A Ribonuclease Coordinates siRNA Amplification and mRNA Cleavage during RNAi

Tsai, Hsin Yue; Chen, Chun Chieh G.; Conte, Darryl; Moresco, James J.; Chaves, Daniel A.; Mitani, Shohei; Yates, John R.; Tsai, Max; Mello, Craig C.

doi:10.1016/j.cell.2015.01.010

Cited by 73 publications

(93 citation statements)

References 68 publications

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“…In addition to the known ERIC components, we also found RDE-8 to strongly co-IP with RRF-3 under these conditions. RDE-8 and ERI-9, another previously identified ERIC factor (Thivierge et al, 2012), are paralog endonucleases that have been implicated in the 26G-RNA pathway (Gent et al, 2010;Tsai et al, 2015).…”

Section: Gtsf-1 Interacts With Rrf-3mentioning

confidence: 99%

“…This factor is a paralog of ERI-9 (Pavelec et al, 2009;Gent et al, 2010;Tsai et al, 2015), which was previously shown to interact with other ERIC factors (Thivierge et al, 2012). RDE-8 and ERI-9 are NYN ribonucleases and have been previously shown to be involved in RNAi processes, including 26G-RNA biogenesis (Pavelec et al, 2009;Gent et al, 2010;Tsai et al, 2015). Their roles in 26G-RNA biogenesis seem to be independent of nucleic acid cleavage since: (i) ERI-9 lacks the conserved catalytic residues required for nucleic acid cleavage, and (ii) RDE-8 transgenes with mutated catalytic residues still accumulate 26G-RNAs.…”

Section: How Is the Eric Recruited To Target Rna?mentioning

confidence: 99%

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GTSF ‐1 is required for formation of a functional RNA ‐dependent RNA Polymerase complex in Caenorhabditis elegans

Almeida

Dietz²,

Redl

et al. 2018

The EMBO Journal

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Argonaute proteins and their associated small RNAs (sRNAs) are evolutionarily conserved regulators of gene expression. Gametocyte-specific factor 1 (Gtsf1) proteins, characterized by two tandem CHHC zinc fingers and an unstructured C-terminal tail, are conserved in animals and have been shown to interact with Piwi clade Argonautes, thereby assisting their activity. We identified the Gtsf1 homolog, named it and characterized it in the context of the sRNA pathways of We report that GTSF-1 is not required for Piwi-mediated gene silencing. Instead, mutants show a striking depletion of 26G-RNAs, a class of endogenous sRNAs, fully phenocopying mutants. We show, both and , that GTSF-1 interacts with RRF-3 via its CHHC zinc fingers. Furthermore, we demonstrate that GTSF-1 is required for the assembly of a larger RRF-3 and DCR-1-containing complex (ERIC), thereby allowing for 26G-RNA generation. We propose that GTSF-1 homologs may act to drive the assembly of larger complexes that act in sRNA production and/or in imposing sRNA-mediated silencing activities.

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Section: Gtsf-1 Interacts With Rrf-3mentioning

confidence: 99%

Section: How Is the Eric Recruited To Target Rna?mentioning

confidence: 99%

GTSF ‐1 is required for formation of a functional RNA ‐dependent RNA Polymerase complex in Caenorhabditis elegans

Almeida

Dietz²,

Redl

et al. 2018

The EMBO Journal

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“…S6), raising the possibility that a selected subset of RNAs are subject to untemplated 3 ′ uridylation in vivo. Thus, an unknown mechanism ensures that 22-nt, and not longer, RNAs are synthesized using stabilized mRNA fragments (Tsai et al 2015) as templates in vivo. Such precise production of 22-nt RNAs could be enabled by proteins like the Dicer-related helicase DRH-3, which interacts with the RdRP RRF-1 (Aoki et al 2007), is required for the production of 22G RNAs (Gu et al 2009), and was recently proposed to bind as a dimer to measure 22 base pairs formed by small RNAs binding mRNA templates (Fitzgerald et al 2014).…”

Section: G Rnas and Their Derivatives Are Made From Characteristic mentioning

confidence: 99%

Reproducible features of small RNAs in C. elegans reveal NU RNAs and provide insights into 22G RNAs and 26G RNAs

Blumenfeld

Jose

2015

RNA

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Small RNAs regulate gene expression and most genes in the worm Caenorhabditis elegans are subject to their regulation. Here, we analyze small RNA data sets and use reproducible features of RNAs present in multiple data sets to discover a new class of small RNAs and to reveal insights into two known classes of small RNAs-22G RNAs and 26G RNAs. We found that reproducibly detected 22-nt RNAs, although are predominantly RNAs with a G at the 5 ′ end, also include RNAs with A, C, or U at the 5 ′ end. These RNAs are synthesized downstream from characteristic sequence motifs on mRNA and have U-tailed derivatives. Analysis of 26G RNAs revealed that they are processed from a blunt end of double-stranded RNAs and that production of one 26G RNA generates a hotspot immediately downstream for production of another. To our surprise, analysis of RNAs shorter than 18 nt revealed a new class of RNAs, which we call NU RNAs (pronounced "new RNAs") because they have a NU bias at the 5 ′ end, where N is any nucleotide. NU RNAs are antisense to genes and originate downstream from U bases on mRNA. Although many genes have complementary NU RNAs, their genome-wide distribution is distinct from that of previously known classes of small RNAs. Our results suggest that current approaches underestimate reproducibly detected RNAs that are shorter than 18 nt, and theoretical considerations suggest that such shorter RNAs could be used for sequence-specific gene regulation in organisms like C. elegans that have small genomes.

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“…The 26G-RNAs are then loaded into the primary AGO ERGO-1 (Gent et al 2010;Vasale et al 2010). Upon RDE-1 and ERGO-1 association with target RNAs, RdRPs directly synthesize secondary siRNAs ∼22 nt in length (22G-RNAs) (Yigit et al 2006;Gent et al 2010;Vasale et al 2010;Tsai et al 2015). The 22G-RNAs primarily contain 5 ′ triphosphates and diphosphates (Pak and Fire 2007;Sijen et al 2007) and associate with secondary worm-specific AGOs (WAGOs) to mediate repression of gene expression (Yigit et al 2006).…”

mentioning

confidence: 99%

DUSP11 activity on triphosphorylated transcripts promotes Argonaute association with noncanonical viral microRNAs and regulates steady-state levels of cellular noncoding RNAs

et al. 2016

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RNA silencing is a conserved eukaryotic gene expression regulatory mechanism mediated by small RNAs. In Caenorhabditis elegans, the accumulation of a distinct class of siRNAs synthesized by an RNA-dependent RNA polymerase (RdRP) requires the PIR-1 phosphatase. However, the function of PIR-1 in RNAi has remained unclear. Since mammals lack an analogous siRNA biogenesis pathway, an RNA silencing role for the mammalian PIR-1 homolog (dual specificity phosphatase 11 [DUSP11]) was unexpected. Here, we show that the RNA triphosphatase activity of DUSP11 promotes the RNA silencing activity of viral microRNAs (miRNAs) derived from RNA polymerase III (RNAP III) transcribed precursors. Our results demonstrate that DUSP11 converts the 5 ′ triphosphate of miRNA precursors to a 5 ′ monophosphate, promoting loading of derivative 5p miRNAs into Argonaute proteins via a Dicer-coupled 5 ′ monophosphate-dependent strand selection mechanism. This mechanistic insight supports a likely shared function for PIR-1 in C. elegans. Furthermore, we show that DUSP11 modulates the 5 ′ end phosphate group and/or steady-state level of several host RNAP III transcripts, including vault RNAs and Alu transcripts. This study shows that steady-state levels of select noncoding RNAs are regulated by DUSP11 and defines a previously unknown portal for small RNA-mediated silencing in mammals, revealing that DUSP11-dependent RNA silencing activities are shared among diverse metazoans.

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A Ribonuclease Coordinates siRNA Amplification and mRNA Cleavage during RNAi

Cited by 73 publications

References 68 publications

GTSF ‐1 is required for formation of a functional RNA ‐dependent RNA Polymerase complex in Caenorhabditis elegans

GTSF ‐1 is required for formation of a functional RNA ‐dependent RNA Polymerase complex in Caenorhabditis elegans

Reproducible features of small RNAs in C. elegans reveal NU RNAs and provide insights into 22G RNAs and 26G RNAs

DUSP11 activity on triphosphorylated transcripts promotes Argonaute association with noncanonical viral microRNAs and regulates steady-state levels of cellular noncoding RNAs

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