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

6533b7dbfe1ef96bd127029c

RESEARCH PRODUCT

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

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

subject

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 Q 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 RNA Splicing Factors 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 RNA Protein Conformation beta-Strand 3111 Biomedicine

description

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.

year	journal	country	edition	language
2018-05-01

10.1038/s41467-018-04370-x https://hal.archives-ouvertes.fr/hal-03339515/file/s41467-018-04370-x.pdf