Five Questions about Viruses and MicroRNAs

MicroRNAs (miRNAs) are ∼22-nt regulatory RNAs expressed by all multicellular eukaryotes [1]. Humans encode >700 miRNAs and similar numbers are likely to exist in other mammalian species. Almost all cellular miRNAs are initially transcribed by RNA polymerase II (Pol II) as part of a long, capped, polyadenylated primary miRNA (pri-miRNA) precursor. The miRNA forms part of one arm of an RNA stem-loop that consists of an ∼32-bp imperfect stem flanked by unstructured RNA sequences. This stem-loop is recognized by the nuclear RNase III enzyme Drosha, which cleaves the stem to liberate an ∼60-nt pre-miRNA hairpin. The pre-miRNA is then transported to the cytoplasm where it is cleaved by a second RNase III enzyme, called Dicer, which removes the terminal loop to generate the miRNA duplex intermediate. One strand of this duplex is incorporated into the RNA-induced silencing complex (RISC), where it acts as a guide RNA to direct RISC to complementary mRNA species [1]. Depending on the level of complementarity, RISC can either cleave bound mRNAs and/or inhibit their translation. Inhibition of mRNA translation generally requires full complementarity of the mRNA to nucleotides 2 through 7 or 8 from the miRNA 5′ end—the miRNA seed region. The primary, and possibly sole, function of mammalian miRNAs is therefore to act as specific post-transcriptional inhibitors of mRNA function.