1. rbFOX1/MBNL1 competition for CCUG RNA repeats binding contributes to myotonic dystrophy type 1/type 2 differences
- Author
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Frédéric H.-T. Allain, Nicolas Charlet-Berguerand, Frank Ruffenach, John W. Day, Giovanni Meola, Masanori P. Takahashi, Chantal Sellier, Estefanía Cerro-Herreros, Jack Puymirat, Denis Furling, Angeline Gaucherot, Guillaume Bassez, Ruben Artero, Markus Blatter, Beatriz Llamusi, Fernande Freyermuth, Harutoshi Fujimura, Partha S. Sarkar, Bjarne Udd, Benedikt Schoser, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Biomedical Research Institute [Valencia, Spain] (INCLIVA ), Universitat de València (UV), Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich), The University of Texas Medical Branch (UTMB), Université Laval [Québec] (ULaval), Neurology Department, Tampere University Hospital, University of Helsinki, Stanford University, University of Milan, Università degli Studi di Milano, IRCCS Policlinico San Donato, Institut de Myologie, Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Sorbonne Université (SU), Toneyama National Hospital, Osaka University Graduate School of Medicine, Suita, Ludwig Maximilian University [Munich] (LMU), Medicum, Department of Medical and Clinical Genetics, Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Università degli Studi di Milano = University of Milan (UNIMI), Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)
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0301 basic medicine ,Models, Molecular ,Protein Conformation, alpha-Helical ,[SDV]Life Sciences [q-bio] ,General Physics and Astronomy ,Gene Expression ,RNA-binding protein ,Crystallography, X-Ray ,chemistry.chemical_compound ,MOLECULAR-BASIS ,Gene expression ,MBNL1 ,Myotonic Dystrophy ,ComputingMilieux_MISCELLANEOUS ,Multidisciplinary ,CHLORIDE CHANNEL ,RNA-Binding Proteins ,Recombinant Proteins ,3. Good health ,Cell biology ,CONGENITAL HEART-DISEASE ,Drosophila melanogaster ,Thermodynamics ,SKELETAL-MUSCLE ,RNA Splicing Factors ,CUG REPEATS ,Protein Binding ,musculoskeletal diseases ,STEADY-STATE ,congenital, hereditary, and neonatal diseases and abnormalities ,Science ,RBFOX1 ,Biology ,Myotonic dystrophy ,Binding, Competitive ,General Biochemistry, Genetics and Molecular Biology ,Article ,03 medical and health sciences ,medicine ,Escherichia coli ,Animals ,Humans ,Protein Interaction Domains and Motifs ,Binding site ,Nucleotide Motifs ,Muscle, Skeletal ,SPLICING REGULATOR RBFOX2 ,MUSCLEBLIND PROTEINS ,Binding Sites ,PRE-MESSENGER-RNA ,RNA ,General Chemistry ,medicine.disease ,Disease Models, Animal ,Kinetics ,030104 developmental biology ,chemistry ,TRIPLET REPEAT ,Protein Conformation, beta-Strand ,3111 Biomedicine - 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., Myotonic dystrophy (DM) type 2 is a neuromuscular pathology caused by large expansions of CCTG repeats. Here the authors find that rbFOX1 RNA binding protein binds to CCUG RNA repeats and competes with MBNL1 for the binding to CCUG repeats, releasing MBNL1 from sequestration in DM2 muscle cells.
- Published
- 2018
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