Research highlights
DOI:
10.1038/nrm2424

siRNA

RISC

S m all R N A s

Nature Reviews | Molecular Cell Biology

Endo-siRNAs truly endogenous
Among animals, endogenous-small-interfering(endo-si) RNA pathways have so far been
restricted to Caenorhabditis elegans. Seven
studies now report the discovery of endo-siRNA
pathways in Drosophila melanogaster and mouseoocytes.
During RNA interference (RNAi), members of
the Dicer family of proteins cleave doublestranded (ds) RNA of an endogenous orexogenous source into 21–24 nucleotide siRNAs.
dsRNA cleavage is coupled to the loading of thesesiRNAs onto the RNA-induced silencing complex(RISC). The siRNA guides the RISC complex to thecorresponding target mRNA, which is degradedthrough cleavage by Argonaute (AGO) proteins.
The groups of Greg Hannon and Hiroyuki
Sasaki found a large number of both Piwiinteracting RNAs (piRNAs) and endo-siRNAs that
corresponded to mRNAs or retrotransposons ingrowing oocytes. Endo-siRNAs were exclusively
mapped to retrotransposons or other genomic
regions that produce transcripts capable offorming dsRNA structures. The genomic sourcesof dsRNAs that generate endo-siRNAs included
inverted repeat structures, sites of bidirectionaltranscription and antisense transcripts fromvarious loci, including retrotransposons andpseudogenes. Loss of Dicer or AGO2 resulted indecreased levels of endo-siRNAs and increased
levels of retrotransposon and protein-coding
transcripts that are complementary to theendo-siRNAs. These findings reveal a rolefor endo-siRNAs in mammals and indicate that theRNAi pathway regulates both protein-coding
transcripts and retrotransposons in mouse
oocytes.
Endo-siRNAs were also reported inD. melanogaster gonadal and somatic cells by thegroups of Greg Hannon, Eric Lai, Haruhiko andnature reviews | molecular cell biology

Mikiko Siomi, and Phil Zamore. Many endo-siRNAs
correspond to transposons, heterochromaticsequences, and cis-natural antisense transcripts,
and can target both protein-coding genes andmobile elements. Endo-siRNAs also derived fromlong hairpin RNA genes and target selected
mRNAs in trans. Intriguingly, fly endo-siRNA
production requires not only canonical RNAifactors (Dicer-2 and AGO2), but also the canonicalmicroRNA biogenesis factor Loquacious. By
contrast, piRNAs are thought to be generated
from single-stranded precursor RNAs and theirproduction in flies and vertebrates does
not require Dicer. Loss of the endo-siRNAs
correlates with loss of transposon silencing, whichindicates that endo-siRNAs silence transposons in
the fly soma, much as piRNAs silence transposons
in the germ line.
Taken together, these studies suggest an
evolutionary conservation of dsRNAs as
regulatory molecules, a property previously
ascribed only to microRNAs, and raise new
regulatory possibilities for endogenous small RNApathways.
Ekat Kritikou
ORIGINAL RESEARCH PAPERS Chung, W.-J. et al. Endogenous
RNA interference provides a somatic defense against Drosophilatransposons. Curr. Biol. 22 May 2008 (doi:10.1016/j.
cub.2008.05.006) | Czech, B. et al. An endogenous small interfering
RNA pathway in Drosophila. Nature 7 May 2008 (doi:10.1038/nature07007) | Ghildiyal, M. et al. Endogenous siRNAs derived fromtransposons and mRNAs in Drosophila somatic cells. Sciencexpress
10 April 2008 (doi:10.1126/science.1157396) | Kawamura, Y. et al.
Drosophila endogenous small RNAs bind to Argonaute 2 in somaticcells. Nature 7 May 2008 (doi:10.1038/nature06938) | Okamura, K.
et al. The Drosophila hairpin RNA pathway generates endogenous
short interfering RNAs. Nature 7 May 2008 (doi:10.1038/nature07015) | Tam, O. H. et al. Pseudogene-derived smallinterfering RNAs regulate gene expression in mouse oocytes.
Nature 10 April 2008 (doi:10.1038/nature06904) | Watanabe, T. et al.
Endogenous siRNAs from naturally formed dsRNAs regulatetranscripts in mouse oocytes. Nature 10 April 2008 (doi:10.1038/nature06908)

volume 9 | June 2008
© 2008 Nature Publishing Group