Small non-coding RNAs mount a silent revolution in gene expression

Abstract

During the past decade, it has become evident that small non-coding RNAs (ncRNAs) participate in widespread and essential regulatory mechanisms in most eukaryotic cells. Novel classes of small RNAs, their biogenesis pathways and cellular effects are continuously being described, and new properties of already established ncRNAs are still being discovered. As the list of small RNA molecules and their roles becomes more and more extensive, one can get lost in the midst of new information. In this review, we attempt to bring order to the small ncRNA transcriptome by covering some of the major milestones of recent years. We go through many of the new properties that have been attributed to already familiar RNA molecules, and introduce some of the more recent novel classes of tiny ncRNAs.

Figure 1. Many ways to make a silencer

Biogenesis pathways of small RNAs (sRNAs). (a) Following transcription of a primary miRNA (pri-miRNA) transcript, the Drosha complex or spliceosome releases the hairpin precursor miRNA (pre-miRNA) from typical or mirtron type miRNAs, respectively. The pre-miRNA or transcribed short hairpin (shRNA) miRNA transcripts undergo final processing by Dicer before incorporation into Argonaute complexes. The pre-miR-451 is an exception that utilizes Argonaute instead of Dicer in the final cleavage step. (b) Primary piRNAs from genomic clusters are loaded onto Piwi-related proteins and target homologous sequences for cleavage and generation of secondary piRNAs. These piRNAs are bound by distinct Piwi family proteins, which catalyze the generation of additional piRNAs through the cleavage and processing of RNAs with antisense sequences. (c) Endo-siRNAs derive from intramolecular hairpins or sense-antisense transcripts that base-pair and are cleaved by Dicer. The ~21 nt endo-siRNAs are bound by Argonaute proteins and in some organisms initiate the production of secondary endo-siRNAs by RNA-dependent RNA polymerases (RdRPs) that use cleaved target RNAs as templates. (d) Precursor tRNAs can be cleaved by RNaseZ to produce Type II tsRNAs from the 3’ termini. Following 3’-end CCA-addition, Dicer processes some tRNAs, potentially those that are misfolded, to produce Type I tsRNAs.

Figure 2. Many roads to silencing

Mechanisms used by sRNAs to silence gene expression. (a) Typically, miRNAs, and possibly milRNAs and sdRNAs, partially pair to mRNA target sequences and promote mRNA degradation through the recruitment of deadenylases by GW182 proteins bound to Argonaute. Alternatively, miRISC inhibits translation initiation, stalls translation elongation or stimulates proteolysis of nascent peptides encoded by the target mRNA. (b) Perfect pairing of many types of sRNAs results in cleavage of the target mRNA by certain Argonaute proteins. (c) Endo-siRNAs, piRNAs and possibly many of the sRNAs derived from protein-coding regions of the genome direct DNA and histone modifications (red stars) that regulate transcriptional activity.