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Article Dans Une Revue Nucleic Acids Research Année : 2012

New function for the RNA helicase p68/DDX5 as a modifier of MBNL1 activity on expanded CUG repeats

François-Xavier Laurent
  • Fonction : Auteur
Alain Sureau
François Trouslard
  • Fonction : Auteur
Erwan Gasnier
  • Fonction : Auteur
Denis Furling
Joëlle Marie
  • Fonction : Auteur

Résumé

Myotonic Dystrophy type I (DM1) is caused by an abnormal expansion of CTG triplets in the 3 0 UTR of the dystrophia myotonica protein kinase (DMPK) gene, leading to the aggregation of the mutant transcript in nuclear RNA foci. The expanded mutant transcript promotes the seques-tration of the MBNL1 splicing factor, resulting in the misregulation of a subset of alternative splicing events. In this study, we identify the DEAD-box RNA helicase p68 (DDX5) in complexes assembled onto in vitro-transcribed CUG repeats. We showed that p68 colocalized with RNA foci in cells expressing the 3 0 UTR of the DMPK gene containing expanded CTG repeats. We found that p68 increased MBNL1 binding onto pathological repeats and the stem-loop structure regulatory element within the cardiac Troponin T (TNNT2) pre-mRNA, splicing of which is misregulated in DM1. Mutations in the helicase core of p68 prevented both the stimulatory effect of the protein on MBNL1 binding and the colocalization of p68 with CUG repeats, suggesting that remodeling of RNA secondary structure by p68 facilitates MBNL1 binding. We also found that the competence of p68 for regulating TNNT2 exon 5 inclusion depended on the integrity of MBNL1 binding sites. We propose that p68 acts as a modifier of MBNL1 activity on splicing targets and pathogenic RNA.
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hal-03001690 , version 1 (12-11-2020)

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François-Xavier Laurent, Alain Sureau, Arnaud F Klein, François Trouslard, Erwan Gasnier, et al.. New function for the RNA helicase p68/DDX5 as a modifier of MBNL1 activity on expanded CUG repeats. Nucleic Acids Research, 2012, 40 (7), pp.3159-3171. ⟨10.1093/nar/gkr1228⟩. ⟨hal-03001690⟩
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