Argonaute2 Is the Catalytic Engine of Mammalian RNAi

Liu, Jidong; Carmell, Michelle A.; Rivas, Fabiola V.; Marsden, Carolyn G.; Thomson, J. Michael; Song, Ji-Joon; Hammond, Scott M.; Joshua‐Tor, Leemor; Hannon, Gregory J.

doi:10.1126/science.1102513

Cited by 2,401 publications

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“…Members of the Argonaute-like class of proteins have been identified as key components of the RISC Rivas et al 2005;Zamore and Haley 2005). In humans, hAgo2 was shown to be responsible for target RNA cleavage whereas other Argonaute subfamily members (hAgo1, hAgo3, and hAgo4) can associate with both siRNAs and miRNAs but do not mediate cleavage (Liu et al 2004a;Rivas et al 2005). In D. melanogaster, both Ago2 and Ago1 have slicer functions but Ago2 is predominantly involved in siRNA-directed target RNA cleavage whereas Ago1 is necessary for miRNA-directed target RNA cleavage (Miyoshi et al 2005;Okamura et al 2004).…”

Section: Nature Of the Ancestral Rnai Machinerymentioning

confidence: 99%

“…siRNAs are then incorporated into a multiprotein complex, the RNA-induced silencing complex (RISC) (Pham et al 2004;Tomari et al 2004). Members of the Argonaute-Piwi (Ago-Piwi) family of proteins are core components of the RISC and some of these polypeptides function as siRNA-guided endonucleases (Baumberger and Baulcombe 2005;Hammond et al 2001;Liu et al 2004a;Qi et al 2005;Tomari and Zamore 2005). Recent evidence suggests that a siRNA duplex may be loaded into RISC and then Ago cleaves one of the siRNA strands (the passenger strand) triggering its dissociation from the complex (Matranga et al 2005;Miyoshi et al 2005;Rand et al 2005).…”

Section: Introductionmentioning

confidence: 99%

“…These proteins are highly basic, approximately 100-kD in size, and contain two conserved motifs, the PAZ (after Piwi/Argonaute/Zwille) and the PIWI domains (Cerutti et al 2000;Lingel et al 2004;Ma et al 2004;Song et al 2004;Yuan et al 2005). A number of experiments have implicated certain argonautes, such as human Ago2, as the catalytic unit ("slicer") of the RISC (Liu et al 2004a;Okamura et al 2004;Rivas et al 2005). However, several other Ago paralogs are not endonucleolytically active (Liu et al 2004a;Rivas et al 2005).…”

Section: Introductionmentioning

confidence: 99%

“…A number of experiments have implicated certain argonautes, such as human Ago2, as the catalytic unit ("slicer") of the RISC (Liu et al 2004a;Okamura et al 2004;Rivas et al 2005). However, several other Ago paralogs are not endonucleolytically active (Liu et al 2004a;Rivas et al 2005). In fact, in several species, there is evidence for functional specialization of Ago-Piwi proteins (Grishok et al 2001;Lee et al 2003;Matzke and Birchler 2005;Okamura et al 2004).…”

Section: Introductionmentioning

confidence: 99%

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On the origin and functions of RNA-mediated silencing: from protists to man

2006

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Double-stranded RNA has been shown to induce gene silencing in diverse eukaryotes and by a variety of pathways. We have examined the taxonomic distribution and the phylogenetic relationship of key components of the RNA interference (RNAi) machinery in members of five eukaryotic supergroups. On the basis of the parsimony principle, our analyses suggest that a relatively complex RNAi machinery was already present in the last common ancestor of eukaryotes and consisted, at a minimum, of one Argonautelike polypeptide, one Piwi-like protein, one Dicer, and one RNAdependent RNA polymerase. As proposed before, the ancestral (but non-essential) role of these components may have been in defense responses against genomic parasites such as transposable elements and viruses. From a mechanistic perspective, the RNAi machinery in the eukaryotic ancestor may have been capable of both small-RNA-guided transcript degradation as well as transcriptional repression, most likely through histone modifications. Both roles appear to be widespread among living eukaryotes and this diversification of function could account for the evolutionary conservation of duplicated Argonaute-Piwi proteins. In contrast, additional RNAi-mediated pathways such as RNA-directed DNA methylation, programmed genome rearrangements, meiotic silencing by unpaired DNA, and miRNA-mediated gene regulation may have evolved independently in specific lineages.

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Section: Nature Of the Ancestral Rnai Machinerymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

On the origin and functions of RNA-mediated silencing: from protists to man

2006

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“…In Drosophila, the division of labor between the two Agos is clear: DmAgo1 acts as a miRNA-guided silencer and DmAgo2 responds to siRNAs. In humans, of the four Ago subfamily members (hAgo1-4), only hAgo2 has slicing activity and the mouse version of this protein is the only one that results in embryonic lethality upon knockout [76][77][78]. On the other hand, all appear to participate in miRNA-mediated silencing.…”

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confidence: 99%

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

Ipsaro

Joshua‐Tor

2015

Nat Struct Mol Biol

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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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Overview of Gene Silencing by RNA Interference

Kim¹,

Rossi

2009

CP Nucleic Acid Chemistry

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The potential of harnessing RNA interference (RNAi) for sequence-specific gene silencing has generated much excitement and progress in the field. Recent advances in RNAi technology suggest that RNAi-based approaches may soon become an effective therapeutic strategy against a myriad of diseases. This overview provides a brief description of important considerations when designing an RNAi-based method for gene silencing and therapeutic development: (a) mechanistic aspects of RNAi-mediated gene silencing in mammalian cells; (b) structural requirements for potent siRNA duplexes; (c) off-target effects and interferon responses; and (d) effective delivery of RNAi-inducing agents. Promising therapeutic applications of RNAi that are currently in the developmental pipeline are also described.

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Argonaute2 Is the Catalytic Engine of Mammalian RNAi

Cited by 2,401 publications

References 44 publications

On the origin and functions of RNA-mediated silencing: from protists to man

On the origin and functions of RNA-mediated silencing: from protists to man

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

Overview of Gene Silencing by RNA Interference

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