RNAi Factors Are Present and Active in Human Cell Nuclei

Gagnon, Keith T.; Li, Liande; Chu, Yongjun; Janowski, Bethany A.; Corey, David R.

doi:10.1016/j.celrep.2013.12.013

Cited by 335 publications

(385 citation statements)

References 58 publications

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“…The latter constitutes evidence of a nuclear PTGS pathway ( Figure 1C). Indeed, increasing evidence supports a functional nuclear PTGS pathway, with a recent study demonstrating not only the presence of PTGS related proteins in the nucleus of mammalian cells, but an active AGO-2-RISC complex able to efficiently cleave two nuclear lncRNAs, Malat1 and Neat1 [101] . These studies add to previous evidence indicating the existence of a nuclear RNAi pathway and suggest that PTGS and TGS may be closely related.…”

Section: Ptgsmentioning

confidence: 99%

“…Recent evidence suggests that it may be also triggered by sncRNAs that target the 3' termini of genes [58,106] . While increasing evidence suggests a role for AGO-2 in nuclear gene silencing [100] , it seems to be predominantly through a nuclear PTGS that involves RNA cleavage [101] , with only few described exceptions [107] . There is also evidence of RNA-induced nuclear silencing without heterochromatin formation, involving both AGO1 and AGO2 [108] , and there seems to be various RNA-directed nuclear-pathways that control transcription at different stages [109] .…”

Section: Tgsmentioning

confidence: 99%

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Post-transcriptional gene silencing, transcriptional gene silencing and human immunodeficiency virus

Méndez

2015

WJV

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Section: Ptgsmentioning

confidence: 99%

Section: Tgsmentioning

confidence: 99%

Post-transcriptional gene silencing, transcriptional gene silencing and human immunodeficiency virus

Méndez

2015

WJV

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“…Although processing of Dicer's substrates occurs in the cytoplasm of mammalian cells, several reports suggest that Dicer may also have additional roles in the nucleus. [24][25][26][27] In support of a nuclear function of Dicer, the C-terminal dsRBD of human Dicer was recently shown to harbor an atypical nuclear localization signal (NLS), composed of a cluster of positively charged residues on the surface of the folded dsRBD (Fig. 1B).…”

Section: Dsrbds and Nuclear Importmentioning

confidence: 99%

Functions of double-stranded RNA-binding domains in nucleocytoplasmic transport

Banerjee

2014

RNA Biology

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International audienceThe double-stranded RNA-binding domain (dsRBD) is a small protein domain found in eukaryotic, prokaryotic and viral proteins, whose central property is to bind to double-stranded RNA (dsRNA). Aside from this major function, recent examples of dsRBDs involved in the regulation of the sub-cellular localization of proteins, suggest that the participation of dsRBDs in nucleocytoplasmic trafficking is likely to represent a widespread auxiliary function of this type of RNA-binding domain. Overall, dsRBDs from proteins involved in many different biological processes have been reported to be implicated in nuclear import and export, as well as cytoplasmic, nuclear and nucleolar retention. Interestingly, the function of dsRBDs in nucleocytoplasmic trafficking is often regulated by their dsRNA-binding capacity, which can either enhance or impair the transport from one compartment to another. Here, we present and discuss the emerging function of dsRBDs in nucleocytoplasmic transport

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“…Recent work has indicated that human AGO proteins can regulate splicing through modulating chromatin structure (9,10) and can promote gene repression in cis by localizing to nascent tRNA (11). Thus, RNAi-mediated control of gene expression exists also in vertebrate cells but functions in mechanisms distinct from those within the cytoplasm (12,13). Despite these reports demonstrating a role for RNAi in regulating the chromatin structure of vertebrates, similar studies have shown that the loss of the RNAi machinery impacts chromatin structure indirectly through miRNA biogenesis and post-transcriptional gene regulation (14).…”

mentioning

confidence: 99%

Human Argonaute 2 Is Tethered to Ribosomal RNA through MicroRNA Interactions

Atwood

Woolnough

Lefèvre

et al. 2016

Journal of Biological Chemistry

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The primary role of the RNAi machinery is to promote mRNA degradation within the cytoplasm in a microRNA-dependent manner. However, both Dicer and the Argonaute protein family have expanded roles in gene regulation within the nucleus. To further our understanding of this role, we have identified chromatin binding sites for AGO2 throughout the 45S region of the human rRNA gene. The location of these sites was mirrored by the positions of AGO2 cross-linking sites identified via PAR-CLIP-seq. AGO2 binding to the rRNA within the nucleus was confirmed by RNA immunoprecipitation and quantitative-PCR. To explore a possible mechanism by which AGO2 could be recruited to the rRNA, we identified 1174 regions within the 45S rRNA transcript that have the ability to form a perfect duplex with position 2-6 (seed sequence) of each microRNA expressed in HEK293T cells. Of these potential AGO2 binding sites, 479 occurred within experimentally verified AGO2-rRNA crosslinking sites. The ability of AGO2 to cross-link to rRNA was almost completely lost in a DICER knock-out cell line. The transfection of miR-92a-2-3p into the noDICE cell line facilitated AGO2 cross-linking at a region of the rRNA that has a perfect seed match at positions 3-8, including a single G-U base pair. Knockdown of AGO2 within HEK293T cells causes a slight, but statistically significant increase in the overall rRNA synthesis rate but did not impact the ratio of processing intermediates or the recruitment of the Pol I transcription factor UBTF.The RNAi machinery has many functions in the eukaryotic cell, and aspects of the RNAi molecular mechanism are highly conserved between yeast and humans (1). Essentially, a small RNA is bound by a member of the Argonaute family of proteins and contributes sequence specificity to a larger protein complex. In the cytoplasm, the RNAi machinery uses Watson-Crick base pairing to target the RNA-induced silencing complex to a specific mRNA and facilitate its degradation. A related process is well established in the nucleus of Schizosaccharomyces pombe, where instead of targeting cytoplasmic mRNAs for destruction, a small RNA targets the RNA-induced transcriptional silencing complex to the pericentromeric regions of each chromosome and facilitates the generation of heterochromatin (2, 3).Work in a chicken-human hybrid cell line supports the possibility that the RNAi machinery is responsible for centromeric chromatin structure in vertebrates as well (4). Indeed, when Dicer is conditionally inactivated, transcription of ␣-satellite DNA from human chromosome 21 increases. Furthermore, the loss of Dicer results in a loss of siRNAs originating from these repeat regions, a delocalization of HP1, and disruption of mitosis (4). The RNAi machinery is also implicated in the creation and/or maintenance of heterochromatin at various sites throughout the genome, in addition to the centromeric regions. Transfection of a siRNA homologous to the EF1a promoter in human cells silences the endogenous gene (5). In a related study, human Argonaute 1 (A...

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RNAi Factors Are Present and Active in Human Cell Nuclei

Cited by 335 publications

References 58 publications

Post-transcriptional gene silencing, transcriptional gene silencing and human immunodeficiency virus

Post-transcriptional gene silencing, transcriptional gene silencing and human immunodeficiency virus

Functions of double-stranded RNA-binding domains in nucleocytoplasmic transport

Human Argonaute 2 Is Tethered to Ribosomal RNA through MicroRNA Interactions

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