNA repeats binding contributes to myotonic dystrophy type 1/type 2 differences," Nature Communications, Nature, vol. 9(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-04370-x
    DOI: 10.1038/s41467-018-04370-x
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