miRNA Processing: Dicer-1 Meets its Match
DOI: 10.1371/journal.pbio.0030244

processing. They both homed in on a new gene with great
similarity to R2D2, and showed that loss of function of the gene
results in the accumulation of pre-miRNAs—very similar toloss of Dicer-1 function, which suggests that the two genes act
together in the same pathway. The new potential partner ofDicer-1 was given the name loquacious (loqs), because failure toprocess the miRNAs in turn causes increased levels of expressionof the target genes for the miRNAs.
Both groups also show that Loqs and Dicer-1 exist in acomplex within the cell, and that the complex is able to process
pre-miRNA into its mature form. The Siomis’ lab went on to showthat the complex contains a protein called Ago-1, which hints
that the complex might also be involved in the action of miRNAs
on their target genes, as well as in miRNA processing itself. Bothgroups also point out the similarity between Loqs and a humandsRBD protein called TRBP, which has been implicated in theresponse to infection by HIV.
There seems little doubt, then, that Dicer-1’s partner has
been found, and that the combined action of an RNAse III and adsRBD protein is a consistent theme in the function of miRNAsand siRNAs. The identification of Loqs will help to refine ourviews of how miRNAs are processed, as well as how they canbe manipulated. The connections made with processes suchas stem cell maintenance (identified by the Zamore lab) andviral infection in these new studies also emphasize that gene
regulation by small RNAs is relevant to a broad range of cellularphysiology.

In recent years, the control of gene expression by small RNA
molecules has emerged as a major new mechanism for generegulation. The small RNAs interfere with the expression of
their target gene by reducing its transcription, triggering thedestruction of the gene transcript, or inhibiting its translation
into a protein. This discovery has not only altered views ofgene regulation, but also provided molecular geneticists
with powerful new tools with which to study and manipulate
the function of any gene. The biology of these small RNAs is,therefore, under intense scrutiny.
Small RNAs are generated by specific pathways, the elementsof which are being rapidly discovered. In this issue of PLoS
Biology, two groups have identified a missing piece in one
such pathway—in the fruitfly Drosophila. The pathway underinvestigation leads to the production of a type of small RNA
called a microRNA (miRNA). These are 21–23 nucleotides inlength, and are involved in regulating the expression of manygenes. miRNAs start life as a much bigger transcript called apri-miRNA, which is processed in two steps. First, it is converted
into a shorter pre-miRNA, by the action of two proteins: Drosha,
an RNAse III enzyme; and Pasha, which contains doublestranded RNA binding domains (dsRBDs). The pre-miRNA isthen transported to the cytoplasm and is trimmed again into adouble-stranded miRNA by a different RNAse III enzyme calledDicer-1.
In a separate pathway, RNAs called small interfering RNAs(siRNAs) depend on the Dicer-2 RNAse III and a dsRBD protein
called R2D2 for their function. These pathways are also
conserved in other organisms. Thus, a pattern emerges: thefunctions of small RNAs tend to require the combined actions of
an RNAse III and a dsRBD protein. But why doesn’t Dicer-1 have apartner? The answer, provided by the two studies from the labsof Phil Zamore and Haruhiko and Mikiko Siomi, is that we justhadn’t found it yet.
The two groups took different approaches to finding Dicer1’s partner. Zamore’s group looked for genes resembling other
dsRBD-encoding genes, while the Siomi lab did a functional
screen for new genes specifically implicated in miRNA

PLoS Biology | www.plosbiology.org

Förstemann K, Tomari Y, Du T, Vagin VV, Denli AM, et al. (2005)
Normal microRNA maturation and germ-line stem cell maintenancerequires Loquacious, a double-stranded RNA-binding domain
protein. DOI: 10.1371/journal.pbio.0030236
Saito K, Ishizuka A, Siomi H, Siomi MC (2005) Processing of premicroRNAs by the Dicer-1–Loquacious complex in Drosophila cells.
DOI: 10.1371/journal.pbio.0030235

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July 2005 | Volume 3 | Issue 7 | e244