Translational Repression and eIF4A2 Activity Are Critical for MicroRNA-Mediated Gene Regulation

Meijer, Hedda A.; Kong, Yi Wen; Lu, Wei-Ting; Wilczynska, Ania; Spriggs, Ruth V.; Robinson, Susan W.; Godfrey, Jack D.; Willis, Anne E.; Bushell, Martin

doi:10.1126/science.1231197

Cited by 292 publications

(350 citation statements)

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“…Several studies reported that miRNAs silence gene expression by targeting eIF4A and interfering with ribosome scanning (Meijer et al , 2013; Ricci et al , 2013; Fukao et al , 2014; Fukaya et al , 2014). However, there were considerable disagreements between these studies.…”

Section: Resultsmentioning

confidence: 99%

“…In particular, we generated a reporter containing a 5′‐UTR consisting of 18 CAA repeats, which is unlikely to adopt secondary structures, and its translation is thought to be independent of eIF4A (Meijer et al , 2013). This 5′‐UTR was also shown to confer resistance to silencing (Meijer et al , 2013). Unexpectedly, translation of this reporter was partially inhibited by silvestrol (Figs 4A and EV3H).…”

Section: Resultsmentioning

confidence: 99%

“…eIF4A proteins are DEAD‐box RNA helicases that unwind secondary structures within mRNA 5′‐UTRs, allowing the 43S preinitiation complex (PIC) to scan the 5′‐UTR toward the start codon (Jackson et al , 2010). Several studies have indicated that miRISCs inhibit 43S scanning by interfering with eIF4A function (Meijer et al , 2013; Ricci et al , 2013; Fukao et al , 2014; Fukaya et al , 2014). How this interference is achieved remains unclear.…”

Section: Introductionmentioning

confidence: 99%

“…How this interference is achieved remains unclear. One study reported that NOT1 interacts with eIF4A2 but not with its paralog eIF4A1 in human cells (Meijer et al , 2013). It was suggested that this interaction locks eIF4A2 onto the mRNA 5′‐UTR and represses translation by blocking 43S scanning (Meijer et al , 2013).…”

Section: Introductionmentioning

confidence: 99%

“…One study reported that NOT1 interacts with eIF4A2 but not with its paralog eIF4A1 in human cells (Meijer et al , 2013). It was suggested that this interaction locks eIF4A2 onto the mRNA 5′‐UTR and represses translation by blocking 43S scanning (Meijer et al , 2013). However, the interaction between NOT1 and eIF4A2 was not confirmed in subsequent studies (Chen et al , 2014; Mathys et al , 2014; Rouya et al , 2014) and the knockout of eIF4A2 in human cells does not suppress silencing (Galicia‐Vazquez et al , 2015).…”

Section: Introductionmentioning

confidence: 99%

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mi RISC and the CCR 4– NOT complex silence mRNA targets independently of 43S ribosomal scanning

et al. 2016

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AbstractmiRNAs associate with Argonaute (AGO) proteins to silence the expression of mRNA targets by inhibiting translation and promoting deadenylation, decapping, and mRNA degradation. A current model for silencing suggests that AGOs mediate these effects through the sequential recruitment of GW182 proteins, the CCR4–NOT deadenylase complex and the translational repressor and decapping activator DDX6. An alternative model posits that AGOs repress translation by interfering with eIF4A function during 43S ribosomal scanning and that this mechanism is independent of GW182 and the CCR4–NOT complex in Drosophila melanogaster. Here, we show that miRNAs, AGOs, GW182, the CCR4–NOT complex, and DDX6/Me31B repress and degrade polyadenylated mRNA targets that are translated via scanning‐independent mechanisms in both human and Dm cells. This and additional observations indicate a common mechanism used by these proteins and miRNAs to mediate silencing. This mechanism does not require eIF4A function during ribosomal scanning.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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mi RISC and the CCR 4– NOT complex silence mRNA targets independently of 43S ribosomal scanning

et al. 2016

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Diagnostic Yield and Novel Candidate Genes by Exome Sequencing in 152 Consanguineous Families With Neurodevelopmental Disorders

et al. 2017

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Because of the high diagnostic yield of 36.8% and the possibility of identifying treatable diseases or the coexistence of several disease-causing variants, using exome sequencing as a first-line diagnostic approach in consanguineous families with neurodevelopmental disorders is recommended. Furthermore, the literature is enriched with 52 convincing candidate genes that are awaiting confirmation in independent families.

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Caps on Eukaryotic mRNAs

Furuichi

2014

Encyclopedia of Life Sciences

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A 5′‐terminal cap is added to most eukaryotic cellular and viral messenger ribonucleic acids (mRNAs) at an early stage of transcription. Capping is essential and modulates several subsequent events in gene expression including pre‐mRNA splicing, 3′‐poly(A) addition, overall stability, nuclear exit to cytoplasm, protein synthesis, and mRNA turnover initiated by decapping. These and other effects involve cap‐binding proteins that recognise the m7GpppN cap structure. Capping proceeds by a similar series of enzymatic steps in a wide range of systems, but differences exist between metazoans and unicellular eukaryotes and viruses, pointing to capping enzymes as potential targets for the development of selective drugs against some fungal, viral and parasitic infections. Moreover, the unique structural features of caps enable us to define the initiation sites and promoter regions of gene transcription, and provide a basis for advanced sequencer‐mediated high‐throughput genome‐wide profiling of gene expression in a wide range of cell types. Key Concepts: mRNA caps are now known to be essential components of gene expression in eukaryotic organisms. The history of the discovery of the presence of 5′ caps on messenger RNA and its subsequent scientific flowering is a good example of how a seemingly small biochemical observation can lead to the deeper understanding of a wide range of fundamental molecular biological phenomena. Evolution has resulted in wide variations in capping structure and function among organisms ranging from viruses to humans; the selective forces underlying such variation requires more research. Research that has documented viral‐specific capping reactions in viruses should prove to be a fertile source of research leading to new and novel anti‐viral agents. The ‘cap‐snatching’ strategies of influenza viruses is a remarkable example of an apparent adaptation to enhance infectivity and is a particularly compelling target for therapeutic intervention. The NMD mRNA surveillance pathway, which includes a pioneer round of translation with cap‐binding proteins, results in a striking decrease of defective mRNA in cells of patients with genetic diseases containing premature termination codons. Methylation of genomic DNA and mRNA is now widely accepted as a major pathway of the regulation of both transcription and translation in eukaryotes. Protein synthesis is a major field of gene expression where many players work for mRNA capping, decapping, decoding, quality control of gene transcripts and peptide elongation. Micro RNAs are now widely accepted as major players in the translational control of protein synthesis. The analysis of cap‐trapped sequences by high‐throughput sequencers enables one to carry out a genome‐wide identification of promoters together with quantification of their expression, thus elucidating a promoter‐based network of transcriptional regulation.

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Translational Repression and eIF4A2 Activity Are Critical for MicroRNA-Mediated Gene Regulation

Cited by 292 publications

References 38 publications

mi RISC and the CCR 4– NOT complex silence mRNA targets independently of 43S ribosomal scanning

mi RISC and the CCR 4– NOT complex silence mRNA targets independently of 43S ribosomal scanning

Diagnostic Yield and Novel Candidate Genes by Exome Sequencing in 152 Consanguineous Families With Neurodevelopmental Disorders

Caps on Eukaryotic mRNAs

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