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Biogenesis of small RNAs in animals

Key Points

  • Recent progress in high-throughput sequencing has uncovered an astounding landscape of small RNAs in eukaryotic cells. Various small RNAs of distinctive characteristics have been found and can be classified into three classes based on their biogenesis mechanism and the type of Argonaute (Ago) protein that they are associated with.

  • MicroRNAs (miRNAs) are generated from local hairpin structures by the action of two RNase III-type proteins, Drosha and Dicer. Mature 22-nucleotide (nt) miRNAs are then bound by Ago-subfamily proteins. miRNAs target mRNAs and thereby function as post-transcriptional regulators.

  • Piwi-interacting RNAs (piRNAs), which are 24–31 nt in length, are associated with Piwi-subfamily proteins. The biogenesis of piRNAs does not depend on Dicer. At least some piRNAs are involved in transposon silencing through heterochromatin formation or RNA destabilization.

  • Endogenous small interfering RNAs (endo-siRNAs), such as miRNAs, associate with Ago-subfamily proteins. However, endo-siRNAs differ from miRNAs in that they are derived from long double-stranded RNAs and are dependent only on Dicer but not on Drosha. They are also slightly shorter (21 nt) than miRNAs. At least some of the endo-siRNAs have been shown to function as post-transcriptional regulators that target RNAs.

  • There are numerous other small RNAs that are generated through non-canonical pathways. Many of them are difficult to classify and their biogenesis pathways remain poorly understood, but they may have species-specific functions that are not yet fully appreciated.

Abstract

Small RNAs of 20–30 nucleotides can target both chromatin and transcripts, and thereby keep both the genome and the transcriptome under extensive surveillance. Recent progress in high-throughput sequencing has uncovered an astounding landscape of small RNAs in eukaryotic cells. Various small RNAs of distinctive characteristics have been found and can be classified into three classes based on their biogenesis mechanism and the type of Argonaute protein that they are associated with: microRNAs (miRNAs), endogenous small interfering RNAs (endo-siRNAs or esiRNAs) and Piwi-interacting RNAs (piRNAs). This Review summarizes our current knowledge of how these intriguing molecules are generated in animal cells.

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Figure 1: Genomic location and gene structure of miRNAs.
Figure 2: miRNA biogenesis pathway.
Figure 3: piRNA biogenesis pathway.
Figure 4: Exo- and endo-siRNA biogenesis pathway.

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Acknowledgements

We are grateful to H. Siomi, T. Watanabe, Y. Watanabe and S. Kuramochi-Miyagawa for helpful discussions and comments. This work was supported by the Creative Research Initiatives Program (V.N.K.), the BK21 Research Funds from the Ministry of Education (J.H.) from Science and Technology of Korea, New Energy and Industrial Technology Development Organization (NEDO) grants (M.C.S.) and Core Research for Evolutionary Science and Technology (CREST) from the Japan Science and Technology Agency (JST) (M.C.S.). M.C.S. is Associate Professor of Global COE for Human Metabolomics Systems Biology by the Ministry of Education, Culture, Science and Technology, Japan.

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Correspondence to V. Narry Kim or Mikiko C. Siomi.

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DATABASES

The miRNA registry

let-7

lin-4

miR-1

miR-7

miR-29b

miR-31

miR-34

miR-105

miR-128

miR-133

miR-138

miR-142

miR-143

miR-145

miR-151

miR-200

miR-203

pri-miR-18

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miRNA database

Glossary

Heterochromatin

Highly condensed regions of the genome in which transcription is generally limited.

RNase III-type protein

An endonuclease that cleaves double-stranded RNAs and creates 5′-phosphate and 3′-hydroxyl termini, leaving 2-nucleotide 3′ overhangs.

Bilaterian

An animal that has a front, a back, an upside and a downside (bilateral symmetry).

Paralogue

A gene or protein with a highly similar sequence to another that is encoded in the same genome.

Polycistronic transcription unit

An RNA transcript that includes regions that represent multiple gene products.

Stem-loop structure

A lollipop-shaped structure that is formed when a single-stranded nucleic acid molecule loops back on itself to form a complementary double helix (stem) topped by a loop.

Mirtron

A microRNA that is generated from a short spliced intron without Drosha-mediated cleavage.

dsRBD

(Double-stranded-RNA-binding domain). A protein domain that binds to the A-form double-stranded RNA helix. Proteins that contain a dsRBD function in RNA localization, editing, translational repression and post-transcriptional gene silencing.

Retrotransposon

A transposon that mobilizes through RNA intermediates; the DNA elements are transcribed into RNA and then reverse-transcribed into DNA, which is inserted at new sites in the genome.

RNA-dependent RNA polymerase

An RNA polymerase that transcribes RNAs from RNA templates.

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Kim, V., Han, J. & Siomi, M. Biogenesis of small RNAs in animals. Nat Rev Mol Cell Biol 10, 126–139 (2009). https://doi.org/10.1038/nrm2632

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