Drug‐induced readthrough of premature stop codons leads to the stabilization of laminin α2 chain mRNA in CMD myotubes

Allamand, Valérie; Bidou, Laure; Arakawa, Masayuki; Floquet, Célia; Shiozuka, Masataka; Paturneau-Jouas, Marion; Gartioux, C.; Butler-Browne, Gillian; Mouly, Vincent; Rousset, Jean Pierre; Matsuda, Ryoichi; Ikeda, Daishiro; Guicheney, Pascale

doi:10.1002/jgm.1140

Cited by 65 publications

(47 citation statements)

References 45 publications

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“…Further, the mechanism of inhibitor-based reporter stabilization is consistent with the production of FLuc from synthetic FLuc mRNA containing different premature termination codons when incubated with HeLa cell-free extracts, as well as the negative data presented in the original study, where it was demonstrated that PTC124 does not produce readthrough of normal or contiguous stop codons or affect mRNA levels (9). Currently, it has been speculated that PTC124 interacts with the ribosome that, through a currently unknown mechanism (31,32), facilitates readthrough specifically of premature stop codons. However, the simplest explanation for PTC124 activity and the congener structure-activity relationship in the cell-based nonsense codon suppression assay is posttranslational stabilization of the luciferase reporter enzyme.…”

Section: Ptc124 and Analogs Show A Strong Correlation Between Fluc Insupporting

confidence: 63%

Mechanism of PTC124 activity in cell-based luciferase assays of nonsense codon suppression

Auld

Thorne

Maguire

et al. 2009

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

188

205

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High-throughput screening (HTS) assays used in drug discovery frequently use reporter enzymes such as firefly luciferase (FLuc) as indicators of target activity. An important caveat to consider, however, is that compounds can directly affect the reporter, leading to nonspecific but highly reproducible assay signal modulation. In rare cases, this activity appears counterintuitive; for example, some reporter gene assays ͉ high-throughput screening ͉ Ataluren

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Section: Ptc124 and Analogs Show A Strong Correlation Between Fluc Insupporting

confidence: 63%

Mechanism of PTC124 activity in cell-based luciferase assays of nonsense codon suppression

Auld

Thorne

Maguire

et al. 2009

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

188

205

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“…However, since stop codon readthrough is known to stabilize the mRNA in several instances-URA3 (Losson and Lacroute 1979), lacZ (Keeling et al 2004), p53 (Floquet et al 2011), laminin a2 (Allamand et al 2008)-in Model 3, the NMD component of the destabilization was dynamically modulated according to the level of readthrough in any system according to Equation 4:…”

Section: Mathematical Model Developmentmentioning

confidence: 99%

Regulation of release factor expression using a translational negative feedback loop: A systems analysis

Betney

Silva

Mertens

et al. 2012

RNA

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The essential eukaryote release factor eRF1, encoded by the yeast SUP45 gene, recognizes stop codons during ribosomal translation. SUP45 nonsense alleles are, however, viable due to the establishment of feedback-regulated readthrough of the premature termination codon; reductions in full-length eRF1 promote tRNA-mediated stop codon readthrough, which, in turn, drives partial production of full-length eRF1. A deterministic mathematical model of this eRF1 feedback loop was developed using a staged increase in model complexity. Model predictions matched the experimental observation that strains carrying the mutant SUQ5 tRNA (a weak UAA suppressor) in combination with any of the tested sup45 UAA nonsense alleles exhibit threefold more stop codon readthrough than that of an SUQ5 yeast strain. The model also successfully predicted that eRF1 feedback control in an SUQ5 sup45 UAA mutant would resist, but not completely prevent, imposed changes in eRF1 expression. In these experiments, the introduction of a plasmid-borne SUQ5 copy into a sup45 UAA SUQ5 mutant directed additional readthrough and full-length eRF1 expression, despite feedback. Secondly, induction of additional sup45 UAA mRNA expression in a sup45 UAA SUQ5 strain also directed increased full-length eRF1 expression. The autogenous sup45 control mechanism therefore acts not to precisely control eRF1 expression, but rather as a damping mechanism that only partially resists changes in release factor expression level. The validated model predicts that the degree of feedback damping (i.e., control precision) is proportional to eRF1 affinity for the premature stop codon. The validated model represents an important tool to analyze this and other translational negative feedback loops.

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“…From 1994, knock-out mouse or spontaneous mutant mouse strains have been identified as animal models for MDC1A with total and partial deficiency [99][100][101][102][103][104][105] , and experimental therapeutic strategies have been attempted 102,103,[106][107][108][109][110][111][112][113][114][115][116] . In mice, Kuang et al 102,103 were successful in obtaining the expression of a human laminin alpha 2 chain transgene under the regulation of a muscle-specific creatine kinase promoter.…”

Section: Therapeutic Perspectivesmentioning

confidence: 99%

“…They demonstrated that the number of C90+cells increases during muscle regeneration process in vivo and as those cells can be transplanted to the animal model of MDC 1A, perhaps they represent a new source of cellular theraphy. Allamand et al 116 using drugs that force reading through premature termination codons (PTCs) demonstrated that the mutant mrNAs were strongly stabilized in myotubes derived from MDC1 A after administration of negamycin but were not able to allow re-expression of laminin alpha-2, perhaps consequently to translational or post-translational troubles. They concluded that this novel form of therapy requires more studies to define the nucleotide context of PTCs, the mechanism of mrNA stability and its translation into a functional protein.…”

Section: Therapeutic Perspectivesmentioning

confidence: 99%

Congenital muscular dystrophy. Part II: a review of pathogenesis and therapeutic perspectives

Reed

2009

Arq. Neuro-Psiquiatr.

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-The congenital muscular dystrophies (CMDs) are a group of genetically and clinically heterogeneous hereditary myopathies with preferentially autosomal recessive inheritance, that are characterized by congenital hypotonia, delayed motor development and early onset of progressive muscle weakness associated with dystrophic pattern on muscle biopsy. The clinical course is broadly variable and can comprise the involvement of the brain and eyes. From 1994, a great development in the knowledge of the molecular basis has occurred and the classification of CMDs has to be continuously up dated. In the last number of this journal, we presented the main clinical and diagnostic data concerning the different subtypes of CMD. In this second part of the review, we analyse the main reports from the literature concerning the pathogenesis and the therapeutic perspectives of the most common subtypes of CMD: MDC1A with merosin deficiency, collagen VI related CMDs (Ullrich and Bethlem), CMDs with abnormal glycosylation of alpha-dystroglycan (Fukuyama CMD, Muscleeye-brain disease, Walker Warburg syndrome, MDC1C, MDC1D), and rigid spine syndrome, another much rare subtype of CMDs not related with the dystrophin/glycoproteins/extracellular matrix complex.Key WorDs: congenital muscular dystrophy, MDC1A, collagen VI related disorders, glycosylation of alphadystroglycan, Fukuyama DMC, muscle-eye-brain (MeB) disease, Walker-Warburg syndrome, rigid spine syndrome. distrofia muscular congênita. parte ii: revisão da patogênese e perspectivas terapêuticas resumo -As distrofias musculares congênitas (DMCs) são miopatias hereditárias geralmente, porém não exclusivamente, de herança autossômica recessiva, que apresentam grande heterogeneidade genética e clínica. são caracterizadas por hipotonia muscular congênita, atraso do desenvolvimento motor e fraqueza muscular de início precoce associada a padrão distrófico na biópsia muscular. o quadro clínico, de gravidade variável, pode também incluir anormalidades oculares e do sistema nervoso central. A partir de 1994, os conhecimentos sobre genética e biologia molecular das DMCs progrediram rapidamente, sendo a classificação continuamente atualizada. os aspectos clínicos e diagnósticos dos principais subtipos de DMC foram apresentados no número anterior deste periódico, como primeira parte desta revisão. Nesta segunda parte apresentaremos os principais mecanismos patogênicos e as perspectivas terapêuticas dos subtipos mais comuns de DMC: DMC tipo 1A com deficiência de merosina, DMCs relacionadas com alterações do colágeno VI (Ullrich e Bethlem), e DMCs com anormalidades de glicosilação da alfa-distroglicana (DMC Fukuyama, DMC "Muscle-eye-brain" ou MeB, síndrome de Walker Warburg, DMC tipo 1C, DMC tipo 1D). A DMC com espinha rígida, mais rara e não relacionada com alterações do complexo distrofina-glicoproteínas associadas-matriz extracelular também será abordada quanto aos mesmos aspectos patogênicos e terapêuticos.PAlAVrAs-ChAVes: distrofia muscular congênita, merosina, colágeno VI, glicosila...

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Drug‐induced readthrough of premature stop codons leads to the stabilization of laminin α2 chain mRNA in CMD myotubes

Cited by 65 publications

References 45 publications

Mechanism of PTC124 activity in cell-based luciferase assays of nonsense codon suppression

Mechanism of PTC124 activity in cell-based luciferase assays of nonsense codon suppression

Regulation of release factor expression using a translational negative feedback loop: A systems analysis

Congenital muscular dystrophy. Part II: a review of pathogenesis and therapeutic perspectives

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