The mechanics of miRNA-mediated gene silencing: a look under the hood of miRISC

Fabian, Marc R.; Sonenberg, Nahum

doi:10.1038/nsmb.2296

Cited by 837 publications

(676 citation statements)

References 102 publications

(237 reference statements)

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“…In addition to accelerating mRNA degradation, miRNAs also trigger translational repression, but the precise repressive mechanism remains poorly understood, and several models have been proposed (Fabian & Sonenberg, 2012). One possible model is that the recruitment of the CCR4–NOT complex is sufficient to mediate silencing (Jonas & Izaurralde, 2015).…”

Section: Introductionmentioning

confidence: 99%

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: Introductionmentioning

confidence: 99%

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

et al. 2016

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“…The upregulation of HIST1H4 can be associated with increased Notch1 stimulation, again connected to cancer metastasis, together with angiogenesis and NF-B production [30,44]; NF-B in turn contributes to the progression of colorectal cancer by regulating cell proliferation, angiogenesis and tumor metastasis [45]. Micro-RNA's block mRNA translation and thus impede the synthesis of specific proteins by recruiting the micro-RNA-induced silencing complex (miRISC) to target mRNAs [46]; downregulation of micro-RNA 222 and 644a thus increases KIT and -actin protein expression, respectively, thereby promoting endothelial cell proliferation and migration (angiogenesis) [36,47] and tumor cell invasiveness and motility [34]. -actin can be upregulated through the IL-6 receptor pathway as well: the increased IL-6 expression after quorum sensing peptide treatment, as observed with our cytokine array, activates -actin phosphorylation, again promoting tumor cell migration [48].…”

Section: Discussionmentioning

confidence: 99%

Crosstalk between the microbiome and cancer cells by quorum sensing peptides

et al. 2015

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Highlights• Some quorum sensing peptides promote colon cancer cell invasion and angiogenesis.• Quorum sensing peptide Phr0662 influences tumor progression by EGFR targeting.• Cytokine profiles confirm the peptide's stimulatory effect on metastasis in vitro.• The microbiome-mammals crosstalk may explain the microbiome's effect on health. ABSTRACTTo date, the precise role of the human microbiome in health and disease states remains largely

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“…These factors are required for effective miRNA silencing in animals where they serve as key mediators between Agos and downstream RNA turnover/translational repression factors [96,98] (Box 2). After binding RISC, these proteins localize to P bodies-cytoplasmic foci that are associated with mRNA decapping, degradation, and translational repression (reviewed in [94,99]). GW182-Ago interactions promote target degradation via the sequestration of stabilizing poly(A)-binding proteins [100,101].…”

Section: Rnai Effector Machinerymentioning

confidence: 99%

“…(a) mi-and si-RNA-induced Silencing Complexes (RISCs) affect silencing either through mRNA endonucleolytic cleavage, termed "slicing" [23,67] or slicing-independent mechanisms (reviewed in [99]). In the miRNA pathway, RISC comprised of Ago loaded with the guide RNA localizes to target mRNAs through imperfect base pairing.…”

Section: Overview Of Effector Step Mechanismsmentioning

confidence: 99%

From guide to target: molecular insights into eukaryotic RNA-interference machinery

Ipsaro

Joshua‐Tor

2015

Nat Struct Mol Biol

210

144

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Since its relatively recent discovery, RNA interference (RNAi) has emerged as a potent, specific, and ubiquitous means of gene regulation. Through a number of pathways that are conserved from yeast to humans, small non-coding RNAs direct molecular machinery to silence gene expression. In this review, we focus on mechanisms and structures that govern RNA silencing in higher organisms. In addition to highlighting recent advances, parallels and differences between RNAi pathways are discussed. Together, the studies reviewed herein reveal the versatility and programmability of RNA-induced Silencing Complexes (RISCs) and emphasize the importance of both upstream biogenesis and downstream silencing factors. Discovery and Biological Perspectives of RNA interferenceRNAi was first described by Fire and Mello in the 1990s when, in an attempt to use antisense RNA to down-regulate gene expression, they observed that double-stranded RNA (dsRNA) was more potent than sense or anti-sense RNA alone [1]. This seminal work boasted robust and specific gene knock down in addition to coining the term "RNA interference" (RNAi). Shortly beforehand, the discovery of individual regulatory RNAs in C. elegans hinted that small, non-coding RNAs might be a pervasive means of gene regulation in higher organisms [2,3]. In the following decade, with the mechanistic insight of Fire and Mello's work in hand, this idea was confirmed and it is now accepted that wellover 1,000 small RNAs are encoded in the human genome that may regulate over 60% of our genes [4,5]. It also became apparent that several seemingly disconnected phenomena are variations of RNAi-type pathways including co-suppression in plants, DNA elimination in Tetrahymena, and quelling in Neurospora [6]. The prevalence of RNAi is impressive and its importance is underscored by the fact that RNAi dysfunction is associated with numerous diseases and disorders including neurological maladies, cancers, and infertility.Shortly after the initial description of RNAi phenomenology, a burst of genetic, biochemical, biophysical, and bioinformatic efforts laid a strong foundation for identifying the molecular pathways, players, and parameters that govern silencing via RNAi. Work from Reprints and permissions information is available online at http://www.nature.com/reprints/index.html. HHMI Author ManuscriptHHMI Author Manuscript HHMI Author Manuscript numerous groups defined the molecular apparatus of RNAi as RISC (RNA-induced Silencing Complex), a ribonucleoprotein complex minimally comprised of a small singlestranded RNA (~20-31 nucleotides) and an Argonaute protein which serves as the effector molecule (reviewed in [7]). In this configuration, the loaded "guide" RNA acts as a specificity determinant that directs Argonaute and any other associated machinery to the target. The guide-loaded Argonaute platform underlies every example in the expansive array of known RNAi pathways in eukaryotes regardless of the source of the guide (structured loci, transposons, viral, etc.), the machinery ...

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The mechanics of miRNA-mediated gene silencing: a look under the hood of miRISC

Cited by 837 publications

References 102 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

Crosstalk between the microbiome and cancer cells by quorum sensing peptides

From guide to target: molecular insights into eukaryotic RNA-interference machinery

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