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• W2138841516 abstract "Small non-coding RNAs, through association with Argonaute protein family members, have a variety of functions during the development of an organism. Although there is increased mechanistic understanding of the RNA interference (RNAi) pathways surrounding these small RNAs, how their effects are modulated by subcellular compartmentalization and cross-pathway functional interactions is only beginning to be explored. This review examines the current understanding of these aspects of RNAi pathways and the biological functions of these pathways. Small non-coding RNAs, through association with Argonaute protein family members, have a variety of functions during the development of an organism. Although there is increased mechanistic understanding of the RNA interference (RNAi) pathways surrounding these small RNAs, how their effects are modulated by subcellular compartmentalization and cross-pathway functional interactions is only beginning to be explored. This review examines the current understanding of these aspects of RNAi pathways and the biological functions of these pathways. During the past decade, following the discovery of RNA interference (RNAi) (Fire et al., 1998Fire A. Xu S. Montgomery M.K. Kostas S.A. Driver S.E. Mello C.C. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans.Nature. 1998; 391: 806-811Crossref PubMed Scopus (6975) Google Scholar), we have witnessed amazing developments in the study of small, noncoding RNA molecules (sRNAs) in animals, plants, and fungi. First noticed as products or intermediates in an experimental silencing process that was at that time poorly understood mechanistically (Hamilton and Baulcombe, 1999Hamilton A.J. Baulcombe D.C. A species of small antisense RNA in posttranscriptional gene silencing in plants.Science. 1999; 286: 950-952Crossref PubMed Scopus (1558) Google Scholar) and as genetically defined sRNA encoding genes (Lee et al., 1993Lee R.C. Feinbaum R.L. Ambros V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14.Cell. 1993; 75: 843-854Abstract Full Text PDF PubMed Scopus (3757) Google Scholar, Wightman et al., 1993Wightman B. Ha I. Ruvkun G. Posttranscriptional regulation of the heterochronic gene lin-14 by lin-4 mediates temporal pattern formation in C. elegans.Cell. 1993; 75: 855-862Abstract Full Text PDF PubMed Scopus (1498) Google Scholar), we now know of many small RNA species (Ghildiyal and Zamore, 2009Ghildiyal M. Zamore P.D. Small silencing RNAs: an expanding universe.Nat. Rev. Genet. 2009; 10: 94-108Crossref PubMed Scopus (721) Google Scholar). One thing that these sRNAs all have in common is that they are embedded in a member of the Argonaute (AGO) protein family (Ender and Meister, 2010Ender C. Meister G. Argonaute proteins at a glance.J. Cell Sci. 2010; 123: 1819-1823Crossref PubMed Scopus (58) Google Scholar), where they act as guides to specific target molecules. While for some of these sRNAs their mode of action remains poorly understood, for others we have learned much about their biogenesis, the proteins they associate with, and the effects they can have on cells. One of the important results from these mechanistic studies is the blurring of the distinctions between various sRNA classes, as different sRNA pathways share components and exhibit crosstalk. Perhaps the most famous class of noncoding sRNA is the microRNA. The specifics of biogenesis and functions of these short stem-loop structure-derived sRNAs are well discussed elsewhere (Bartel, 2009Bartel D.P. MicroRNAs: target recognition and regulatory functions.Cell. 2009; 136: 215-233Abstract Full Text Full Text PDF PubMed Scopus (3595) Google Scholar, Fabian et al., 2010Fabian M.R. Sonenberg N. Filipowicz W. Regulation of mRNA translation and stability by microRNAs.Annu. Rev. Biochem. 2010; 79: 351-379Crossref PubMed Scopus (537) Google Scholar, Kaufman and Miska, 2010Kaufman E.J. Miska E.A. The microRNAs of Caenorhabditis elegans.Semin. Cell Dev. Biol. 2010; 21: 728-737Crossref PubMed Scopus (9) Google Scholar). This review will instead focus on providing an overview of the great variety of other endogenous sRNA pathways, exploring their subcellular compartmentalization, functional interactions, and biological functions in the control of cell fate and development. The one unifying theme between all RNA interference (RNAi)-related pathways is the involvement of an AGO protein. The number of AGO genes varies widely, from one in the fission yeast Schizosaccharomyces pombe to 27 in the nematode Caenorhabditis elegans. AGO proteins identify the targets of an RNAi pathway through basepairing between the AGO-bound sRNA and the target RNA. At the target, AGO proteins can induce a number of effects. Some AGO proteins have a catalytically active RNaseH-like domain and can cleave the targeted RNA molecule. Other AGOs do not rely on target cleavage, either due to the absence of key catalytic residues in their active sites or because of slow enzyme kinetics. These AGOs employ different mechanisms to affect the activity of their targets, often involving the recruitment of additional factors (Ender and Meister, 2010Ender C. Meister G. Argonaute proteins at a glance.J. Cell Sci. 2010; 123: 1819-1823Crossref PubMed Scopus (58) Google Scholar, Hutvagner and Simard, 2008Hutvagner G. Simard M.J. Argonaute proteins: key players in RNA silencing.Nat. Rev. Mol. Cell Biol. 2008; 9: 22-32Crossref PubMed Scopus (412) Google Scholar). The AGO proteins and their associated sRNAs that will be discussed in this Review are detailed in Table 1. In this section, a number of RNAi pathways from different organisms will be discussed using the mechanism by which the relevant sRNA is generated as a guide (Figure 1).Table 1Characteristics of AGO Proteins and Associated sRNAsOrganismArgonauteSmall RNA5′ EndSequence BiasDicer Dependent / IndependentSubcellular LocalizationMolecular FunctionBiological FunctionS. pombeAgo1siRNAP5′Udependentnucleus∗Only when loaded with a small RNA. (chromatin associated)heterochromatin formationcentromere functionTetrahymenaTwi1pscnRNAP5′Udependen.nucleus∗Only when loaded with a small RNA. (chromatin associated)heterochromatin formationchromosome diminutionC. elegansRDE-122-23 nt exo-siRNAP?dependentcytoplasminitiate 22G RNA productionvirus resistanceALG-326GP5′Gdependentnuage (perinuclear)initiate 22G RNA productionspermatogenesisALG-426GP5′Gdependent?initiate 22G RNA productionspermatogenesisERGO-126GP5′Gdependent?initiate 22G RNA productiongene regulation?22-23 nt endo-siRNAP-dependent???CSR-122GPPP5′Gindependentnuage (perinuclear), chromatin associated, around metaphase plate?centromere function, MSUCWAGO's22GPPP5′Gindependentnuage (perinuclear)RNA destabilizationgene regulationNRDE-322GPPP5′Gindependentnucleus∗Only when loaded with a small RNA.inhibition of transcription elongationgene regulationPRG-121U (piRNA)P5′Uindependentnuage (perinuclear)initiate 22G RNA productiongerm cell maintenance, spermatogenesis, transposon silencingPRG-221U (piRNA)P5′Uindependent?initiate 22G RNA productiongerm cell maintenance, spermatogenesis, transposon silencingDrosophilaAgo1miRNA (siRNA)P5′UdependentP-bodiesmRNA destabilization / translation inhibitiongene regulationAgo2siRNA (miRNA)P-dependentP-bodiestarget RNA cleavageembryonic development, gene regulation, transposon silencing, anti-viral defensePiwipiRNA (only primary)P5′Udependentnucleus∗Only when loaded with a small RNA., nuage (perinuclear)target RNA cleavage, heterochromatin formationtransposon silencing, gene regulation, oogenesis, spermatogenesis, embryogenesisAubpiRNAP5′Uindependentnuage (perinuclear)target RNA cleavagetransposon silencing, gene regulation, oogenesis, spermatogenesis, embryogenesisAgo3piRNAP10Aindependentnuage (perinuclear)target RNA cleavagetransposon silencing, gene regulation, oogenesis, spermatogenesis, embryogenesisMouseAgo-2siRNA, miRNAP5′UdependentP-bodies, nuage (chromatoid body)target RNA cleavagegene regulation, oogenesis, embryonic developmentMiwipiRNA (pachytene)P5′UIndependentnuage (chromatoid body)?spermatogenesisMilipiRNA (pachytene and pre-pachytene)P5′Uindependentnuage (perinuclear and chromatoid body)target RNA cleavagetransposon silencing, gene regulation?, spermatogenesisMiwi2piRNA(pre-pachytene)P10AindependentpiP-bodies, nucleus∗Only when loaded with a small RNA.target RNA cleavage, heterochromatin formation?transposon silencing, spermatogenesisXenopusXiwipiRNAP?independentnuage (balbiani body), around metaphase platetarget RNA cleavagetransposon silencingZebrafishZiwipiRNAP5′Uindependentnuage (perinuclear)target RNA cleavagetransposon silencing, germ cell maintenanceZilipiRNAP10Aindependentnucleus∗Only when loaded with a small RNA., nuage (perinuclear)target RNA cleavagetransposon silencing, germ cell differentiationAGO proteins that are discussed in this Review are listed here, together with their bound small RNAs and a number of other characteristics. This table is not intended to be exhaustive but is meant instead to serves as a quick guide to the key characteristics of the various RNAi pathways discussed. P, 5′ mono-phosphate; PPP, 5′ tri-phosphate; 10A, adenosine at position 10 counted from the 5′ end; nt, nucleotide.∗ Only when loaded with a small RNA. Open table in a new tab AGO proteins that are discussed in this Review are listed here, together with their bound small RNAs and a number of other characteristics. This table is not intended to be exhaustive but is meant instead to serves as a quick guide to the key characteristics of the various RNAi pathways discussed. P, 5′ mono-phosphate; PPP, 5′ tri-phosphate; 10A, adenosine at position 10 counted from the 5′ end; nt, nucleotide. A number of RNAi pathways utilize double-stranded RNA (dsRNA) to generate sRNAs through the action of the enzyme Dicer (Bernstein et al., 2001Bernstein E. Caudy A.A. Hammond S.M. Hannon G.J. Role for a bidentate ribonuclease in the initiation step of RNA interference.Nature. 2001; 409: 363-366Crossref PubMed Scopus (2420) Google Scholar) (Figure 1A). Sources of the dsRNA can vary between pathways. For example, most miRNAs derive from Dicer activity on intramolecular “fold-back” structures, or hairpins. Endogenous siRNAs (endo-siRNAs), another sRNA species (Table 1), can derive from more extended hairpin structures or from dsRNA assembled through intermolecular basepairing between transcripts from bidirectional transcription at a single locus or between transcripts produced from distinct loci. These types of endo-siRNAs have been described in mouse and in Drosophila (Chung et al., 2008Chung W.J. Okamura K. Martin R. Lai E.C. Endogenous RNA interference provides a somatic defense against Drosophila transposons.Curr. Biol. 2008; 18: 795-802Abstract Full Text Full Text PDF PubMed Scopus (129) Google Scholar, Czech et al., 2008Czech B. Malone C.D. Zhou R. Stark A. Schlingeheyde C. Dus M. Perrimon N. Kellis M. Wohlschlegel J.A. Sachidanandam R. et al.An endogenous small interfering RNA pathway in Drosophila.Nature. 2008; 453: 798-802Crossref PubMed Scopus (305) Google Scholar, Ghildiyal et al., 2008Ghildiyal M. Seitz H. Horwich M.D. Li C. Du T. Lee S. Xu J. Kittler E.L. Zapp M.L. Weng Z. Zamore P.D. Endogenous siRNAs derived from transposons and mRNAs in Drosophila somatic cells.Science. 2008; 320: 1077-1081Crossref PubMed Scopus (267) Google Scholar, Okamura et al., 2008bOkamura K. Chung W.J. Ruby J.G. Guo H. Bartel D.P. Lai E.C. The Drosophila hairpin RNA pathway generates endogenous short interfering RNAs.Nature. 2008; 453: 803-806Crossref PubMed Scopus (193) Google Scholar, Tam et al., 2008Tam O.H. Aravin A.A. Stein P. Girard A. Murchison E.P. Cheloufi S. Hodges E. Anger M. Sachidanandam R. Schultz R.M. Hannon G.J. Pseudogene-derived small interfering RNAs regulate gene expression in mouse oocytes.Nature. 2008; 453: 534-538Crossref PubMed Scopus (429) Google Scholar, Watanabe et al., 2008Watanabe T. Totoki Y. Toyoda A. Kaneda M. Kuramochi-Miyagawa S. Obata Y. Chiba H. Kohara Y. Kono T. Nakano T. et al.Endogenous siRNAs from naturally formed dsRNAs regulate transcripts in mouse oocytes.Nature. 2008; 453: 539-543Crossref PubMed Scopus (475) Google Scholar). In Drosophila, endo-siRNAs are usually loaded into the AGO protein Ago2, triggering cleavage of their targets (Czech et al., 2008Czech B. Malone C.D. Zhou R. Stark A. Schlingeheyde C. Dus M. Perrimon N. Kellis M. Wohlschlegel J.A. Sachidanandam R. et al.An endogenous small interfering RNA pathway in Drosophila.Nature. 2008; 453: 798-802Crossref PubMed Scopus (305) Google Scholar, Ghildiyal et al., 2008Ghildiyal M. Seitz H. Horwich M.D. Li C. Du T. Lee S. Xu J. Kittler E.L. Zapp M.L. Weng Z. Zamore P.D. Endogenous siRNAs derived from transposons and mRNAs in Drosophila somatic cells.Science. 2008; 320: 1077-1081Crossref PubMed Scopus (267) Google Scholar, Okamura et al., 2008bOkamura K. Chung W.J. Ruby J.G. Guo H. Bartel D.P. Lai E.C. The Drosophila hairpin RNA pathway generates endogenous short interfering RNAs.Nature. 2008; 453: 803-806Crossref PubMed Scopus (193) Google Scholar). Interestingly, the Drosophila endo-siRNA pathway is characterized by a biogenesis mechanism that appears to be a hybrid between that of miRNAs exogenous dsRNA-induced RNAi (Czech et al., 2008Czech B. Malone C.D. Zhou R. Stark A. Schlingeheyde C. Dus M. Perrimon N. Kellis M. Wohlschlegel J.A. Sachidanandam R. et al.An endogenous small interfering RNA pathway in Drosophila.Nature. 2008; 453: 798-802Crossref PubMed Scopus (305) Google Scholar, Okamura et al., 2008aOkamura K. Balla S. Martin R. Liu N. Lai E.C. Two distinct mechanisms generate endogenous siRNAs from bidirectional transcription in Drosophila melanogaster.Nat. Struct. Mol. Biol. 2008; 15: 998Crossref PubMed Scopus (9) Google Scholar). In both mouse and Drosophila, endo-siRNA pathways mainly target transposable elements, although endo-siRNAs that target genes are present as well (Czech et al., 2008Czech B. Malone C.D. Zhou R. Stark A. Schlingeheyde C. Dus M. Perrimon N. Kellis M. Wohlschlegel J.A. Sachidanandam R. et al.An endogenous small interfering RNA pathway in Drosophila.Nature. 2008; 453: 798-802Crossref PubMed Scopus (305) Google Scholar, Ghildiyal et al., 2008Ghildiyal M. Seitz H. Horwich M.D. Li C. Du T. Lee S. Xu J. Kittler E.L. Zapp M.L. Weng Z. Zamore P.D. Endogenous siRNAs derived from transposons and mRNAs in Drosophila somatic cells.Science. 2008; 320: 1077-1081Crossref PubMed Scopus (267) Google Scholar, Okamura et al., 2008bOkamura K. Chung W.J. Ruby J.G. Guo H. Bartel D.P. Lai E.C. The Drosophila hairpin RNA pathway generates endogenous short interfering RNAs.Nature. 2008; 453: 803-806Crossref PubMed Scopus (193) Google Scholar). Another source of dsRNA, found in S. pombe, plants, and C. elegans, is RNA-dependent RNA polymerases (RdRPs) (Figure 1B). The S. pombe RdRP enzyme Rdp1 synthesizes dsRNA at centromeric loci that is subsequently diced and loaded into the AGO protein Ago1 to direct the formation of pericentromeric heterochromatin (for reviews, see (Grewal, 2010Grewal S.I. RNAi-dependent formation of heterochromatin and its diverse functions.Curr. Opin. Genet. Dev. 2010; 20: 134-141Crossref PubMed Scopus (100) Google Scholar, Martienssen et al., 2005Martienssen R.A. Zaratiegui M. Goto D.B. RNA interference and heterochromatin in the fission yeast Schizosaccharomyces pombe.Trends Genet. 2005; 21: 450-456Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar, White and Allshire, 2008White S.A. Allshire R.C. RNAi-mediated chromatin silencing in fission yeast.Curr. Top. Microbiol. Immunol. 2008; 320: 157-183Crossref PubMed Scopus (33) Google Scholar). In the plant Arabidopsis thaliana, multiple RdRP enzymes are involved in intricate networks of different RNAi pathways. In each case, the RdRP enzyme appears to make dsRNA that is then used by one of the four Dicer-like enzymes as substrate (for review, see Herr and Baulcombe, 2004Herr A.J. Baulcombe D.C. RNA silencing pathways in plants.Cold Spring Harb. Symp. Quant. Biol. 2004; 69: 363-370Crossref PubMed Scopus (21) Google Scholar, Voinnet, 2008Voinnet O. Use, tolerance and avoidance of amplified RNA silencing by plants.Trends Plant Sci. 2008; 13: 317-328Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar, Xie and Qi, 2008Xie Z. Qi X. Diverse small RNA-directed silencing pathways in plants.Biochim. Biophys. Acta. 2008; 1779: 720-724Crossref PubMed Scopus (35) Google Scholar). In animals, RdRP activity has so far only been described in C. elegans. In this nematode, at least one RdRP enzyme, RRF-3, may be involved in producing dsRNA that is processed by Dicer (DCR-1). RRF-3, together with DCR-1 and a number of other factors, is involved in generating a subset of the endo-siRNAs in C. elegans, both in the germline as well as in the soma (Gent et al., 2009Gent J.I. Schvarzstein M. Villeneuve A.M. Gu S.G. Jantsch V. Fire A.Z. Baudrimont A. A Caenorhabditis elegans RNA-directed RNA polymerase in sperm development and endogenous RNA interference.Genetics. 2009; 183: 1297-1314Crossref PubMed Scopus (36) Google Scholar, Gent et al., 2010Gent J.I. Lamm A.T. Pavelec D.M. Maniar J.M. Parameswaran P. Tao L. Kennedy S. Fire A.Z. Distinct phases of siRNA synthesis in an endogenous RNAi pathway in C. elegans soma.Mol. Cell. 2010; 37: 679-689Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar, Pavelec et al., 2009Pavelec D.M. Lachowiec J. Duchaine T.F. Smith H.E. Kennedy S. Requirement for the ERI/DICER complex in endogenous RNA interference and sperm development in Caenorhabditis elegans.Genetics. 2009; 183: 1283-1295Crossref PubMed Scopus (44) Google Scholar). C. elegans endo-siRNAs include a 26-nucleotide-long species (Gent et al., 2009Gent J.I. Schvarzstein M. Villeneuve A.M. Gu S.G. Jantsch V. Fire A.Z. Baudrimont A. A Caenorhabditis elegans RNA-directed RNA polymerase in sperm development and endogenous RNA interference.Genetics. 2009; 183: 1297-1314Crossref PubMed Scopus (36) Google Scholar, Han et al., 2009Han T. Manoharan A.P. Harkins T.T. Bouffard P. Fitzpatrick C. Chu D.S. Thierry-Mieg D. Thierry-Mieg J. Kim J.K. 26G endo-siRNAs regulate spermatogenic and zygotic gene expression in Caenorhabditis elegans.Proc. Natl. Acad. Sci. USA. 2009; 106: 18674-18679Crossref PubMed Scopus (44) Google Scholar, Pavelec et al., 2009Pavelec D.M. Lachowiec J. Duchaine T.F. Smith H.E. Kennedy S. Requirement for the ERI/DICER complex in endogenous RNA interference and sperm development in Caenorhabditis elegans.Genetics. 2009; 183: 1283-1295Crossref PubMed Scopus (44) Google Scholar), also known as 26G RNA (Ruby et al., 2006Ruby J.G. Jan C. Player C. Axtell M.J. Lee W. Nusbaum C. Ge H. Bartel D.P. Large-scale sequencing reveals 21U-RNAs and additional microRNAs and endogenous siRNAs in C. elegans.Cell. 2006; 127: 1193-1207Abstract Full Text Full Text PDF PubMed Scopus (465) Google Scholar). This class of endo-siRNAs appears to be divided into at least two subclasses. One loads into the AGO proteins ALG-3 and ALG-4 (Conine et al., 2010Conine C.C. Batista P.J. Gu W. Claycomb J.M. Chaves D.A. Shirayama M. Mello C.C. Argonautes ALG-3 and ALG-4 are required for spermatogenesis-specific 26G-RNAs and thermotolerant sperm in Caenorhabditis elegans.Proc. Natl. Acad. Sci. USA. 2010; 107: 3588-3593Crossref PubMed Scopus (42) Google Scholar, Han et al., 2009Han T. Manoharan A.P. Harkins T.T. Bouffard P. Fitzpatrick C. Chu D.S. Thierry-Mieg D. Thierry-Mieg J. Kim J.K. 26G endo-siRNAs regulate spermatogenic and zygotic gene expression in Caenorhabditis elegans.Proc. Natl. Acad. Sci. USA. 2009; 106: 18674-18679Crossref PubMed Scopus (44) Google Scholar) and appears to function primarily in sperm to target genes active in spermatogenesis. The other subclass is associated with the AGO protein ERGO-1 (Gent et al., 2010Gent J.I. Lamm A.T. Pavelec D.M. Maniar J.M. Parameswaran P. Tao L. Kennedy S. Fire A.Z. Distinct phases of siRNA synthesis in an endogenous RNAi pathway in C. elegans soma.Mol. Cell. 2010; 37: 679-689Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar, Han et al., 2009Han T. Manoharan A.P. Harkins T.T. Bouffard P. Fitzpatrick C. Chu D.S. Thierry-Mieg D. Thierry-Mieg J. Kim J.K. 26G endo-siRNAs regulate spermatogenic and zygotic gene expression in Caenorhabditis elegans.Proc. Natl. Acad. Sci. USA. 2009; 106: 18674-18679Crossref PubMed Scopus (44) Google Scholar, Vasale et al., 2010Vasale J.J. Gu W. Thivierge C. Batista P.J. Claycomb J.M. Youngman E.M. Duchaine T.F. Mello C.C. Conte Jr., D. Sequential rounds of RNA-dependent RNA transcription drive endogenous small-RNA biogenesis in the ERGO-1/Argonaute pathway.Proc. Natl. Acad. Sci. USA. 2010; 107: 3582-3587Crossref PubMed Scopus (38) Google Scholar) and functions in both the soma as well as the germline. Apart from the 26G endo-siRNAs, there are also 22- to 23-nucleotide-long endo-siRNA that are produced by DCR-1, but the molecular characteristics of these have not yet been well defined (Welker et al., 2010Welker N.C. Pavelec D.M. Nix D.A. Duchaine T.F. Kennedy S. Bass B.L. Dicer's helicase domain is required for accumulation of some, but not all, C. elegans endogenous siRNAs.RNA. 2010; 16: 893-903Crossref PubMed Scopus (27) Google Scholar). Some RNAi pathways function independently of Dicer. For example, in C. elegans, a prominent population of endo-siRNAs is, most likely, derived directly from RNA-dependent RNA polymerase (RdRP) activity. That is, the RdRP makes short RNA transcripts that directly bind to AGO proteins (Aoki et al., 2007Aoki K. Moriguchi H. Yoshioka T. Okawa K. Tabara H. In vitro analyses of the production and activity of secondary small interfering RNAs in C. elegans.EMBO J. 2007; 26: 5007-5019Crossref PubMed Scopus (89) Google Scholar, Pak and Fire, 2007Pak J. Fire A. Distinct populations of primary and secondary effectors during RNAi in C. elegans.Science. 2007; 315: 241-244Crossref PubMed Scopus (267) Google Scholar, Sijen et al., 2007Sijen T. Steiner F.A. Thijssen K.L. Plasterk R.H. Secondary siRNAs result from unprimed RNA synthesis and form a distinct class.Science. 2007; 315: 244-247Crossref PubMed Scopus (204) Google Scholar). These small RNAs, known as 22G, are characterized by the presence of a triphosphate group at their 5′ end, possibly resulting from the first NTP residue used in their synthesis (Figure 1C). They are made in the soma, as well as in the germline, and almost any type of genomic locus, including genes, pseudogenes, transposons, and intergenic regions, can be a source of 22G RNA (Conine et al., 2010Conine C.C. Batista P.J. Gu W. Claycomb J.M. Chaves D.A. Shirayama M. Mello C.C. Argonautes ALG-3 and ALG-4 are required for spermatogenesis-specific 26G-RNAs and thermotolerant sperm in Caenorhabditis elegans.Proc. Natl. Acad. Sci. USA. 2010; 107: 3588-3593Crossref PubMed Scopus (42) Google Scholar, Gent et al., 2010Gent J.I. Lamm A.T. Pavelec D.M. Maniar J.M. Parameswaran P. Tao L. Kennedy S. Fire A.Z. Distinct phases of siRNA synthesis in an endogenous RNAi pathway in C. elegans soma.Mol. Cell. 2010; 37: 679-689Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar, Gu et al., 2009Gu W. Shirayama M. Conte Jr., D. Vasale J. Batista P.J. Claycomb J.M. Moresco J.J. Youngman E.M. Keys J. Stoltz M.J. et al.Distinct argonaute-mediated 22G-RNA pathways direct genome surveillance in the C. elegans germline.Mol. Cell. 2009; 36: 231-244Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar, Lee et al., 2006Lee R.C. Hammell C.M. Ambros V. Interacting endogenous and exogenous RNAi pathways in Caenorhabditis elegans.RNA. 2006; 12: 589-597Crossref PubMed Scopus (99) Google Scholar, Vasale et al., 2010Vasale J.J. Gu W. Thivierge C. Batista P.J. Claycomb J.M. Youngman E.M. Duchaine T.F. Mello C.C. Conte Jr., D. Sequential rounds of RNA-dependent RNA transcription drive endogenous small-RNA biogenesis in the ERGO-1/Argonaute pathway.Proc. Natl. Acad. Sci. USA. 2010; 107: 3582-3587Crossref PubMed Scopus (38) Google Scholar). Many different AGO proteins associate with these small RNAs. This has been directly demonstrated for WAGO-1, -6 and -8 (Gu et al., 2009Gu W. Shirayama M. Conte Jr., D. Vasale J. Batista P.J. Claycomb J.M. Moresco J.J. Youngman E.M. Keys J. Stoltz M.J. et al.Distinct argonaute-mediated 22G-RNA pathways direct genome surveillance in the C. elegans germline.Mol. Cell. 2009; 36: 231-244Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar, Yigit et al., 2006Yigit E. Batista P.J. Bei Y. Pang K.M. Chen C.C. Tolia N.H. Joshua-Tor L. Mitani S. Simard M.J. Mello C.C. Analysis of the C. elegans Argonaute family reveals that distinct Argonautes act sequentially during RNAi.Cell. 2006; 127: 747-757Abstract Full Text Full Text PDF PubMed Scopus (221) Google Scholar), NRDE-3 (Guang et al., 2008Guang S. Bochner A.F. Pavelec D.M. Burkhart K.B. Harding S. Lachowiec J. Kennedy S. An Argonaute transports siRNAs from the cytoplasm to the nucleus.Science. 2008; 321: 537-541Crossref PubMed Scopus (106) Google Scholar) and CSR-1 (Claycomb et al., 2009Claycomb J.M. Batista P.J. Pang K.M. Gu W. Vasale J.J. van Wolfswinkel J.C. Chaves D.A. Shirayama M. Mitani S. Ketting R.F. et al.The Argonaute CSR-1 and its 22G-RNA cofactors are required for holocentric chromosome segregation.Cell. 2009; 139: 123-134Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar), but also other WAGO proteins have also been suggested to bind 22G (Conine et al., 2010Conine C.C. Batista P.J. Gu W. Claycomb J.M. Chaves D.A. Shirayama M. Mello C.C. Argonautes ALG-3 and ALG-4 are required for spermatogenesis-specific 26G-RNAs and thermotolerant sperm in Caenorhabditis elegans.Proc. Natl. Acad. Sci. USA. 2010; 107: 3588-3593Crossref PubMed Scopus (42) Google Scholar, Gu et al., 2009Gu W. Shirayama M. Conte Jr., D. Vasale J. Batista P.J. Claycomb J.M. Moresco J.J. Youngman E.M. Keys J. Stoltz M.J. et al.Distinct argonaute-mediated 22G-RNA pathways direct genome surveillance in the C. elegans germline.Mol. Cell. 2009; 36: 231-244Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar, Yigit et al., 2006Yigit E. Batista P.J. Bei Y. Pang K.M. Chen C.C. Tolia N.H. Joshua-Tor L. Mitani S. Simard M.J. Mello C.C. Analysis of the C. elegans Argonaute family reveals that distinct Argonautes act sequentially during RNAi.Cell. 2006; 127: 747-757Abstract Full Text Full Text PDF PubMed Scopus (221) Google Scholar). Interestingly, most of these AGO proteins are not believed to trigger target cleavage, as they do not have all the residues required to be catalytically active, implying they employ different mechanisms to affect their targets. Another Dicer-independent pathway is the so-called Piwi-pathway (Malone and Hannon, 2009Malone C.D. Hannon G.J. 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• W2138841516 created "2016-06-24" @default.
• W2138841516 creator A5028745417 @default.
• W2138841516 date "2011-02-01" @default.
• W2138841516 modified "2023-10-18" @default.
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