Svetlana, et al 2008. Origins and evolution of eukaryotic RNA interference..pdf

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Review Origins and evolution of eukaryotic RNA interference Svetlana A. Shabalina and Eugene V. Koonin National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD 20894, USA Small interfering RNAs (siRNAs) and genome-encoded degradation of exogenous (e.g. viral) double-stranded microRNAs (miRNAs) silence genes via complementary (ds)RNAs or transcr
  Origins and evolution of eukaryoticRNA interference Svetlana A. Shabalina and Eugene V. Koonin National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD 20894,USA Small interfering RNAs (siRNAs) and genome-encodedmicroRNAs (miRNAs) silence genes via complementaryinteractions with mRNAs. With thousands of miRNAgenes identified and genome sequences of diverseeukaryotes available for comparison, the opportunityemerges for insights into the origin and evolution ofRNA interference (RNAi). The miRNA repertoires ofplants and animals appear to have evolved indepen-dently. However, conservation of the key proteinsinvolved in RNAi suggests that the last common ances-torofmoderneukaryotespossessedsiRNA-basedmech-anisms. Prokaryotes have an RNAi-like defense systemthat is functionally analogous but not homologous toeukaryotic RNAi. The protein machinery of eukaryoticRNAiseemstohavebeenpiecedtogetherfromancestralarchaeal, bacterial and phage proteins that are involvedin DNA repair and RNA processing.The miRNA and siRNA machinery Recent transcriptome analyses have shown that most of the eukaryotic genome is transcribed [1,2], and the gen-omes of all cellular life forms, in addition to protein-coding genes, contain varying numbers of non-protein-coding RNA  [3,4]. MicroRNAs (miRNAs) are an abundant classof small (21 – 22 nucleotides) non-protein-coding RNAs thatregulate translation in eukaryotes [5]. miRNAs are key components of a major, evolutionarily conserved system of gene regulation in plants and animals that typically post-transcriptionally downregulates gene expression either by inducing degradation of the target mRNAs, or by blocking their translation [6,7]. miRNA-mediated pathways belong to a vast network of regulatory systems known as RNA interference (RNAi) [4,8]. RNAi consists of three majorbranches. These branches are small interfering (si)RNA-mediated pathways and miRNA-based pathways that areinvolved, respectively, in defense against viruses andtransposableelementsandinregulationofeukaryoticgeneexpression, and the Piwi-interacting (pi)RNA pathway that appears to be mechanistically distinct from the othertwo pathways [9].There are two key differences between miRNA- andsiRNA-mediated systems:(i) miRNAs are endogenous non-protein-coding RNA molecules that are encoded by their own, distinctgenes; by contrast, there are no dedicated genes forsiRNAs. Instead, siRNAs are either generated by degradation of exogenous (e.g. viral) double-stranded(ds)RNAs or transcribed from transposable elementsintegrated in the genome, or from other types of inverted repeats; and(ii) siRNAs are fully complementary to their targets,whereas miRNAs, at least in animals, show limitedcomplementarity to their recognition sites. Although the structures and mechanisms of animal andplant miRNAs differ substantially, the same or homolo-gous key proteins are involved both in miRNA biogenesisand in the siRNA pathways, suggesting that animal andplantmiRNAsderivefrom thesame,ancestralproto-RNAisystem but subsequently evolved along widely differenttrajectories so that the extant repertoires of miRNAs areunrelated.Prokaryoteshave noRNAisystems homologousto the eukaryotic ones, but seem to possess an indepen-dently evolved, analogous defense mechanism. However,apparentancestorsofthekeyproteincomponentsofeukar-yotic RNAi can be identified among prokaryotic proteinsinvolved in other processes.Here we discuss the srcin and evolution of RNAi sys-tems and miRNAs, with an emphasis on their deep eukar-yotic roots and prokaryotic connections. We reviewevidence on conservation of the key proteins involved in Review Glossary  Bilaterians : members of the animal kingdom exhibiting bilateral symmetry(two similar sides with definite upper and lower surfaces and anterior andposterior ends). Dicer : ribonuclease that produces   22 nucleotide long mature miRNAscontaining 5 0 phosphate and 3 0 hydroxy termini. Drosha : nuclear endonuclease that cuts stem-loop precursor miRNAs fromprimary miRNA (pri-miRNA) transcripts in animals. microRNAs : (miRNAs): an abundant class of small (21 – 22 nucleotide) non-protein-coding RNAs that regulate translation in eukaryotes. Mirtrons : pre-miRNAs that are located in introns of different genes andprocessed first by the pre-mRNA splicing machinery in the nucleus, rather thanDrosha, and then by Dicer in the cytoplasm. piRNAs : Piwi-interacting RNAs, 24 – 30 nucleotide long RNAs found in germcells of animals. piRNAs are unique among small silencing RNAs in that theyrequire neither an RdRP nor Dicer for their production. RNAi : RNA interference, a mechanism that inhibits gene expression at thestage of translation or transcription of specific genes. RNAi consists of twomajor branches, namely siRNA-mediated gene-silencing and miRNA-basedpathways that are involved, respectively, in defense against viruses andtransposable elements, and in regulation of eukaryotic gene expression. Seed complementarity : complementarity of the target to nucleotides 2 – 7 of miRNA. siRNAs : small interfering RNAs that are involved in the defense response toalien nucleic acids (e.g. primary antiviral defense) and are fully complementaryto their targets. Slicer : ribonuclease of the Ago family that cleaves target mRNA in siRNApathways. Corresponding authors:  Shabalina, S.A. (;Koonin, E.V. ( 578  0169-5347/$  –  see front matter. Published by Elsevier Ltd. doi:10.1016/j.tree.2008.06.005 Available online 18 August 2008  RNAi suggesting that the last common ancestor of moderneukaryotes (LECA) already possessed siRNA-based mech-anisms, and implying that miRNA-like regulation inplants and metazoans evolved before the divergence of these two distinct types of multicellular life. Origin and evolution of eukaryotic RNA interferencesystems The staggering complexity of RNAi phenomena notwith-standing, there are only three key proteins involved inRNAi, namely Ago-Piwi, Dicer-like protein that typically consists of RNase III and helicase domains, and RNA-dependent RNA polymerase (RdRP). The diversity of RNAi-related complexes and pathways is created by multiple paralogous forms of these proteins that emerged vianumerousduplicationsatdifferentstagesofeukaryoticevolution, along with several accessory proteins (Table 1;Figure1)[8].Thesethreekeycomponentsarepresentinat least some members of four of the five supergroups of eukaryotes. Notably, excavates either lack Dicer homologsor possess Dicer-like proteins that lack either the helicasecomponent or the tandem RNase III portion (Table 1) [10]. The existence of RNAi in most of the excavates remains anopen question [11], but considering the ‘star phylogeny’ of thefivesupergroupsthatisthecurrentbestapproximationof early eukaryotic evolution [12], it appears most likely that a functional RNAi system containing, at least, thesethree proteins antedates the last common ancestor of theextant eukaryotes [13]. Moreover, members of the ancientparalogous pair Ago-Piwi show a scattered distribution infour eukaryotic supergroups (Table 1) [8,14], suggesting  that, multiple losses during subsequent evolution notwith-standing, this duplication antedates the radiation of thesupergroups. Thus, LECA might have had the capacity forsmall-RNA-mediated gene silencing both at the level of translation (which involves Ago) and at the level of tran-scription (which involves Piwi).Considering the major difference in the miRNA struc-turesinplantsandanimals(Box1),itseemslikelythattheancestral RNAi system functioned, primarily, in defenseagainst viruses (via cytoplasmic, Ago-centered pathways)and transposons (via nuclear, Piwi-based pathways) [15 – 18]. The notion that the ancestral RNAi primarily had adefense function is further supported by the inference thatLECA possessed RdRP, because in extant eukaryotes theRdRP is primarily involved in siRNA amplification but notin miRNA pathways [19,20]. The defense role of RNAi iswidely conserved among eukaryotes but, in addition, dis-tinct miRNA pathways appear to have evolved in animalsand plants, and perhaps in fungi as well. An intriguing  Table 1. Distribution of RNAi machinery components in the five supergroups of eukaryotes a Argonaute-Piwi-likeSpecies Argonaute Piwi Dicer-like RdRP miRNAs (Rfam v10)Excavata Giardia intestinalis     1 (1) No helicase domain; might notbe Dicer ortholog1   Trypanosoma brucei   1 1 (1) Dicer-like helicase only    Trypanosoma cruzi        Leishmania major        Leishmania braziliensis     1     Chromalveolata Paramecium tetraurelia     4 2 (Dcr1p without helicase domain) 2   Tetrahymena thermophila     4 2 (Dcr1p without helicase domain) 1   Plasmodium falciparum       Phytophthora infestans   1    ? ?   Thalassiosira pseudonana        Archaeplastida Cyanidioschyzon merolae       Chlamydomonas reinhardtii   4    3    + Arabidopsis thaliana   10    4 6 + Oryza sativa (japonica)   18    5 5 + Unikonta Dictyostelium discoideum    4 2 (No helicase domain) 3 (2 fused toDicer-like helicase) Entamoeba histolytica     3    1   Saccharomyces cerevisiae        Schizosaccharomyces pombe   1    1 1   Neurospora crassa   2    3 3   Aspergillus nidulans   1    2 2   Caenorhabditis elegans  b 5 3 2 (Dicer + Drosha) 4 + Drosophila melanogaster   2 3 3 (2 Dicers + Drosha)    + Strongylocentrotus purpuratus   1 1 2 (Dicer + Drosha)    Danio rerio   4 4 2 (Dicer + Drosha)    + Homo sapiens   4 4 2 (Dicer + Drosha)    + a The number of detectable paralogs in each genome is indicated; the data are from Refs [8,14] (Argonaute-Piwi) and additional BLASTP searches (for species that encode asingle version of the respective protein or no more than four paralogs, all sequences were used as queries to search the NCBI nonredundant protein sequence database; forspecies with more than four paralogs, 2 – 3 representative sequences were used). b In addition, the nematode genome encodes a large family of highly derived Argonaute proteins, the Argonaute group 3 [58]. Review  Trends in Ecology and Evolution   Vol.23 No.10 579  question remains as to whether or not LECA also pos-sessed proto-miRNAs, and if it did, what the structure andmechanism of these were.Several lineages of unicellular eukaryotes from differ-ent supergroups, namely   Saccharomyces cerevisiae  (Uni-konta),  Trypanosoma cruzi  and  Leishmania major  (Excavata),  Cyanidioschyzon merolae  (Archaeplastida)and  Plasmodium falciparum  (Chromalveolata), appearto have lost the RNAi machinery independently and com-pletely. This supports the notion that, however prominentas a defense and regulatory mechanism, RNAi is nones-sential in eukaryotes, specifically in unicellular forms [8].In many multicellular eukaryotic lineages, RNAi seems tohave become essential (as evidenced by the embryoniclethality of Dicer mutants) owing to the involvement of miRNAs in developmental gene regulation [21]. Origin of the key proteins Ago-Piwi, Dicer and RdRP  There seems to be no prokaryotic ancestor of eukaryoticRNAi as a functional system. However, prokaryotic homo-logsofthethreekeyproteinsofeukaryoticRNAihavebeenidentified. These proteins show a peculiar gamut of archaeal and bacterial connections (Table 2). The twoenzymatic domains of Dicer, namely RNase III and Super-family II RNA helicase, are common in prokaryotes, buttheir combination in a single protein is a eukaryotic sig-nature that is shared by all eukaryotic supergroups. Thehelicase domain of Dicer is specifically related to thearchaeal family of Superfamily II helicases (Hef proteins)[22]. Archaeal Hef proteins have been shown to play animportant role in DNA replication [23,24]. By contrast, theRNase III domain, the nuclease domain of Dicer, is mostly of bacterial provenance. In bacteria, RNase III is involved Figure 1 . A scenario for the srcin and earliest stages of evolution of eukaryotic RNAi protein machinery. The scenario is based on the symbiotic model of eukaryotic cellsrcin [60]. Domains are depicted by unique shapes; proteins are not shown to scale. Arrows denote inferred derivation of the coding regions for proteins or (in the case of Dicer) individual domains from homologous sequences residing in the genomes of the postulated archaea-related host, the proto-mitochondrial ( a -proteobacterial)endosymbiont and a bacteriophage. Considering the spread of protein involved in RNAi among the eukaryotic supergroups (Table 2), the assembly of Dicer from domainsof distinct srcins and the duplication of Argonaute that produced Ago and Piwi are mapped to the ’stem’ phase of eukaryotic evolution (between the symbiosis event that isassumed here to have triggered eukaryogenesis and the radiation of the supergroups that is shown as a multifurcation in the upper part of the figure as per Ref. [12]). Thedashed arrow shows the likely derivation of the PAZ domain of Dicer from Piwi subsequent to Argonaute duplication [8]. Evolution of the eukaryotic supergroups involvedmultiple duplications and losses of key components of RNAi that are not elaborated on in the figure (see Table 1 and Refs [8,13,14]). Review  Trends in Ecology and Evolution   Vol.23 No.10 580  in essentialreactionsofrRNAprocessing aswellasmRNA degradation [25]. Conceivably, fusion of the helicase andRNase III domains from different sources was one of thepivotal, early events that led to the consolidation of theeukaryotic RNAi system.The second key protein, Ago, also displays apparentarchaeal roots, because archaeal Ago homologs seem tobe more closely related to eukaryotic Ago than bacterialhomologs are [26]. The biological functions of the archaealand bacterial Ago homologs remain unclear, althoughthere is some evidence to suggest that they are involvedin chromatin remodeling  [27,28]. Ultimately, Ago proteinsprobably srcinated from basal DNA replication machin-ery, as suggested by the structure of the RNase (Slicer)domain which possesses a derived RNase H fold. Thepresence of multiple Ago-Piwi paralogs in metazoaindicates that animals possess multiple RNA-inducedsilencing complexes (RISC) that carry out related but Box 1. Plant and animal miRNAs In animals, miRNA genes mostly reside within introns of annotatedgenes and often form clusters that can be transcribed as a singleprimary transcript [69]. The majority of plant miRNAs are producedfrom individual transcription units that are located in intergenicregions [70]. In both animals and plants, the mechanism throughwhich miRNAs are generated is dictated by the highly conservedsecondary structures of their transcripts that form stable imperfectlypaired hairpins. These hairpins are processed by RNAi machinery intomiRNA precursor duplexes [6,71]. The miRNA duplex has essentiallythe same structure as a double-stranded siRNA [64,72 – 74], except thatthe mature miRNA strand is only partially paired to the complemen-tary miRNA* strand.Processing of miRNA precursors is mediated by proteins of the Dicerfamily that contain a helicase domain and two tandem RNase IIIdomains [75]. miRNA-processing pathways vary in plants and animalsin multiple aspects (see Table I and Figure I). Plants lack an ortholog of  Drosha that is predominantly localized in the nucleus in animals (seeFigure I). Instead, it is thought that the function of Drosha is carried outby one or more of the specialized Dicer paralogs found in plants.However, Drosha-mediated cleavage is not the only way to producecanonical pre-miRNA hairpins in animals. An alternative pathwayutilizes splicing of suitable RNAs transcribed from introns (mirtrons)that mimic the structural features of pre-miRNAs and enter themiRNA-processing pathway without Drosha-mediated cleavage(Figure Ia). This pathway has been identified in flies, worms [62,63] and mammals [76,77]. The evolutionary conservation of mammalianmirtrons suggests that mirtrons were incorporated into endogenousregulatory pathways at a very early stage. Thus, there seems to be adirect link between the evolution of introns and the evolution of miRNAs. Given that the positions of numerous introns have beenconserved throughout the evolution of eukaryotes [78] and massiveintron invasion is thought to be one of the pivotal events of eukaryotegenesis [60], it seems plausible that mirtrons were already opera-tional in LECA.The miRNA:miRNA* duplex is further processed in the cytosol bythe RNA-induced silencing complex (RISC). The RISC directs genesilencing in both miRNA and siRNA pathways in plants and animals,although the subunit compositions of the miRNA-specific and siRNA-specific RISCs differ (Figure I). The common features of miRNAs andsiRNAs in plants suggest that complex RNA-silencing systemsevolved before multicellularity and were a feature of primitiveeukaryotic cells [79].Plant miRNAs are almost perfectly complementary to their mRNAtargets. By contrast, the complementarity between animal miRNAsand their targets is usually much lower and restricted to the 5 0 coremiRNA region and, in some cases, an additional region in the 3 0 partof the miRNA that compensates for imperfect core pairing [80]. Thedegree of complementarity between miRNAs and their targetsdetermines, at least in part, the regulatory mechanism (cleavageversus translation repression). Table 2. The prokaryotic connections of the key components of the eukaryotic RNAi machinery Protein Taxonomic range of homologsin prokaryotesClosest archaeal homolog(E-value, % identity)Closest bacterial homolog(E-value, % identity)Functions of prokaryotichomologs (Ref.) Dicer helicase a All archaea; no bacteria (onlydistantly related helicases withstatistically insignificantsimilarity)ERCC4-like helicase (Hef),uncultured crenarchaeote31-F-01 (5e-19; 24%)No significant similarity Resolution of stalledreplication forks [23]Dicer-RNase III a Several mesophilic archaea;all bacteriaRNase III,  Methanococcus maripaludis   S2 (9e-14; 25%)RNase III,  Mannheimia haemolytica   PHL213(1e-14; 27%)rRNA and mRNA processing[25]Argonaute b Scattered distribution amongarchaea and bacteria (mostly,in cyanobacteria)No significant similarity No significant similarity No direct evidence; prokaryoticPiwi-domain proteins are DNA-guided RNA endonucleases, sothought to participate inchromatin remodeling [27,59]Piwi c Homolog of the eukaryoticArgonaute protein, implicatedin translation or RNA processing, Methanopyrus kandleri   AV19(0.14, 24%); limited sequenceconservation only inPiwi domainNo significant similarityRdRP d Bacteriophages and prophagesfrom diverse bacteria;uncharacterized cyanobacterialproteins (possibly, prophage-derived)No significant similarity Hypothetical DNA-directedRNA polymerase, Bacillusphage 0305phi8 – 36 (1e-14,14%, detected in secondPSI-BLAST iteration)Putative DNA-dependent RNApolymerases a The Human Dicer protein sequence (Q9UPY3.2) was employed as the query for searching the NCBI nonredundant protein sequence database using BLASTP. b The Human Argonaute protein sequence (NP_036331) was used as the query. c The Human Piwi-like protein sequence (Q96J94) was used as the query. d The  C. elegans   RdRP sequence (CAA91312) was used as the query. Review  Trends in Ecology and Evolution   Vol.23 No.10 581
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