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.
Highlights
Myotonic dystrophy type 1 and type 2 (DM1, DM2) are caused by expansions of CTG and CCTG repeats, respectively
To identify novel RNA binding proteins involved in myotonic dystrophy, we incubated radioactively labeled CUG or CCUG RNA repeats with nuclear extract of differentiated mouse C2C12 muscle cells and analyzed the RNA-bound proteins by UV-light crosslink followed by SDS page gel electrophoresis (Fig. 1a)
We observed no displacement of MBNL1 localization upon modulation of rbFOX1 expression in DM1 muscle cell cultures (Fig. 5c and Supplementary Fig. 5C). These results suggest that rbFOX1 competes with MBNL1 to bind to CCUG RNA repeats
Summary
Myotonic dystrophy type 1 and type 2 (DM1, DM2) are caused by expansions of CTG and CCTG repeats, respectively. Only subtle or even no detectable fusion defects or splicing alterations are observed in cultures of DM2 myoblasts[32,33,34] These milder clinical and cellular features are in contradiction with the 3 to 5 folds higher expression of the CNBP mRNA, which first intron hosts the expanded CCUG repeat, compared to the DMPK mRNA, which 3’UTR hosts the expanded CUG repeats[7,35,36]. We propose that the rbFOX proteins, by competing with and reducing the titration of MBNL1 within CCUG RNA foci, may participate to the lesser toxicity of the CCTG repeat expansion in myotonic dystrophy type 2
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