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WIREs RNA
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RNAs with multiple personalities

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In the last decade, advances in sequencing technology and a renewed focus on the regulatory potential of RNA molecules have combined to stimulate an enormous expansion in the catalog of known eukaryotic RNAs. Beyond the sheer numerical diversity of RNA species, recent studies have begun to uncover hints of even greater functional complexity. An increasing number of RNA molecules, including those from classic, well‐studied classes, have been found to act in previously unanticipated regulatory roles, or as substrate for the biogenesis of functionally distinct RNA molecules, or both. Thus, these molecules can fulfill multiple, parallel functions, compounding the already rich landscape of RNA biology, and potentially connecting disparate biological regulatory networks in unexpected ways. In this article, we review recently discovered instances of RNA multifunctionality, with a particular focus on regulatory small RNAs. WIREs RNA 2014, 5:1–13. doi: 10.1002/wrna.1193 This article is categorized under: RNA Processing > Processing of Small RNAs Regulatory RNAs/RNAi/Riboswitches > Regulatory RNAs

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Multifunctional microRNA (miRNA) precursors. MiRNAs can be harbored within several types of multifunctional RNA progenitors, including (a) the introns of coding transcripts, which can be translated into functional proteins, (b) long noncoding RNA transcripts, which, post‐splicing, may produce RNA entities with regulatory function, (c) Small nucleolar RNA (snoRNAs), which primarily function in ribosomal RNA maturation, and (d) transfer RNAs (tRNAs), which primarily serve to deliver amino acids to the ribosome during protein translation.
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Multiple alternative functions of transfer RNAs (tRNAs). In addition to their primary role in delivering amino acids to the ribosome during translation, tRNAs also function in a multitude of signaling pathways. From clockwise, these functions include the post‐transcriptional enhancement of at least one acetyl synthetase protein, via an alternatively folded hairpin structure; production of the 3′ U, 5′, and 3′ CCA tRNA fragments; production of tRNA stress fragments; and inhibition of apoptosis via cytochrome‐c binding.
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Effects of microRNA (miRNA)/target perturbation. The competitive dynamics of miRNA signaling can result in unexpected consequences upon network perturbation. Overexpression of Target Y can competitively sequester miRNA A, thus indirectly de‐repressing Target X (left), while overexpression of miRNA B can competitively occupy Argonaute complexes, thus reducing the potency of miRNA A, and indirectly de‐repressing Target X.
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MicroRNA (miRNA) signaling pathways. In addition to their well‐studied repressive function, miRNAs can act in a context‐dependent fashion to increase translation of targets by both transcriptional and post‐transcriptional mechanisms.
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Cooperative or antagonistic activity of microRNAs (miRNAs) and proteins sharing the same host gene. The miRNA and protein products of multifunctional host genes may act to reinforce a common phenotype (left); alternatively, a miRNA may serve as a negative modulator of the primary host gene phenotype (right). In this context a miRNA could potentially target also the protein encoded by its host gene, a hypothesis that still lacks experimental evidences based on the few experimentally validated miRNA–target interactions.
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RNA Processing > Processing of Small RNAs
Regulatory RNAs/RNAi/Riboswitches > Regulatory RNAs

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