Abstract. An RNA hairpin is an essential secondary structure of RNA. It can guide RNA folding, determine interactions in a ribozyme, protect messenger RNA (mRNA) from degradation, serve as a recognition motif for RNA binding proteins or act as a substrate for enzymatic reactions. In this review, we have focused on cis-acting RNA hairpins in metazoa, which regulate histone gene expression, mRNA localization and translation. We also review evolution, mechanism of action and experimental use of Cell. Mol. Life Sci. 63 (2006) 901-918 1420-682X/06/080901-18 DOI 10.1007/s00018-005-5558-5 © Birkhäuser Verlag, Basel, 2006 trans-acting microRNAs, which are coded by short RNA hairpins. Finally, we discuss the existence and effects of long RNA hairpin in animals. We show that several proteins previously recognized to play a role in a specific RNA stem-loop function in cis were also linked to RNA silencing pathways where a different type of hairpin acts in trans. Such overlaps indicate that the relationship between certain mechanisms that recognize different types of RNA hairpins is closer than previously thought.Keywords. dsRNA, miRNA, RNAi, stem-loop, hairpin, localization, translation.
IntroductionAn RNA hairpin consists of a double-stranded RNA (dsRNA) stem, often containing mismatches and bulges (i.e. unpaired sequences within the stem), and a terminal loop. It is the most common secondary structure found in almost every RNA folding prediction. RNA hairpins originate by two mechanisms: (i) transcription by DNAdependent RNA polymerase of an inverted repeat DNA resulting in the RNA folding into a stem-loop structure, and (ii) an RNA molecule formed as a folded-back template for RNA-dependent RNA polymerase, which synthesizes the second strand of the stem. This review will focus exclusively on the first case -RNA hairpins folded within RNA transcripts. The second mechanism, which produces perfect long dsRNA hairpins, is not widespread in nature and is probably restricted to a 'copy-back' mechanism of replication in certain viruses [1]. It is difficult to classify RNA hairpins into distinct categories because these structures easily arise and differ in many aspects. Structurally, RNA hairpins can occur in different positions within different types of RNAs; they differ in the length of the stem, the size of the loop, the number and size of bulges, and in the actual nucleotide sequence (Fig. 1a). These parameters provide an extreme variability allowing specific interactions with proteins (discussed in detail in [2]). Functionally, RNA hairpins can regulate gene expression in cis or trans, i.e. an RNA hairpin within an RNA molecule can regulate just that molecule (cis) or it can induce effects on other RNAs or pathways (trans). Hairpins serve as binding sites for a variety of proteins, act as substrates for enzymatic reactions as well as display intrinsic enzymatic activities. Many of the pathways utilizing and/or responding to RNA hairpins have evolved independently and are not linked to others. It is not possible to pr...