Passenger-Strand Cleavage Facilitates Assembly of siRNA into Ago2-Containing RNAi Enzyme Complexes

Matranga, Christian B.; Tomari, Yukihide; Shin, Chanseok; Bartel, David P.; Zamore, Phillip D.

doi:10.1016/j.cell.2005.08.044

Cited by 1,004 publications

(838 citation statements)

References 54 publications

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“…Pre-miRNA hairpin precursor is exported into the cytoplasm by the Exportin-5/Ran-GTP complex 28,29 and is then bound by the RISC Loading Complex (RLC) containing Dicer, TRBP, and Ago2. [30][31][32] Dicer cleaves the pre-miRNA into the mature miRNA, which enters the RISC complex and binds to complementary sequences within the 3 0 -UTR of the target mRNA. 33,34 RISC-bound mRNA transcripts may be suppressed in protein translation, destabilized by deadenylation, or degraded by Ago2 RNase activity.…”

Section: Discussionmentioning

confidence: 99%

Argonaute2 promotes tumor metastasis by way of up-regulating focal adhesion kinase expression in hepatocellular carcinoma

Cheng

Han

2013

Hepatology

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Hepatocellular carcinoma (HCC) is one of the most common cancers and shows a propensity to metastasize and infiltrate adjacent and more distant tissues. However, the mechanisms that contribute to tumor metastasis remain unclear. Here we evaluate the effect of Argonaute2 (Ago2), a member of the Ago gene family that plays a role in short interfering RNA-mediated gene silencing, on HCC tumorigenesis, and metastasis. We found that Ago2 was frequently up-regulated in HCC specimens compared to that in corresponding adjacent nontumor liver. Interestingly, Ago2 overexpression can promote proliferation, colony formation in an anchor-independent manner, migration, tumorigenicity, and metastasis of HCC cells in vivo; in contrast, Ago2 knockdown can restrict anchor-independent colony formation, migration, and tumor metastasis of HCC cells in vivo. However, known microRNAs related to tumor metastasis appeared not be deregulated with Ago2 overexpression in HCC cells; even the knockdown of Dicer, which is responsible for micro-RNA biosynthesis, did not abolish the actions of Ago2 in HCC cells. Significantly, focal adhesion kinase (FAK), a well-known molecule associated with tumor metastasis, was upregulated as a result of Ago2 overexpression. Chromatin immunoprecipitation assay showed that Ago2 can bind to the FAK promoter and then trigger its transcription. Moreover, an increased DNA copy number of Ago2 on chromosome 8q24, one of the most frequent DNA amplified regions, was validated and shown by way of fluorescence in situ hybridization. Conclusion: Our data demonstrate that Ago2 overexpression, as a result of genomic DNA amplification, promotes HCC tumorigenesis and metastasis by way of upregulation of FAK transcription, thereby providing new insight into HCC progression and

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Section: Discussionmentioning

confidence: 99%

Argonaute2 promotes tumor metastasis by way of up-regulating focal adhesion kinase expression in hepatocellular carcinoma

Cheng

Han

2013

Hepatology

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“…In spite of the fact, that the recombinant hAgo2 are not capable of unwinding short RNA duplexes, genetic data in flies suggest that Ago2 is indispensable for this process (Okamura et al, 2004). In fact, it has been recently demonstrated that the cleavage competent fly and the human Ago2 actively participate in the unwinding mechanism by cleaving the passenger strand of the perfectly double-stranded siRNA (Matranga et al, 2005;Miyoshi et al, 2005;Leuschner et al, 2006).…”

Section: Risc Formationmentioning

confidence: 99%

Principles and effects of microRNA-mediated post-transcriptional gene regulation

2006

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MicroRNAs (miRNAs) are abundant regulatory RNAs involved in the regulation of many key biological processes. Recent advances in understanding the mechanism of RNA interference and miRNA-mediated mechanisms shed light on major principals of the formation of the regulatory complex and provide models to explain how these small regulatory RNA species interfere with gene expression and how they influence the translational status of the transcriptome.

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“…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). Activated RISC then functions as a multiple-turnover enzyme that recognizes and cleaves RNA molecules complementary to the incorporated single-stranded guide siRNA Sontheimer 2005;Tomari and Zamore 2005).…”

Section: Introductionmentioning

confidence: 99%

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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Passenger-Strand Cleavage Facilitates Assembly of siRNA into Ago2-Containing RNAi Enzyme Complexes

Cited by 1,004 publications

References 54 publications

Argonaute2 promotes tumor metastasis by way of up-regulating focal adhesion kinase expression in hepatocellular carcinoma

Argonaute2 promotes tumor metastasis by way of up-regulating focal adhesion kinase expression in hepatocellular carcinoma

Principles and effects of microRNA-mediated post-transcriptional gene regulation

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

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