(CCUG)n RNA toxicity in a <i>Drosophila</i> model for myotonic dystrophy type 2 (DM2) activates apoptosis

Yenigün, Vildan Betül; Sirito, Mario; Amcheslavky, Alla; Czernuszewicz, T.; Colonques-Bellmunt, Jordi; Garcia-Alcover, Irma; Wojciechowska, Marzena; Bolduc, Clare; Chen, Zhihong; Castel, Arturo López; Krahe, Ralf; Bergmann, Andreas

doi:10.1242/dmm.026179

Cited by 10 publications

(6 citation statements)

References 75 publications

(131 reference statements)

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“…Moreover, one mechanism of toxicity of repeat-expansion RNAs appears to be the formation of RNA aggregates through RNA-RNA interactions [25], which can sequester RBPs, thereby altering RNA processing in pathogenic manners [129][130][131][132]. Notably, expression of repeat-expansion RNAs, or promoting RNP granule formation by knockdown of DHX36, can activate the dsRNA-sensing eIF2α kinase PKR and the integrated stress response [133][134][135][136]. This raises the possibility that aberrant RNA condensation triggers a cellular response, which in some cases may lead to toxic effects.…”

Section: Dysregulation Of Rna Condensation and Diseasementioning

confidence: 99%

Mechanisms and Regulation of RNA Condensation in RNP Granule Formation

Tauber

Parker

2020

Trends in Biochemical Sciences

152

132

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Ribonucleoprotein (RNP) granules are RNA-protein assemblies that are involved in multiple aspects of RNA metabolism and are linked to memory, development, and disease. Some RNP granules form, in part, through the formation of intermolecular RNA-RNA interactions. In vitro, such trans RNA condensation occurs readily, suggesting that cells require mechanisms to modulate RNA-based condensation. We assess the mechanisms of RNA condensation and how cells modulate this phenomenon. We propose that cells control RNA condensation through ATP-dependent processes, static RNA buffering, and dynamic post-translational mechanisms. Moreover, perturbations in these mechanisms can be involved in disease. This reveals multiple cellular mechanisms of kinetic and thermodynamic control that maintain the proper distribution of RNA molecules between dispersed and condensed forms. Ribonucleoprotein Granules Are Built via a Summation of Multivalent InteractionsEukaryotic cells contain a variety of ribonucleoprotein (RNP) granules (see Glossary). RNP granules are large non-membrane-bound assemblies of RNA and protein and are present in the nucleus and the cytosol. Examples of RNP granules include the nucleolus (the site of rRNA biogenesis), stress granules (SGs; which form from untranslating RNAs [1]), and neuronal granules (that are important for the transport and translation of synaptic mRNAs and synaptic plasticity [2]).RNP granules are members of a growing class of biological assemblies referred to as biomolecular condensates (reviewed in [3]). Biomolecular condensates are non-membranous assemblies that form through multivalent interactions between their components. Condensates differ from traditional assemblies in that the diverse and multivalent nature of the interactions allows condensates to be variable in their assembly and size and lack any unique stoichiometry or stereospecificity.RNP granules generally require a specific population of RNA for their formation and can be enriched for many RNAs. As examples, SGs and P-bodies (PBs) require a cytoplasmic population of untranslating RNAs, the nucleolus requires rRNA transcripts to maintain its organization [4], and nuclear paraspeckles require the NEAT1 long noncoding (lnc)RNA [5]. RNP granules also compartmentalize specific RNA-binding proteins (RBPs). For instance, distinct RBPs accumulate in SGs and PBs, although they can also share some components [6][7][8][9][10].RNP granules form from a summation of both protein-protein and RNA-RNA interactions between RNPs (Figure 1). Protein-protein interactions that promote RNP granule formation occur between RBPs bound to the RNA and can involve well-folded domains of RBPs [11]. For example, the G3BP1 protein can bind to mRNAs, and then through dimerization can increase the formation of SGs [12]. Many RNP granule proteins also contain intrinsically disordered Highlights Intermolecular RNA-RNA interactions contribute to the formation, content, and biophysical properties of many RNP granules. Cells utilize both genetically programmed and prom...

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Section: Dysregulation Of Rna Condensation and Diseasementioning

confidence: 99%

Mechanisms and Regulation of RNA Condensation in RNP Granule Formation

Tauber

Parker

2020

Trends in Biochemical Sciences

152

132

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“…A likely contribution to this difference of toxicity is their genomic localization as CCUG repeats are embedded in the first intron of the CNBP pre-mRNA, which is presumably less stable compared to the 3′UTR of the DMPK mRNA that hosts the CUG repeats. In favor of this hypothesis, transgenic Drosophila expressing either expanded CUG or CCUG repeats, embedded in a comparable genomic context deprived of any DMPK or CNBP sequences, show similar DM-like phenotypes 37 , 38 . Nonetheless, it is not excluded that other mechanisms may further contribute to the lesser toxicity of expanded CCUG repeats in DM2.…”

Section: Introductionmentioning

confidence: 99%

rbFOX1/MBNL1 competition for CCUG RNA repeats binding contributes to myotonic dystrophy type 1/type 2 differences

et al. 2018

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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.

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“…Using gene sets generated from the combined study of developmental axes and DET, it was possible to identify candidate genes that may be responsible for the differences in muscle mass between the two chicken breeds. Putative PPI analysis revealed several upregulated genes in AA broiler, that play pivotal roles in regulating muscle growth and hypertrophy as strong stimulators of myoblast and satellite cell proliferation and differentiation, such as TNNT3 [ 49 ], MUSTN1 [ 50 ], HOXP [ 51 ], ANXA2 [ 52 ], and AK1 [ 53 ]. In addition, the EEF1A2 gene, which encodes a protein involved in the elongation step of protein synthesis [ 54 ], as well as the RPS14 and RPS29 genes, which encode ribosomal proteins [ 55 ], can respond to the mTOR signaling pathway and subsequently regulate the accumulation of proteins in skeletal muscle, thereby leading to myofiber hypertrophy [ 56 , 57 ].…”

Section: Discussionmentioning

confidence: 99%

Comparative analyses of dynamic transcriptome profiles highlight key response genes and dominant isoforms for muscle development and growth in chicken

Wang,

Tian,

Wang

et al. 2023

Genet Sel Evol

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Background Modern breeding strategies have resulted in significant differences in muscle mass between indigenous chicken and specialized broiler. However, the molecular regulatory mechanisms that underlie these differences remain elusive. The aim of this study was to identify key genes and regulatory mechanisms underlying differences in breast muscle development between indigenous chicken and specialized broiler. Results Two time-series RNA-sequencing profiles of breast muscles were generated from commercial Arbor Acres (AA) broiler (fast-growing) and Chinese indigenous Lushi blue-shelled-egg (LS) chicken (slow-growing) at embryonic days 10, 14, and 18, and post-hatching day 1 and weeks 1, 3, and 5. Principal component analysis of the transcriptome profiles showed that the top four principal components accounted for more than 80% of the total variance in each breed. The developmental axes between the AA and LS chicken overlapped at the embryonic stages but gradually separated at the adult stages. Integrative investigation of differentially-expressed transcripts contained in the top four principal components identified 44 genes that formed a molecular network associated with differences in breast muscle mass between the two breeds. In addition, alternative splicing analysis revealed that genes with multiple isoforms always had one dominant transcript that exhibited a significantly higher expression level than the others. Among the 44 genes, the TNFRSF6B gene, a mediator of signal transduction pathways and cell proliferation, harbored two alternative splicing isoforms, TNFRSF6B-X1 and TNFRSF6B-X2. TNFRSF6B-X1 was the dominant isoform in both breeds before the age of one week. A switching event of the dominant isoform occurred at one week of age, resulting in TNFRSF6B-X2 being the dominant isoform in AA broiler, whereas TNFRSF6B-X1 remained the dominant isoform in LS chicken. Gain-of-function assays demonstrated that both isoforms promoted the proliferation of chicken primary myoblasts, but only TNFRSF6B-X2 augmented the differentiation and intracellular protein content of chicken primary myoblasts. Conclusions For the first time, we identified several key genes and dominant isoforms that may be responsible for differences in muscle mass between slow-growing indigenous chicken and fast-growing commercial broiler. These findings provide new insights into the regulatory mechanisms underlying breast muscle development in chicken.

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(CCUG)n RNA toxicity in a Drosophila model for myotonic dystrophy type 2 (DM2) activates apoptosis

Cited by 10 publications

References 75 publications

Mechanisms and Regulation of RNA Condensation in RNP Granule Formation

Mechanisms and Regulation of RNA Condensation in RNP Granule Formation

rbFOX1/MBNL1 competition for CCUG RNA repeats binding contributes to myotonic dystrophy type 1/type 2 differences

Comparative analyses of dynamic transcriptome profiles highlight key response genes and dominant isoforms for muscle development and growth in chicken

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