DDX6 regulates sequestered nuclear CUG-expanded DMPK-mRNA in dystrophia myotonica type 1

Pettersson, Olof; Aagaard, Lars; Andrējeva, Diāna; Thomsen, Rie; Jensen, Thomas G.; Damgaard, Christian Kroun

doi:10.1093/nar/gku352

Cited by 44 publications

(49 citation statements)

References 54 publications

(62 reference statements)

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“…Nevertheless, the interaction of MBNL proteins with C(C)UG exp RNAs may be indirect and mediated by other factors in affected human tissues. Indeed, additional proteins bind to C(C)UG exp RNAs (Kim et al, 2005; Pettersson et al, 2014; Ravel-Chapuis et al, 2012) or co-localize with nuclear foci (Laurent et al, 2012). …”

Section: Introductionmentioning

confidence: 99%

MBNL Sequestration by Toxic RNAs and RNA Misprocessing in the Myotonic Dystrophy Brain

et al. 2015

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SUMMARY For some neurological disorders, disease is primarily RNA-mediated due to expression of non-coding microsatellite expansion RNAs (RNAexp). Toxicity is thought to result from enhanced binding of proteins to these expansions and depletion from their normal cellular targets. However, experimental evidence for this sequestration model is lacking. Here, we use HITS-CLIP and pre-mRNA processing analysis of human control versus myotonic dystrophy (DM) brains to provide compelling evidence for this RNA toxicity model. MBNL2 binds directly to DM repeat expansions in the brain resulting in depletion from its normal RNA targets with downstream effects on alternative splicing and polyadenylation. Similar RNA processing defects were detected in Mbnl compound knockout mice, highlighted by dysregulation of Mapt splicing and fetal tau isoform expression in adults. These results demonstrate that MBNL proteins are directly sequestered by RNAexp in the DM brain and introduce a powerful experimental tool to evaluate RNA-mediated toxicity in other expansion diseases.

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Section: Introductionmentioning

confidence: 99%

MBNL Sequestration by Toxic RNAs and RNA Misprocessing in the Myotonic Dystrophy Brain

et al. 2015

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“…3A and SI Appendix, Fig. S4A), whereas DDX6 disassembles CUG foci without degradation of the mutant DMPK mRNA (15). In addition, DDX6 does not reduce the stability of CCUG foci (15), whereas correction of p68 improves disintegration and degradation of both CUG and CCUG mutant RNAs (Figs.…”

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

confidence: 96%

“…It has been proposed that these RNA helicases have a different effect on the mutant CUG repeats. 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).…”

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

confidence: 98%

“…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).…”

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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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Myotonic Dystrophy and Developmental Regulation of RNA Processing

Thomas

Oliveira

Sznajder

et al. 2018

Comprehensive Physiology

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Myotonic dystrophy (DM) is a multisystemic disorder caused by microsatellite expansion mutations in two unrelated genes leading to similar, yet distinct, diseases. DM disease presentation is highly variable and distinguished by differences in age-of-onset and symptom severity. In the most severe form, DM presents with congenital onset and profound developmental defects. At the molecular level, DM pathogenesis is characterized by a toxic RNA gain-of-function mechanism that involves the transcription of noncoding microsatellite expansions. These mutant RNAs disrupt key cellular pathways, including RNA processing, localization, and translation. In DM, these toxic RNA effects are predominantly mediated through the modulation of the muscleblind-like and CUGBP and ETR-3-like factor families of RNA binding proteins (RBPs). Dysfunction of these RBPs results in widespread RNA processing defects culminating in the expression of developmentally inappropriate protein isoforms in adult tissues. The tissue that is the focus of this review, skeletal muscle, is particularly sensitive to mutant RNA-responsive perturbations, as patients display a variety of developmental, structural, and functional defects in muscle. Here, we provide a comprehensive overview of DM1 and DM2 clinical presentation and pathology as well as the underlying cellular and molecular defects associated with DM disease onset and progression. Additionally, fundamental aspects of skeletal muscle development altered in DM are highlighted together with ongoing and potential therapeutic avenues to treat this muscular dystrophy. © 2018 American Physiological Society. Compr Physiol 8:509-553, 2018.

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DDX6 regulates sequestered nuclear CUG-expanded DMPK-mRNA in dystrophia myotonica type 1

Cited by 44 publications

References 54 publications

MBNL Sequestration by Toxic RNAs and RNA Misprocessing in the Myotonic Dystrophy Brain

MBNL Sequestration by Toxic RNAs and RNA Misprocessing in the Myotonic Dystrophy Brain

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

Myotonic Dystrophy and Developmental Regulation of RNA Processing

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