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How Does the Royal Family of Tudor Rule the PIWI-Interacting RNA Pathway?

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How Does the Royal Family of Tudor Rule the PIWI-Interacting RNA Pathway? Downloaded from genesdev.cshlp.org on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press REVIEW How does the Royal Family of Tudor rule the PIWI-interacting RNA pathway? Mikiko C. Siomi,1,2,3 Taro Mannen,1 and Haruhiko Siomi1,3 1Keio University School of Medicine, Tokyo 160-8582, Japan; 2Japanese Science and Technology Agency, Core Research for Evolutional Science and Technology, Saitama 332-0012, Japan PIWI (P-element-induced wimpy testis) proteins are and Simard 2008). Each Argonaute member falls into one a subset of the Argonaute proteins and are expressed of two subgroups: the AGO and PIWI (P-element-induced predominantly in the germlines of a variety of organisms, wimpy testis) subfamilies (Farazi et al. 2008). Expression including Drosophila and mammals. PIWI proteins asso- of AGO members is ubiquitous, whereas PIWI proteins ciate specifically with PIWI-interacting RNAs (piRNAs), are detected predominantly in germline cells (Farazi et al. small RNAs that are also expressed predominantly in 2008). Depletion of AGO functions often causes develop- germlines, and silence transposable DNA elements and mental defects; for example, Ago2-null mice show em- other genes showing complementarities to the sequences bryonic lethality (Liu et al. 2004), while PIWI mutants of associated piRNAs. This mechanism helps to main- show defects in gametogenesis, but otherwise develop tain the integrity of the genome and the development of normally (Cox et al. 1998; Harris and Macdonald 2001; gametes. PIWI proteins have been shown recently to Deng and Lin 2002; Kuramochi-Miyagawa et al. 2004; contain symmetrical dimethyl arginines (sDMAs), and Carmell et al. 2007; Li et al. 2009). this modification is mediated by the methyltransferase AGO proteins associate with microRNAs (miRNAs), PRMT5 (also known as Dart5 or Capsuleen). It was then ubiquitously expressed small RNAs that function in RNA demonstrated that multiple members of the Tudor (Tud) silencing (Kim et al. 2009). In Drosophila, endogenous family of proteins, which are necessary for gametogene- siRNAs (endo-siRNAs) are also ubiquitous, and associate sis in both flies and mice, associate with PIWI proteins with AGO proteins (predominantly with AGO2). Further- specifically through sDMAs in various but particular more, exo-siRNAs (siRNAs exogenously introduced into combinations. Although Tud domains in Tud family cells to artificially induce RNAi) also associate with AGO members are known to be sDMA-binding modules, in Drosophila and mice (Siomi and Siomi 2009). PIWI involvement of the Tudor family at the molecular level proteins associate specifically with PIWI-interacting in the piRNA pathway has only recently come into focus. RNAs (piRNAs) in germline cells, although endo-siRNAs and/or miRNAs are coexpressed with piRNAs in these Argonaute (AGO) proteins associate with small noncod- cells (Kim et al. 2009). Thus, loading of different kinds of ing RNAs of 20–30 nucleotides (nt) to negatively regulate small RNAs onto individual Argonaute proteins is consid- the expression of genes targeted by the Argonaute–small ered to be a ‘‘molecule-specific’’ event. RNA complexes (Siomi and Siomi 2009). In this mecha- piRNAs have been studied extensively with regard to nism, termed RNA silencing, genes silenced by the their biogenesis, characteristics, and functions, especially in catalytic activities of Argonaute proteins are involved in Drosophila, fish, nematodes, and mice (in Caenorhabditis fundamental cellular processes, such as development, elegans, piRNAs are known as 21U RNAs) (Aravin et al. differentiation, metabolism, and apoptosis (Kim et al. 2006; Girard et al. 2006; Grivna et al. 2006; Ruby et al. 2006; 2009). Thus, Argonaute proteins are essential for many, Saito et al. 2006; Vagin et al. 2006; Watanabe et al. 2006; if not all, living organisms (Bartel 2009; Malone and Brennecke et al. 2007; Gunawardane et al. 2007; Houwing Hannon 2009; Voinnet 2009). et al. 2007; Batista et al. 2008; Das et al. 2008). piRNAs The number of Argonaute family members in a species are longer than miRNAs and endo-siRNAs by several bases; differs; for example, Schizosaccharomyces pombe has for example, in Drosophila, piRNAs range between 24 and only one Argonaute, while Drosophila and humans 30 nt, while miRNAs and endo-siRNAs are ;20–23 nt long. possess five and eight members, respectively (Hutvagner In addition, piRNAs contain 29-O-methyl groups at their 39 ends, unlike miRNAs (except in plants) (Horwich et al. 2007; Houwing et al. 2007; Kirino and Mourelatos 2007; [Keywords: PIWI; PRMT5; RNA silencing; Tudor; piRNA; sDMA] Ohara et al. 2007; Saito et al. 2007). piRNAs are derived 3Corresponding authors. mostly from repetitive intergenic DNA elements, includ- E-MAIL [email protected]; FAX 81-3-53633266. ing transposons, and these loci are collectively called Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1899210. Freely available online through the Genes & Development Open Access ‘‘piRNA clusters’’ (Aravin et al. 2007a). Protein-codinggenes option. such as traffic jam (tj) could also account for piRNA 636 GENES & DEVELOPMENT 24:636–646 Ó 2010 by Cold Spring Harbor Laboratory Press ISSN 0890-9369/10; www.genesdev.org Downloaded from genesdev.cshlp.org on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press Tudor in the piRNA pathway production (Robine et al. 2009; Saito et al. 2009). Because of sequencing analyses of small RNAs in piRNA-related these features, and considering their limited expression in mutants also provided strong evidence for an Aub– germlines and their specific associations with PIWI pro- AGO3-independent piRNA pathway in somatic cells in teins, piRNAs are considered to be a unique set of endoge- ovaries (Li et al. 2009; Malone et al. 2009). The require- nous small RNAs. ment for MILI and MIWI2 in the mouse somatic primary Loss of PIWI proteins in Drosophila and mice causes processing pathway remains undetermined. Factors nec- derepression of transposons and results in severe defects essary for primary piRNA processing may include in gametogenesis (Vagin et al. 2006; Carmell et al. 2007; Zucchini (Zuc), a putative cytoplasmic nuclease, because Kuramochi-Miyagawa et al. 2008; Li et al. 2009). As loss of Zuc function caused a severe reduction in the ex- a result, the homozygous mutant lines cannot be main- pression levels of primary piRNAs, such as flam-origina- tained. Deletion of a Drosophila piRNA cluster, flamenco ting piRNAs (in ovaries) (Malone et al. 2009) and tj-origi- (flam), located on the X chromosome, also causes de- nating piRNAs (in OSCs) (Saito et al. 2009). dicer mutant repression of particular transposons, such as gypsy, ZAM, ovaries accumulate piRNAs, similarly to wild-type ova- and Idefix (Prud’homme et al. 1995; Desset et al. 2003; ries (Vagin et al. 2006). Dicer-independent piRNA pro- Me´vel-Ninio et al. 2007), because flam gives rise to duction was also observed in zebrafish (Houwing et al. piRNAs that show strong complementarities to tran- 2007). Thus, it seems that both the amplification loop and scripts from these transposons (Brennecke et al. 2007). primary processing pathways for piRNA production These studies have made it very clear that both PIWI do not require Dicer. Other genes—such as Armitage, proteins and piRNAs are required for transposon silenc- Spindle E (Spn-E), Maelstrom, Krimper, Vasa, and ing. Targets of PIWI–piRNA complexes are not limited to Squash—might be involved in piRNA biogenesis (Vagin transposons. In fact, a subset of piRNAs in Drosophila has et al. 2006; Lim and Kai 2007; Pane et al. 2007). However, been shown to function in silencing protein-coding genes. the molecular details of the requirement of these genes in The best examples are piRNAs derived from suppressor of piRNA biogenesis remain unclear. stellate [su(ste)] and tj, which down-regulate protein- A recent study has shown that PIWI proteins in coding stellate (ste) and fasciclin III (fas III) genes, Drosophila, mice, and Xenopus contain sDMAs (sym- respectively (Livak 1984; Aravin et al. 2001, 2004; Vagin metrical dimethyl arginines), and that the factor mediat- et al. 2006; Nishida et al. 2007; Saito et al. 2009). ing this post-translational modification is PRMT5 (Kirino In Drosophila, AGO3 (Argonaute3), Piwi , and Aub et al. 2009). sDMA is one of various methyl group mod- (Aubergine) belong to the PIWI protein family, while in ifications found on specific arginines in protein molecules mice, MILI, MIWI, and MIWI2 belong to the mouse PIWI (Bedford and Clarke 2009). sDMA is known to modify the family (Siomi and Siomi 2009). Bioinformatic analyses of ability of a protein to perform its biological activities. For piRNAs that associate with PIWI proteins in both Dro- example, Sm proteins, factors needed for splicing machin- sophila and mice germlines have led to two models for ery, contain sDMAs in their arginine–glycine-rich (RG) piRNA biogenesis: the amplification loop pathway (also domains and associate, through their sDMAs, with a Tud termed the Ping-Pong pathway) and the primary process- domain-containing protein, SMN (Survival motor neuron) ing pathway (Aravin et al. 2007a; Siomi and Siomi 2009). protein (Brahms et al. 2001; Friesen et al. 2001). This Sm– Observations in Drosophila support the concepts that, in SMN association recruits U snRNA, leading to the the amplification loop pathway, Aub (mainly associated efficient assembly of U snRNP (Meister et al. 2002). This with antisense piRNAs, which show a preference for whole system serves as a ‘‘gatekeeper’’ that prevents the a uracil [U] at the 59 end) and AGO3 (mainly associated misassembly of Sm proteins to nontarget RNA and also with sense piRNAs, which show a preference for an prevents Sm protein aggregation (Pellizzoni et al. 2002; adenine [A] at position 10) reciprocally cleave target Chari et al. 2008). Other Tud family members interact RNAs in sense and antisense orientations, respectively, with particular proteins through methylated arginines in and that this reciprocal target RNA cleavage by Aub and the target proteins and to regulate their functions (Coˆte´ AGO3 constantly gives rise to abundant piRNAs in and Richard 2005).
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