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First published online 20 February 2008
doi: 10.1242/dev.005629

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The growing catalog of small RNAs and their association with distinct Argonaute/Piwi family members

Thalia A. Farazi^1,2,*, Stefan A. Juranek^1,* and Thomas Tuschl^1,

¹ Howard Hughes Medical Institute, Laboratory of RNA Molecular Biology, The Rockefeller University, 1230 York Avenue, Box 186, New York, NY 10065, USA.
² Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.

View larger version (56K): [in this window] [in a new window]   Fig. 1. Phylogenetic tree and crystal structure of the Ago/Piwi proteins. (A) Phylogenetic tree of the Ago/Piwi protein family. Alignments were generated using ClustalW (http://www.ebi.ac.uk/Tools/clustalw/). The length of each branch represents an estimate of the genetic distance. The alignment was done using the PAZ domain (when present), the PIWI domain and the C terminus. The sequences are based mainly on published RefSeqs for PAZ/PIWI domain-containing proteins at PubMed (http://www.ncbi.nlm.nih.gov/sites/entrez). The Accession numbers of the sequences can be obtained from the authors. Asterisks indicate Ago/Piwi members with experimentally determined cleavage activity. The interacting classes of small RNAs are indicated next to their corresponding Ago/Piwi family members (evidence stems from biochemical and/or genetic experiments). Ago/Piwi family members are designated according to their affiliation to either the Ago protein family, the Class 3 protein family or the Piwi protein family. C. elegans Alg1, Alg2, T23D8.7, ZK757.3, T22B3.2 comprise the Ago family; PRG-1, PRG-2 comprise the Piwi family; Sago-1, Sago-2, PPW-1, R06C7.1, F55A12.1, PPW-2, F58G1.1, C06A1.4, R04A9.2, Y49F6A.1, T22H9.3, C16C10.3, CSR-1, M03D4.6, ZK1248.7, C14B1.7, C04F12.1 comprise the Class 3 family. Mammalian Ago proteins are also known as eIF2Cs (eukaryotic translation initiation factors). Mammalian Piwil1 is also known as Hiwi; Miwi or Riwi depending on the species (human or mouse or rat), Piwil2 is also known as Hili, and Piwil4 as Hiwi2. Cniwi is the Piwi protein in Podocoryne carnea, and Seawi is the Piwi member in the sea urchins Strongylocentrotus purpuratus and Paracentrotus lividus. (B) Ribbon diagram of the structure of the Aquifex aeolicus Piwi protein, showing its bilobed architecture. The functions of the protein domains are further discussed in the text.

View larger version (57K): [in this window] [in a new window]   Fig. 2. Biogenesis and mode of action of miRNAs. miRNA biogenesis in (A) animals and (B) plants. The red miRNA strand is the strand incorporated into the Ago effector complex. The blue miRNA strand, referred to as miRNA*, becomes degraded. Drosha acts as the RNase III in some animal nuclei, and nuclear Dicer as the RNase III in the plant nucleus, where it cleaves the pri-miRNA in two steps (1,2). The cytoplasmic RNase III in animals is Dicer. RNAse III enzymes usually partner with distinct double-stranded RNA-binding-domain-containing proteins (dsRBPs, in gold) in the nucleus. Following their export from the nucleus, miRNAs then associate with Ago. In animals, the AGO-containing miRNPs predominantly associate with GW182, a protein with glycine-tryptophan (GW) repeats that is required for P body integrity. The miRNA subsequently translationally represses its target and is then localized to P bodies. In plants, miRNAs predominantly function through target mRNA cleavage, which can also occur in animals (see text for more details). m7G, 5' methyl(7)G cap of target mRNA; me, 2'-O-methyl group on the 3' end of the RNA; miRNP, effector ribonucleoprotein complex that mediates translational repression or target mRNA cleavage directed by miRNAs; p, 5' phosphate group.

View larger version (86K): [in this window] [in a new window]   Fig. 3. Biogenesis of siRNAs and hcRNAs. (A) Biogenesis of different classes of siRNA (see text for more details). Endogenous siRNAs are transcribed in the nucleus, whereas exogenous siRNAs are either chemically synthesized or virally derived. siRNAs are further processed by RNase III enzymes, such as Dicer. tasiRNAs are specific to plants and, after initial cleavage by specific miRNAs (red) and complementary strand synthesis by the RNA-dependent RNA polymerase (RdRp) RDR6, are processed by the Dicer DCL4. They are then phosphorylated (P) and subsequently methylated (me) by the RNA methyltransferase HEN1. In C. elegans and plants, secondary siRNAs participate in a signal amplification loop. In plants, the cleaved mRNA is converted into dsRNA by a RdRP, and is further processed by Dicer (the RNase III in green). In C. elegans, secondary siRNAs have a 5' di- or triphosphate group and associate with Class 3 Ago/Piwi protein members, Sago-1/Sago-2, leading to target mRNA (black) cleavage. (B) Biogenesis of hcRNAs (see also text for more details). In the yeast S. pombe and in plants, hcRNAs are processed by RNase III enzymes. In S. pombe, hcRNAs associate with Ago1 and form the RNA-induced transcriptional gene silencing (RITS) complex, which participates in RNA-directed RNA polymerase complex (RDRC) formation and histone (gray circles) methylation. In plants, hcRNAs form a complex with AGO4, which participates in DNA methylation. Chp1, chromodomain protein 1; Clr4, cryptic loci regulator 4; Cid12, caffeine induced death protein; DRD1, defective in RNA-directed DNA methylation 1 (an SNF2-like chromatin remodeling protein); DRM2, domain rearranged methyltransferase 2; Hrr1, a helicase required for RNAi-mediated heterochromatin assembly; Rdp1, RNA-directed RNA polymerase 1; Tas3, targeting complex subunit 3.

View larger version (37K): [in this window] [in a new window]   Fig. 4. Biogenesis of piRNAs and rasiRNAs. (A) Biogenesis of piRNAs. In mammals, piRNAs are likely to be processed from single-stranded (ss)RNA precursors, and are further processed by as yet undefined endonucleases (green) before being methylated (me) by methyltransferases. They associate with members of the Piwi subfamily to participate in transposon control and/or other germline-specific functions. (B) Biogenesis of D. melanogaster rasiRNAs/piRNAs. In D. melanogaster, rasiRNAs/piRNAs are also likely to be derived from ssRNA precursors and are further processed by endonucleases (green), including specific members of the Piwi subfamily (as shown in C), before being methylated (me) by methyltransferases. They associate with the Piwi subfamily to participate in histone methylation. Su(var)205 (suppressor of variegation 205) is a heterochromatin-associated protein. (C) Ping-Pong model of D. melanogaster piRNA biogenesis. After the piRNA-directed cleavage of transposon mRNA (piRNA in red; transposon mRNA in black and blue) by the Piwi family member Aubergine (AUB), the resulting blue strand (sense to the transposon mRNA) associates with AGO3, to guide cleavage of the rasiRNA cluster transcript (black and red) that produces additional piRNAs.

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