Production and actions of
small RNAs
V. Narry Kim and Mikiko C. Siomi
Small (20–30 nt) RNAs are associated with members
of the Argonaute (Ago) family, which comprises two
subfamilies: Ago and Piwi. Based on their biogenesis
mechanism and the type of Argonaute proteins
that they associate with, at least three classes of
small RNAs can be distinguished in eukaryotes:
microRNAs (miRNAs), endogenous small interfering
MOLECULAR
CELL BIOLOGY
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RNAs (endo-siRNAs) and Piwi-interacting RNAs
(piRNAs). miRNAs control mRNA stability and
translation by targeting cognate mRNAs. endosiRNAs suppress repetitive genes by cleaving their
transcripts. Some piRNAs mediate RNA cleavage or
heterochromatin formation of transposons, although
the functions of most piRNAs are still unknown.
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The figure shows the mammalian processing pathways with fly components
in brackets. miRNAs are ssRNAs of ~22 nt that are generated from
transcripts that can fold into hairpin structures. Two RNase III type proteins,
Drosha and Dicer, mediate nuclear and cytoplasmic processing, respectively,
thereby producing the miRNAs that subsequently associate with Agosubfamily proteins (AGO1–4 in humans). In flies, most miRNAs are loaded
onto AGO1, whereas miRNAs from highly base-paired precursors are sorted
into AGO2. exo-siRNAs are derived from experimentally introduced dsRNAs
or viral RNAs. Human exo-siRNAs are loaded onto AGO1–4, but only AGO2
has ‘slicer’ activity. endo-siRNAs are derived from cis or trans sense–
antisense dsRNAs or long hairpins. They are produced by Dicer and interact
with Ago-subfamily proteins. In humans, endo-siRNAs are thought to be
loaded onto AGO2; it has not been determined whether they associate with
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other Ago proteins. piRNAs (24–31 nt) are processed from ssRNA precursors
that are transcribed from transposons or large piRNA clusters. piRNAs
associate with Piwi-subfamily proteins; they are not dependent on either
Drosha or Dicer, although the requirement of Drosha has not been formally
tested. They may instead use the nuclease activity of the Piwi proteins
themselves for their processing. piRNA biogenesis involves primary and
secondary processing mechanisms. The strand bias of piRNAs in secondary
processing differs between mice and flies (for this reason, fly components are
not shown). Primary processing and loading might occur in the cytoplasm
because Piwi proteins MIWI and MILI are localized in the cytoplasm. Factors
that are needed for primary processing are unknown. Not shown here are less
abundant groups of miRNA-like RNAs that are derived from various sources
of short hairpins in a Drosha-independent manner.
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Table | Eukaryotic small RNAs are associated with Argonaute-family proteins
Subfamily
Mammals
Ago
Piwi
Ago-family protein
Class of small RNA*
Length of small RNA
Origin of small RNA‡
Mechanism of action
AGO1–4
miRNA
21–23 nt
miRNA genes
endo-siRNA§
Pre-pachytene piRNA and
pachytene piRNA
Pachytene piRNA
Pre-pachytene piRNA
?
21–22 nt
24–28 nt
Intergenic repetitive genes, pseudogenes and endo-siRNA clusters
Transposons and piRNA clusters
Translational repression, mRNA degradation, mRNA cleavage
and heterochromatin formation?
mRNA cleavage?
Heterochromatin formation (DNA methylation)
29–31 nt
27–29 nt
?
piRNA clusters
Transposons and piRNA clusters
?
?
Heterochromatin formation (DNA methylation)
?
miRNA
endo-siRNA
exo-siRNA
piRNA
piRNA
piRNA
21–23 nt
~21 nt
~21 nt
23–27 nt
24–27 nt
24–29 nt
miRNA genes
Transposons, mRNAs and repeats
Viral genome
Transposons, repeats, piRNA clusters and Su(Ste) locus
Transposons and repeats (unknown in testis)
Transposons, repeats and piRNA clusters
Translational repression and mRNA degradation
RNA cleavage
Viral RNA cleavage
RNA cleavage
RNA cleavage
Heterochromatin formation?
endo-siRNA
~21 nt
Outer centromeric repeats, mating-type locus and
subtelomeric regions
Heterochromatin formation
miRNA
endo-siRNA (tasiRNA including TAS3)
exo-siRNA
rasiRNA
miR-390
20–24 nt
21 nt
20–22 nt
24 nt
21 nt
miRNA genes
TAS genes
Viral genome
Transposons and repetitive elements
miRNA gene
mRNA cleavage and translational repression
mRNA cleavage
Viral RNA cleavage
Heterochromatin formation
Cleavage of TAS3 RNA
MILI (PIWIL2 in humans)
MIWI (PIWIL1 in humans)
MIWI2 (PIWIL4 in humans)
(PIWIL3 in humans)
Drosophila melanogaster
Ago
Piwi
AGO1
AGO2
AUB
AGO3
PIWI
Schizosaccharomyces pombe
Ago
Ago1
Arabidopsis thaliana||
Ago
AGO1
AGO4 and AGO6
AGO7
*Small RNAs that are the main partners of a given Ago protein are listed. ‡miRNAs, as a class, are expressed in all cell types, whereas endo-siRNAs and piRNAs are expressed abundantly in germline cells and contribute to germline development.
§
So far, only AGO2 has been shown to be required for endo-siRNAs. ||Plants have ten Ago proteins, but only those with known small RNA partners are shown.
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Abbreviations
Contact information
Ago, Argonaute; AUB, Aubergine; CCR4, C-C chemokine type 4; DGCR8,
DiGeorge syndrome critical region gene 8; DNMT, DNA methyltransferase;
dsRNA, double-stranded RNA; endo-siRNA; endogenous small interfering
RNA; exo-siRNA, exogenous small interfering RNA; H, histone;
HMT, histone methyltransferase; HP1, heterochromatin protein 1;
LOQS, Loquacious; m7G, 7-methylguanosine; Me, methyl; miRNA,
microRNA; nt, nucleotide; piRNA, Piwi-interacting RNA; Pol II, RNA
polymerase II; PACT, PKR-activating protein; pre-miRNA, precursor miRNA;
pri-miRNA, primary miRNA; rasiRNA, repeat-associated small interfering
RNA; ssRNA, single-stranded RNA; Su(Ste), Suppressor of Stellate; TAS, tasi
gene; tasiRNA, trans-acting siRNA; TRBP, HIV-1 TAR RNA-binding protein.
V. Narry Kim is at the School of Biological Sciences and Center for
National Creative Research, Seoul National University, Seoul, 151-742,
South Korea. | Mikiko C. Siomi is at Keio University School of Medicine,
35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, and at the Japan Science
and Technology Agency (JST), Core Research for Evolutional Science and
Technology (CREST), Saitama 332-0012, Japan.
e-mails: narrykim@snu.ac.kr; siomim@sc.itc.keio.ac.jp
Poster design by Vicky Askew, edited by Arianne Heinrichs,
copyedited by Simon Bishop. © 2009 Nature Publishing Group.
Kim, V. N., Han, J. & Siomi, M. C. Biogenesis of small RNAs in animals.
Nature Rev. Mol. Cell Biol. (doi:10.1038/nrm2608).
For further reading, see www.nature.com/nrm/posters/smallrnas
Linked review article
1/12/08 11:42:02