DHX36 prevents the accumulation of translationally inactive mRNAs with G4-structures in untranslated regions

Sauer, Markus; Juranek, Stefan; Marks, James; Magis, Alessio De; Kazemier, Hinke G.; Hilbig, Daniel; Benhalevy, Daniel; Wang, Xiantao; Hafner, Markus; Paeschke, Katrin

doi:10.1038/s41467-019-10432-5

Cited by 119 publications

(125 citation statements)

References 67 publications

(114 reference statements)

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“…Although the RNA G‐quadruplex topologies are limited in terms of strand orientation by the strong preference of RNA to form all‐anti all‐parallel G‐quadruplexes, dimerization or multimerization can lead to a number of different general topologies that can alter biological function immensely (Scheme ). While focusing primarily on the biological context and putting great emphasis on the role of G‐quadruplexes in regulatory systems, we wish to remark here that many cell biology studies do not involve any (or involve only sparse) biophysical characterization of G‐quadruplex structures …”

Section: Introductionmentioning

confidence: 99%

Structure Validation of G‐Rich RNAs in Noncoding Regions of the Human Genome

2020

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We present the rapid biophysical characterization of six previously reported putative G‐quadruplex‐forming RNAs from the 5′‐untranslated region (5′‐UTR) of silvestrol‐sensitive transcripts for investigation of their secondary structures. By NMR and CD spectroscopic analysis, we found that only a single sequence—[AGG]2[CGG]2C—folds into a single well‐defined G‐quadruplex structure. Sequences with longer poly‐G strands form unspecific aggregates, whereas CGG‐repeat‐containing sequences exhibit a temperature‐dependent equilibrium between a hairpin and a G‐quadruplex structure. The applied experimental strategy is fast and provides robust readout for G‐quadruplex‐forming capacities of RNA oligomers.

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Section: Introductionmentioning

confidence: 99%

Structure Validation of G‐Rich RNAs in Noncoding Regions of the Human Genome

2020

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“…Consistent with other helicases limiting SG formation, we demonstrate over-expression of DDX19A, which is closely related to eIF4A, can limit SG formation without restoring translation (Figure 4). Interestingly, knockout of the DHX36 helicase has been shown to lead to increased SG formation (Sauer et al, 2019), but this appears to be due to constitutive activation of PKR and increased translation repression. An important area of future work will be identifying additional helicases that limit RNA condensation and determining if they act in RNA specific manners.…”

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confidence: 99%

Modulation of RNA condensation by the DEAD-box protein eIF4A

Tauber

Khong

et al. 2019

Preprint

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eTOC Blurb: The RNA helicase eIF4A limits stress granule formation by reducing RNA condensation. Highlights:•! RNA condensates promote intermolecular RNA-RNA interactions at their surfaces! •! eIF4A helicase activity limits the recruitment of RNAs to stress granules in cells! •! eIF4A helicase activity reduces the nucleation of stress granules in cells! •! Recombinant eIF4A1 inhibits the condensation of RNA in vitro in an ATP-dependent manner! Keywords: DEAD-box protein, RNA-RNA interactions, stress granule, ribonucleoprotein ! 2 SUMMARY:Stress granules are condensates of non-translating mRNAs and proteins involved in the stress response and neurodegenerative diseases. Stress granules are proposed to form in part through intermolecular RNA-RNA interactions, although the process of RNA condensation is not well understood. In vitro, we demonstrate that the minimization of surface free energy promotes the recruitment and interaction of RNAs on RNA or RNP condensate surfaces. We demonstrate that the ATPase activity of the DEAD-box RNA helicase eIF4A reduces RNA recruitment to RNA condensates in vitro and in cells, as well as limiting stress granule formation. This defines a new function for eIF4A, and potentially other RNA helicases, to limit thermodynamically favored intermolecular RNA-RNA interactions in cells, thereby allowing for proper RNP function.

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“…DHX36 (also known as RHAU and G4R1) is a G4-specific helicase and has been shown to bind preferentially to G4 and G-rich sequences on over 4500 mRNA transcripts, preventing accumulation of translationally repressed mRNAs (53). Chen et al recently co-crystallised DHX36 bound to the c-Myc G4, providing valuable insight into the mechanisms underpinning helicase mediated G4 unwinding (75).…”

Section: Discussionmentioning

confidence: 99%

“…The DEAH-box helicase 36 (DHX36) is a G4 resolving helicase (52). Binding to G4s increases translation, prevents the accumulation of translationally repressed mRNAs (53) and has also been shown to be important in the neurite localisation of certain RNA species (54). We therefore next investigated whether overexpression of DHX36 in HEK293 cells could relieve the G4 mediated translation repression observed for Task3 M1 mRNA.…”

Section: Overexpression Of the G-quadruplex Helicase Dhx36 Partially mentioning

confidence: 99%

A 5’ UTR G-quadruplex controls localisation and translation of a potassium leak channel mRNA

Maltby

Schofield

Houghton

et al. 2019

Preprint

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RNA G-quadruplexes (G4s) are non-canonical secondary structures that have been proposed to function as regulators of post-transcriptional mRNA localisation and translation. G4s within 3' UTRs of some neuronal mRNAs are known to control their distal localisation and local translation, contributing to the 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 KCNK9 mRNA, encoding the potassium 2-pore domain leak channel Task3. Using circular dichroism, we show that this (GGN)13 repeat forms a parallel G4 that exhibits the stereotypical potassium specificity of a G4, remaining thermostable under physiological ionic conditions. The G4 is inhibitory to translation of Task3, which can be overcome through the activity of the G4-specific helicase DHX36, consequently increasing K + leak currents and decreasing resting membrane potentials in HEK293 cells. Additionally, we observe that this G4 is fundamental to ensuring the delivery of Task3 mRNA to distal primary cortical neurites. It has previously been shown that abnormal Task3 expression correlates with neuronal dysfunction, we therefore posit that this G4 is required for regulated local expression of Task3 leak channels that maintain K + leak currents within neurons.

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DHX36 prevents the accumulation of translationally inactive mRNAs with G4-structures in untranslated regions

Cited by 119 publications

References 67 publications

Structure Validation of G‐Rich RNAs in Noncoding Regions of the Human Genome

Structure Validation of G‐Rich RNAs in Noncoding Regions of the Human Genome

Modulation of RNA condensation by the DEAD-box protein eIF4A

A 5’ UTR G-quadruplex controls localisation and translation of a potassium leak channel mRNA

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