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SMaRT lncRNA controls translation of a G-quadruplex containing mRNA antagonizing the DHX36 helicase

ABSTRACT: Guanine-quadruplexes (G4) included in RNA molecules exert several functions in controlling gene expression at post-transcriptional level; however, the molecular mechanisms of G4-mediated regulation are still poorly understood. Here we describe a regulatory circuitry operating in the early phases of murine muscle differentiation in which a long non coding RNA (SMaRT) base pairs with a G4-containing mRNA (Mlx-gamma) and represses its translation by counteracting the activity of the DHX36 RNA helicase. The time-restricted, specific effect of lnc-SMaRT on the translation of Mlx-gamma isoform modulates the general subcellular localization of total MLX proteins, impacting on their transcriptional output and promoting proper myogenesis and mature myotube formation. Therefore, the circuitry made of lnc-SMaRT, Mlx-gamma and DHX36 not only plays an important role in the control of myogenesis but also unravels a molecular mechanism where G4 structures and G4 unwinding activities are regulated in living cells.

SUBMITTER: Prof. Irene Bozzoni

PROVIDER: S-SCDT-EMBOR-2019-49942V1 | biostudies-other |

REPOSITORIES: biostudies-other

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SMaRT lncRNA controls translation of a G-quadruplex-containing mRNA antagonizing the DHX36 helicase.

Project description:Guanine-quadruplexes (G4) included in RNA molecules exert several functions in controlling gene expression at post-transcriptional level; however, the molecular mechanisms of G4-mediated regulation are still poorly understood. Here, we describe a regulatory circuitry operating in the early phases of murine muscle differentiation in which a long non-coding RNA (SMaRT) base pairs with a G4-containing mRNA (Mlx-γ) and represses its translation by counteracting the activity of the DHX36 RNA helicase. The time-restricted, specific effect of lnc-SMaRT on the translation of Mlx-γ isoform modulates the general subcellular localization of total MLX proteins, impacting on their transcriptional output and promoting proper myogenesis and mature myotube formation. Therefore, the circuitry made of lnc-SMaRT, Mlx-γ, and DHX36 not only plays an important role in the control of myogenesis but also unravels a molecular mechanism where G4 structures and G4 unwinding activities are regulated in living cells.

| S-EPMC7271651 | biostudies-literature

SMaRT lncRNA controls translation of a G-quadruplex containing mRNA antagonizing the DHX36 helicase

Project description:Guanine-quadruplexes (G4) present in RNA and DNA exert a number of different functions in the nucleus and in the cytoplasm. However, the molecular mechanisms of G4-mediated regulation are still poorly understood. We describe a regulatory circuitry operating in the early phases of muscle differentiation in which a long non coding RNA (SMaRT) base pairs with a G4-containing mRNA (Mlx-g) and represses its translation in an antagonistic way with the RNA helicase DHX36. MLX-g is required to allow the nuclear translocation of the MLX-a and b dimerization partners and to control proper myogenesis. We show that by controlling MLX-g, lnc-SMaRT is able to regulate the overall quantity of nuclear MLX proteins and their transcriptional output. Therefore, the circuitry composed by lnc-SMaRT, Mlx-g and Dhx36 not only plays an important role in the control of myogenesis but unravels a molecular mechanism where G4 structures and G4 unwinding activities are controlled in vivo.

2020-03-18 | GSE128486 | GEO

SMaRT lncRNA controls translation of a G-quadruplex containing mRNA antagonizing the DHX36 helicase

Project description:SMaRT lncRNA controls translation of a G-quadruplex containing mRNA antagonizing the DHX36 helicase

| PRJNA527830 | ENA

m<sup>6</sup>A in mRNA coding regions promotes translation via the RNA helicase-containing YTHDC2.

Project description:Dynamic mRNA modification in the form of N6-methyladenosine (m6A) adds considerable richness and sophistication to gene regulation. The m6A mark is asymmetrically distributed along mature mRNAs, with approximately 35% of m6A residues located within the coding region (CDS). It has been suggested that methylation in CDS slows down translation elongation. However, neither the decoding feature of endogenous mRNAs nor the physiological significance of CDS m6A has been clearly defined. Here, we found that CDS m6A leads to ribosome pausing in a codon-specific manner. Unexpectedly, removing CDS m6A from these transcripts results in a further decrease of translation. A systemic analysis of RNA structural datasets revealed that CDS m6A positively regulates translation by resolving mRNA secondary structures. We further demonstrate that the elongation-promoting effect of CDS methylation requires the RNA helicase-containing m6A reader YTHDC2. Our findings established the physiological significance of CDS methylation and uncovered non-overlapping function of m6A reader proteins.

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G-Quadruplex Regulation of VEGFA mRNA Translation by RBM4.

Project description:In eukaryotes, mRNAs translation is mainly mediated in a cap-dependent or cap-independent manner. The latter is primarily initiated at the internal ribosome entry site (IRES) in the 5'-UTR of mRNAs. It has been reported that the G-quadruplex structure (G4) in the IRES elements could regulate the IRES activity. We previously confirmed RBM4 (also known as LARK) as a G4-binding protein in human. In this study, to investigate whether RBM4 is involved in the regulation of the IRES activity by binding with the G4 structure within the IRES element, the IRES-A element in the 5'-UTR of vascular endothelial growth factor A (VEGFA) was constructed into a dicistronic reporter vector, psiCHECK2, and the effect of RBM4 on the IRES activity was tested in 293T cells. The results showed that the IRES insertion significantly increased the FLuc expression activity, indicating that this G4-containing IRES was active in 293T cells. When the G4 structure in the IRES was disrupted by base mutation, the IRES activity was significantly decreased. The IRES activity was notably increased when the cells were treated with G4 stabilizer PDS. EMSA results showed that RBM4 specifically bound the G4 structure in the IRES element. The knockdown of RBM4 substantially reduced the IRES activity, whereas over-expressing RBM4 increased the IRES activity. Taking all results together, we demonstrated that RBM4 promoted the mRNA translation of VEGFA gene by binding to the G4 structure in the IRES.

| S-EPMC8776124 | biostudies-literature

A 5' UTR GGN repeat controls localisation and translation of a potassium leak channel mRNA through G-quadruplex formation.

Project description:RNA G-quadruplexes (G4s) are secondary structures proposed to function as regulators of post-transcriptional mRNA localisation and translation. G4s within some neuronal mRNAs are known to control distal localisation and local translation, contributing to distinct local proteomes that facilitate the synaptic remodelling attributed to normal cellular function. In this study, we characterise the G4 formation of a (GGN)13 repeat found within the 5' UTR of the potassium 2-pore domain leak channel Task3 mRNA. Biophysical analyses show that this (GGN)13 repeat forms a parallel G4 in vitro exhibiting the stereotypical potassium specificity of G4s, remaining thermostable under physiological ionic conditions. Through mouse brain tissue G4-RNA immunoprecipitation, we further confirm that Task3 mRNA forms a G4 structure in vivo. The G4 is inhibitory to translation of Task3 in vitro and is overcome through activity of a G4-specific helicase DHX36, increasing K+ leak currents and membrane hyperpolarisation in HEK293 cells. Further, we observe that this G4 is fundamental to ensuring delivery of Task3 mRNA to distal primary cortical neurites. It has been shown that aberrant Task3 expression correlates with neuronal dysfunction, we therefore posit that this G4 is important in regulated local expression of Task3 leak channels that maintain K+ leak within neurons.

| S-EPMC7515701 | biostudies-literature

m6A in mRNA coding regions promotes translation via the RNA helicase-containing YTHDC2

Project description:Dynamic mRNA modification in the form of N6-methyladenosine (m6A) adds considerable richness and sophistication to gene regulation. The m6A mark is asymmetrically distributed along mature mRNAs, with a strong preference around the stop codon and 3’UTR. Nevertheless, approximately 35% of m6A residues are located within the coding region (CDS). It has been suggested that methylation in CDS slows down translation elongation by interfering the decoding process. However, neither the decoding feature of endogenous mRNAs nor the physiological significance of CDS m6A has been clearly defined. By integrating Ribo-seq and m6A-seq data sets, we found that CDS m6A methylation leads to ribosome pausing in a codon-specific manner. Unexpectedly, removing CDS m6A modification from these transcripts results in a further decrease of translation. A systemic analysis of RNA structural datasets revealed that CDS m6A methylation positively regulates translation by resolving mRNA secondary structures. We further demonstrate that the elongation-promoting effect of CDS methylation requires the RNA helicase-containing m6A reader YTHDC2. Our findings established the physiological significance of CDS methylation and uncovered non-overlapping function of m6A reader proteins.

2019-07-01 | GSE129194 | GEO

Codon optimality controls differential mRNA translation during amino acid starvation.

Project description:It is common wisdom that codon usage bias has evolved in the selection for efficient translation, in which highly expressed genes are encoded predominantly by optimal codons. However, a growing body of evidence suggests regulatory roles for non-optimal codons in translation dynamics. Here we report that in mammalian cells, non-optimal codons play a critical role in promoting selective mRNA translation during amino acid starvation. During starvation, in contrast to genes encoding ribosomal proteins whose translation is highly sensitive to amino acid deprivation, translation of genes involved in the cellular protein degradation pathways remains unaffected. We found that these two gene groups bear different codon composition, with non-optimal codons being highly enriched in genes encoding the ubiquitin-proteasome system. Supporting the selective tRNA charging model originally proposed in Escherichia coli, we demonstrated that tRNA isoacceptors decoding rare codons are maintained in translating ribosomes under amino acid starvation. Finally, using luciferase reporters fused with endogenous gene-derived sequences, we show that codon optimality contributes to differential mRNA translation in response to amino acid starvation. These results highlight the physiological significance of codon usage bias in cellular adaptation to stress.

| S-EPMC5066624 | biostudies-literature

FMRP - G-quadruplex mRNA - miR-125a interactions: Implications for miR-125a mediated translation regulation of PSD-95 mRNA.

Project description:Fragile X syndrome, the most common inherited form of intellectual disability, is caused by the CGG trinucleotide expansion in the 5'-untranslated region of the Fmr1 gene on the X chromosome, which silences the expression of the fragile X mental retardation protein (FMRP). FMRP has been shown to bind to a G-rich region within the PSD-95 mRNA, which encodes for the postsynaptic density protein 95, and together with microRNA-125a to mediate the reversible inhibition of the PSD-95 mRNA translation in neurons. The miR-125a binding site within the PSD-95 mRNA 3'-untranslated region (UTR) is embedded in a G-rich region bound by FMRP, which we have previously demonstrated folds into two parallel G-quadruplex structures. The FMRP regulation of PSD-95 mRNA translation is complex, being mediated by its phosphorylation. While the requirement for FMRP in the regulation of PSD-95 mRNA translation is clearly established, the exact mechanism by which this is achieved is not known. In this study, we have shown that both unphosphorylated FMRP and its phosphomimic FMRP S500D bind to the PSD-95 mRNA G-quadruplexes with high affinity, whereas only FMRP S500D binds to miR-125a. These results point towards a mechanism by which, depending on its phosphorylation status, FMRP acts as a switch that potentially controls the stability of the complex formed by the miR-125a-guided RNA induced silencing complex (RISC) and PSD-95 mRNA.

| S-EPMC6529005 | biostudies-literature

Triazole-containing monophosphate mRNA cap analogs as effective translation inhibitors.

Project description:Synthetic analogs of the 5' end of mRNA (cap structure) are widely used in molecular studies on mechanisms of cellular processes such as translation, intracellular transport, splicing, and turnover. The best-characterized cap binding protein is translation initiation factor 4E (eIF4E). Recognition of the mRNA cap by eIF4E is a critical, rate-limiting step for efficient translation initiation and is considered a major target for anticancer therapy. Here, we report a facile methodology for the preparation of N2-triazole-containing monophosphate cap analogs and present their biological evaluation as inhibitors of protein synthesis. Five analogs possessing this unique hetero-cyclic ring spaced from the m7-guanine of the cap structure at a distance of one or three carbon atoms and/or additionally substituted by various groups containing the benzene ring were synthesized. All obtained compounds turned out to be effective translation inhibitors with IC50 similar to dinucleotide triphosphate m(7)GpppG. As these compounds possess a reduced number of phosphate groups and, thereby, a negative charge, which may support their cell penetration, this type of cap analog might be promising in terms of designing new potential therapeutic molecules. In addition, an exemplary dinucleotide from a corresponding mononucleotide containing benzyl substituted 1,2,3-triazole was prepared and examined. The superior inhibitory properties of this analog (10-fold vs. m(7)GpppG) suggest the usefulness of such compounds for the preparation of mRNA transcripts with high translational activity.

| S-EPMC4174436 | biostudies-literature

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