rbFOX1/MBNL1 competition for CCUG RNA repeats binding contributes to myotonic dystrophy type 1/type 2 differences.
Fiche publication
Date publication
mai 2018
Journal
Nature communications
Auteurs
Membres identifiés du Cancéropôle Est :
Dr CHARLET BERGUERAND Nicolas , Mr RUFFENACH Frank
Tous les auteurs :
Sellier C, Cerro-Herreros E, Blatter M, Freyermuth F, Gaucherot A, Ruffenach F, Sarkar P, Puymirat J, Udd B, Day JW, Meola G, Bassez G, Fujimura H, Takahashi MP, Schoser B, Furling D, Artero R, Allain FHT, Llamusi B, Charlet-Berguerand N
Lien Pubmed
Résumé
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.
Mots clés
Animals, Binding Sites, Binding, Competitive, Crystallography, X-Ray, Disease Models, Animal, Drosophila melanogaster, genetics, Escherichia coli, genetics, Gene Expression, Humans, Kinetics, Models, Molecular, Muscle, Skeletal, metabolism, Myotonic Dystrophy, classification, Nucleotide Motifs, Protein Binding, Protein Conformation, alpha-Helical, Protein Conformation, beta-Strand, Protein Interaction Domains and Motifs, RNA, chemistry, RNA Splicing Factors, chemistry, RNA-Binding Proteins, chemistry, Recombinant Proteins, chemistry, Thermodynamics
Référence
Nat Commun. 2018 05 22;9(1):2009