The Argonaute CSR-1 and Its 22G-RNA Cofactors Are Required for Holocentric Chromosome Segregation

Claycomb, Julie M.; Batista, Pedro J.; Pang, Ka Ming; Gu, Weifeng; Vasale, Jessica J.; Wolfswinkel, Josien C. van; Chaves, Daniel A.; Shirayama, Masaki; Mitani, Shohei; Ketting, René F.; Conte, Darryl; Mello, Craig C.

doi:10.1016/j.cell.2009.09.014

Cited by 430 publications

(963 citation statements)

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“…Consistent with P granules functioning as regulators of mRNA accumulation in the germline, many RNAi factors localize to P granules, including Dicer/DCR-1, the RNAdependent RNA polymerase EGO-1, and the argonaute proteins PRG-1 and CSR-1 (Batista et al 2008;Claycomb et al 2009). PRG-1 is a Piwi-related argonaute that prevents the expression of foreign genetic elements, including transposon and transgene mRNAs.…”

Section: Discussionmentioning

confidence: 99%

“…This information could then be relayed back into the nucleus to repress inappropriately activated, soma-specific genes through epigenetic mechanisms (Kasper et al 2014; Figure 8). CSR-1, another P granule-associated argonaute, recognizes its targets through associated 22G-RNAs that base pair with germline-expressed mRNAs including those important for embryogenesis (Claycomb et al 2009). Interestingly, CSR-1 was recently found to tune the levels of certain germline mRNAs in a manner that is dependent on its slicer activity (Gerson-Gurwitz et al 2016).…”

Section: Discussionmentioning

confidence: 99%

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Germ Granules Prevent Accumulation of Somatic Transcripts in the AdultCaenorhabditis elegansGermline

et al. 2017

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The germ cells of multicellular organisms protect their developmental potential through specialized mechanisms. A shared feature of germ cells from worms to humans is the presence of nonmembrane-bound, ribonucleoprotein organelles called germ granules. Depletion of germ granules in Caenorhabditis elegans (i.e., P granules) leads to sterility and, in some germlines, expression of the neuronal transgene unc-119::gfp and the muscle myosin MYO-3. Thus, P granules are hypothesized to maintain germ cell totipotency by preventing somatic development, although the mechanism by which P granules carry out this function is unknown. In this study, we performed transcriptome and single molecule RNA-FISH analyses of dissected P granule-depleted gonads at different developmental stages. Our results demonstrate that P granules are necessary for adult germ cells to downregulate spermatogenesis RNAs and to prevent the accumulation of numerous soma-specific RNAs. P granule-depleted gonads that express the unc-119::gfp transgene also express many other genes involved in neuronal development and concomitantly lose expression of germ cell fate markers. Finally, we show that removal of either of two critical P-granule components, PGL-1 or GLH-1, is sufficient to cause germ cells to express UNC-119::GFP and MYO-3 and to display RNA accumulation defects similar to those observed after depletion of P granules. Our data identify P granules as critical modulators of the germline transcriptome and guardians of germ cell fate.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Germ Granules Prevent Accumulation of Somatic Transcripts in the AdultCaenorhabditis elegansGermline

et al. 2017

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“…S6). Recent studies have shown that DRH-3 is required for germline development and RNAi by participating in the biogenesis of 22G RNAs (25,38,39), suggesting a possible role for DRH-3 in antiviral RNAi. We investigated FHV replication and Orsay virus infection in worms containing the ne4253 allele of drh-3.…”

Section: The Helicase and Ctd Domains Of Rig-i Were Functional In A Fmentioning

confidence: 99%

Homologous RIG-I–like helicase proteins direct RNAi-mediated antiviral immunity in C. elegans by distinct mechanisms

Guo

Zhang

Wang

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

128

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RNAi-mediated antiviral immunity in Caenorhabditis elegans requires Dicer-related helicase 1 (DRH-1), which encodes the helicase and C-terminal domains homologous to the mammalian retinoic acid inducible gene I (RIG-I)-like helicase (RLH) family of cytosolic immune receptors. Here we show that the antiviral function of DRH-1 requires the RIG-I homologous domains as well as its wormspecific N-terminal domain. We also demonstrate that the helicase and C-terminal domains encoded by either worm DRH-2 or human RIG-I can functionally replace the corresponding domains of DRH-1 to mediate antiviral RNAi in C. elegans. Notably, substitutions in a three-residue motif of the C-terminal regulatory domain of RIG-I that physically interacts with viral double-stranded RNA abolish the antiviral activity of C-terminal regulatory domains of both RIG-I and DRH-1 in C. elegans. Genetic analysis revealed an essential role for both DRH-1 and DRH-3 in C. elegans antiviral RNAi targeting a natural viral pathogen. However, Northern blot and small RNA deep sequencing analyses indicate that DRH-1 acts to enhance production of viral primary siRNAs, whereas DRH-3 regulates antiviral RNAi by participating in the biogenesis of secondary siRNAs after Dicer-dependent production of primary siRNAs. We propose that DRH-1 facilitates the acquisition of viral double-stranded RNA by the worm dicing complex for the subsequent processing into primary siRNAs. The strong parallel for the antiviral function of RLHs in worms and mammals suggests that detection of viral doublestranded RNA may activate completely unrelated effector mechanisms or, alternatively, that the mammalian RLHs have a conserved activity to stimulate production of viral siRNAs for antiviral immunity by an RNAi effector mechanism.I nnate immunity refers to ancient host defense systems that act immediately after pathogen attack and are under the control of germline-encoded immune receptors. Pathogen sensing by several classes of immune receptors such as retinoic acid inducible gene I (RIG-I)-like cytosolic sensors in mammals leads to the transcriptional activation of effector genes in the nucleus (1). In contrast, detection of viral double-stranded RNA (dsRNA) by Dicer endonucleases is associated with the production of small interfering RNAs (siRNAs), which subsequently direct sequencespecific antiviral immunity through RNA interference (RNAi) (2-5). Antiviral RNAi is a major antiviral defense mechanism in fungi, plants, insects, and nematodes, so that suppression of the defense by a virus-encoded suppressor of RNAi is essential to establish infection (6-8). Although the RNAi machinery is highly conserved in mammals, conclusive evidence for a natural antiviral role of RNAi in mammals is not available (9).The nematode Caenorhabditis elegans has recently emerged as a small-animal model for innate immunity studies (10, 11). Genetic studies indicate that antiviral RNAi in C. elegans requires the genes essential for RNAi induced by exogenous dsRNA (12-17). These include Dicer-1 and dsRNA-bind...

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“…Some reports have suggested that it is as a component of germline perinuclear P--granule structures which are sites of mRNA export and possibly degradation (KAWASAKI et al 1998;SHETH et al 2010), and others have shown that these P--granules' structure or stability depends, at least indirectly, on RNAi components including CSR--1, EGO--1, DCR--1, DRH--3, PRG--1, and RDE--4 (BESHORE et al 2011;CLAYCOMB et al 2009;SPIKE et al 2008; UPDIKE and STROME 2009). While PGL--1's link to RNAs is genetically and biochemically well--established (HANAZAWA et al 2011;SCHISA et al 2001), especially for those in the germline, there are conflicting reports on its role in RNAi.…”

Section: Pgl--1's Link To Rnaimentioning

confidence: 99%

The Nuclear Argonaute NRDE-3 Contributes to Transitive RNAi inCaenorhabditis elegans

Zhuang

Banse²,

Hunter

2013

Genetics

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The Caenorhabditis elegans nuclear RNA interference defective (Nrde) mutants were identified by their inability to silence polycistronic transcripts in enhanced RNAi (Eri) mutant backgrounds. Here, we report additional nrde-3-dependent RNAi phenomena that extend the mechanisms, roles, and functions of nuclear RNAi. We show that nrde-3 mutants are broadly RNAi deficient and that overexpressing NRDE-3 enhances RNAi. Consistent with NRDE-3 being a dose-dependent limiting resource for effective RNAi, we find that NRDE-3 is required for eri-dependent enhanced RNAi phenotypes, although only for a subset of target genes. We then identify pgl-1 as an additional limiting RNAi resource important for eri-dependent silencing of a nonoverlapping subset of target genes, so that an nrde-3; pgl-1; eri-1 triple mutant fails to show enhanced RNAi for any tested gene. These results suggest that nrde-3 and pgl-1 define separate and independent limiting RNAi resource pathways. Limiting RNAi resources are proposed to primarily act via endogenous RNA silencing pathways. Consistent with this, we find that nrde-3 mutants misexpress genes regulated by endogenous siRNAs and incompletely silence repetitive transgene arrays. Finally, we find that nrde-3 contributes to transitive RNAi, whereby amplified silencing triggers act in trans to silence sequence-similar genes. Because nrde-dependent silencing is thought to act in cis to limit the production of primary transcripts, this result reveals an unexpected role for nuclear processes in RNAi silencing. GENETIC analysis of RNA interference (RNAi) in Caenorhabditis elegans initially identified and characterized genes and activities important for post-transcriptional gene silencing (PTGS) in response to exogenous double-stranded RNA (dsRNA) (Tabara et al. 1999(Tabara et al. , 2002. Because these gene products target mature RNAs (mRNAs), they were presumed to act in the cytoplasm . However, a genetic screen for mutants specifically defective for pan-operon RNAi silencing (Bosher et al. 1999) identified genes important for transcriptional gene silencing (TGS) processes that operate in the nucleus (Guang et al. 2008(Guang et al. , 2010Burkhart et al. 2011;Burton et al. 2011). These genes were termed nuclear RNAi defective (nrde).The best-characterized nrde is NRDE-3, an Argonaute that shuttles secondary short-interfering RNAs (siRNAs) from the cytoplasm to the nucleus (Guang et al. 2008). When siRNA are absent or reduced, NRDE-3 is primarily detected in the cytoplasm, and when siRNAs are abundant, NRDE-3 is readily detected in the nucleus. In the nucleus, the siRNAbound NRDE-3 forms a complex with the nuclear restricted NRDE-1, -2, and -4 (Burton et al. 2011). The associated siRNA guides the NRDE complex to cognate nascent mRNA transcripts, which impedes RNA polymerase II transcription elongation and further initiates histone methylation-dependent TGS (Guang et al. 2010;Burton et al. 2011). This RNA-directed epigenetic mechanism also enables multigenerational silencing ; the recently ident...

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The Argonaute CSR-1 and Its 22G-RNA Cofactors Are Required for Holocentric Chromosome Segregation

Cited by 430 publications

References 56 publications

Germ Granules Prevent Accumulation of Somatic Transcripts in the AdultCaenorhabditis elegansGermline

Germ Granules Prevent Accumulation of Somatic Transcripts in the AdultCaenorhabditis elegansGermline

Homologous RIG-I–like helicase proteins direct RNAi-mediated antiviral immunity in C. elegans by distinct mechanisms

The Nuclear Argonaute NRDE-3 Contributes to Transitive RNAi inCaenorhabditis elegans

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