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

Chantal Sellier, Estefanía Cerro-Herreros, Markus Blatter, Fernande Freyermuth, Angeline Gaucherot, Frank Ruffenach, Partha Sarkar, Jack Puymirat, Bjarne Udd, John W. Day, Giovanni Meola, Guillaume Bassez, Harutoshi Fujimura, Masanori P. Takahashi, Benedikt Schoser, Denis Furling, Ruben Artero, Frédéric H. T. Allain, Beatriz Llamusi () and Nicolas Charlet-Berguerand ()
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Chantal Sellier: University of Strasbourg
Estefanía Cerro-Herreros: Interdisciplinary Research Structure for Biotechnology and Biomedicine BIOTECMED, University of Valencia
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
John W. Day: Stanford University
Giovanni Meola: University of Milan
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
Frédéric H. T. Allain: Swiss Federal Institute of Technology (ETH) Zurich
Beatriz Llamusi: Interdisciplinary Research Structure for Biotechnology and Biomedicine BIOTECMED, University of Valencia
Nicolas Charlet-Berguerand: University of Strasbourg

Nature Communications, 2018, vol. 9, issue 1, 1-15

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-04370-x

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