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

Laurent, François-Xavier; Sureau, Alain; Klein, Arnaud; Trouslard, François; Gasnier, E.; Furling, Denis; Marie, Joëlle

doi:10.1093/nar/gkr1228

Cited by 67 publications

(74 citation statements)

References 64 publications

(84 reference statements)

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“…Aberrant RNA processing by alternative splicing of genes related to schizophrenia had been frequently observed in the past (69,70), and this was correlated with the pathophysiology of the disorder. In future studies, it will be clarified whether ARVCF contributes to malfunctions in alternative splicing that may lead to aberrant pre-mRNA splicing events giving rise to neurological disorders, such as schizophrenia, or other human diseases, such as myotonic dystrophy or cancer (33,61,71,72).…”

Section: Discussionmentioning

confidence: 99%

Nuclear ARVCF Protein Binds Splicing Factors and Contributes to the Regulation of Alternative Splicing

Rappe

Schlechter

Aschoff

et al. 2014

Journal of Biological Chemistry

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Background: ARVCF occurs both at adherens junctions and in the nucleus, but little is known about its nuclear function. Results: ARVCF interacts with RNA-binding proteins involved in splicing and contributes to alternative splicing of specific transcripts. Conclusion: ARVCF influences splicing of specific pre-mRNAs. Significance: We propose a new role of nuclear ARVCF in post-transcriptional regulation of gene expression.

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Section: Discussionmentioning

confidence: 99%

Nuclear ARVCF Protein Binds Splicing Factors and Contributes to the Regulation of Alternative Splicing

Rappe

Schlechter

Aschoff

et al. 2014

Journal of Biological Chemistry

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“…Ectopic expression of DDX6 decreased CUG foci in DM1 cells (15). In contrast, p68 might increase the stability of CUG repeats because inhibition of p68 in tet-regulated HeLa cells by siRNA to p68/p72 reduces the number of CUG foci (14). The findings described in this paper show that the correction of p68 levels in DM1 cells reduces the number of CUG foci (Fig.…”

Section: Fish Analysis Of Dm1 Myoblasts Transfected With P68-gfp Usinmentioning

confidence: 51%

“…2A). Recent analysis of the proteins bound to CUG repeats showed that p68 binds to CUG foci and modulates splicing activity of MBNL1 (14). It appears that p68 levels are increased in immortalized cultured DM1 myoblasts (17).…”

Section: Resultsmentioning

confidence: 99%

“…Whereas many studies are focused on the correction of toxic effects caused by the mutant CUG and CCUG repeats, the mechanisms which prevent degradation of these repeats are not well understood. Recent reports showed that RNA helicases p68/DDX5 and DDX6 bind to and remodel the mutant CUG RNA (14,15). It has been proposed that these RNA helicases have a different effect on the mutant CUG repeats.…”

Section: Fish Analysis Of Dm1 Myoblasts Transfected With P68-gfp Usinmentioning

confidence: 99%

“…CUG and CCUG repeats form double-stranded hairpin structures and sequester MBNL1 (9,11,12). Several other RNA-binding proteins, such as Staufen1 and two members of the DEAD-box RNA helicases family, DDX5/p68 and DDX6, are also involved in DM1 (13)(14)(15).…”

mentioning

confidence: 99%

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Reduction of toxic RNAs in myotonic dystrophies type 1 and type 2 by the RNA helicase p68/DDX5

Jones

Wei

Schöser

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Myotonic dystrophies type 1 (DM1) and type 2 (DM2) are neuromuscular diseases, caused by accumulation of CUG and CCUG RNAs in toxic aggregates. Here we report that the increased stability of the mutant RNAs in both types of DM is caused by deficiency of RNA helicase p68. We have identified p68 by studying CCUG-binding proteins associated with degradation of the mutant CCUG repeats. Protein levels of p68 are reduced in DM1 and DM2 biopsied skeletal muscle. Delivery of p68 in DM1/2 cells causes degradation of the mutant RNAs, whereas delivery of p68 in skeletal muscle of DM1 mouse model reduces skeletal muscle myopathy and atrophy. Our study shows that correction of p68 may reduce toxicity of the mutant RNAs in DM1 and in DM2.myotonic dystrophy | RNA foci | p68 RNA helicase | CUG repeats M yotonic dystrophy type 1 (DM1) is a neuromuscular disease characterized by myotonia, distal muscle weakness, heart conduction defects, and, in the congenital form, a delay in myogenesis and severe cognitive abnormalities (1). DM1 is caused by expanded CTG repeats within the 3′ untranslated region of the DMPK gene (2). Myotonic dystrophy type 2 (DM2) is a late-onset disease that is caused by expanded CCTG repeats in intron 1 of the ZNF9/CNBP gene (3). Development of therapeutic approaches for DM1 or DM2 is an urgent need. Numerous data suggest that DM1 and DM2 are caused by RNA gain-offunction mechanisms (4-6). Initial studies showed that mutant RNAs mainly affect two RNA-binding proteins, CUG-binding protein 1 (CUGBP1) and muscleblind-like protein 1 (MBNL1) (7-9). CUG repeats elevate protein levels of CUGBP1 by increasing its stability (5). In addition, CUG repeats change signal transduction pathways, such as the glycogen synthase kinase 3β (GSK3β)-cyclin D3 pathway, regulating CUGBP1 activity (5, 10). CUG and CCUG repeats form double-stranded hairpin structures and sequester MBNL1 (9,11,12). Several other RNA-binding proteins, such as Staufen1 and two members of the DEAD-box RNA helicases family, DDX5/p68 and DDX6, are also involved in DM1 (13-15).We showed that the mutant CUG and CCUG RNAs are very stable (16), suggesting that the activity of RNA-binding proteins regulating RNA decay is reduced in DM1 and in DM2. In this study, we tested this hypothesis by isolation and analysis of several CCUG-binding proteins. We found that the levels of one of these proteins, p68, are reduced in DM1 and DM2 biopsied muscle and that correction of p68 leads to degradation of the mutant CUG and CCUG RNAs, disintegration of RNA foci, and reduction of DM muscle pathology. Results and DiscussionIdentification of p68 Helicase as CUG/CCUG-Binding Protein, Which is Reduced During Degradation of CCUG Repeats. Given the critical role of RNA CUG and CCUG repeats in DM1/2, we performed a careful analysis of CCUG-binding proteins with altered activities upon accumulation and degradation of the mutant CCUG repeats in tetracycline (tet)-regulated CHO cell model of DM2. In this model, CCUG 100 repeats mainly increased activities of two RNA-binding proteins ...

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Overlapping mechanisms of lncRNA and expanded microsatellite RNA

Johnson

Cooper

2020

WIREs RNA

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RNA has major regulatory roles in a wide range of biological processes and a surge of RNA research has led to the classification of numerous functional RNA species. One example is long noncoding RNAs (lncRNAs) that are structurally complex transcripts >200 nucleotides (nt) in length and lacking a canonical open reading frame (ORF). Despite a general lack of sequence conservation and low expression levels, many lncRNAs have been shown to have functionality in diverse biological processes as well as in mechanisms of disease. In parallel with the growing understanding of lncRNA functions, there is a growing subset of microsatellite expansion disorders in which the primary mechanism of pathogenesis is an RNA gain of function arising from RNA transcripts from the mutant allele. Microsatellite expansion disorders are caused by an expansion of short (3-10 nt) repeats located within coding genes. Expanded repeat-containing RNA mediates toxicity through multiple mechanisms, the details of which remain only partially understood. The purpose of this review is to highlight the links between functional mechanisms of lncRNAs and the potential pathogenic mechanisms of expanded microsatellite RNA. These shared mechanisms include protein sequestration, peptide translation, micro-RNA (miRNA) processing, and miRNA sequestration. Recognizing the parallels between the normal functions of lncRNAs and the negative impact of expanded microsatellite RNA on biological processes can provide reciprocal understanding to the roles of both RNA species.

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

Cited by 67 publications

References 64 publications

Nuclear ARVCF Protein Binds Splicing Factors and Contributes to the Regulation of Alternative Splicing

Nuclear ARVCF Protein Binds Splicing Factors and Contributes to the Regulation of Alternative Splicing

Reduction of toxic RNAs in myotonic dystrophies type 1 and type 2 by the RNA helicase p68/DDX5

Overlapping mechanisms of lncRNA and expanded microsatellite RNA

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