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Small RNAs with big implications: new insights into H/ACA snoRNA function and their role in human disease

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A myriad of structurally and functionally diverse noncoding RNAs (ncRNAs) have recently been implicated in numerous human diseases including cancer. Small nucleolar RNAs (snoRNAs), the most abundant group of intron‐encoded ncRNAs, are classified into two families (box C/D snoRNAs and box H/ACA snoRNAs) and are required for post‐transcriptional modifications on ribosomal RNA (rRNA). There is now a growing appreciation that nucleotide modifications on rRNA may impart regulatory potential to the ribosome; however, the functional consequence of site‐specific snoRNA‐guided modifications remains poorly defined. Discovered almost 20 years ago, H/ACA snoRNAs are required for the conversion of specific uridine residues to pseudouridine on rRNA. Interestingly, recent reports indicate that the levels of subsets of H/ACA snoRNAs required for pseudouridine modifications at specific sites on rRNA are altered in several diseases, particularly cancer. In this review, we describe recent advances in understanding the downstream consequences of H/ACA snoRNA‐guided modifications on ribosome function, discuss the possible mechanism by which H/ACA snoRNAs may be regulated, and explore prospective expanding functions of H/ACA snoRNAs. Furthermore, we discuss the potential biological implications of alterations in H/ACA snoRNA expression in several human diseases. WIREs RNA 2015, 6:173–189. doi: 10.1002/wrna.1266 This article is categorized under: Translation > Translation Regulation RNA Processing > RNA Editing and Modification RNA in Disease and Development > RNA in Disease
Schematic secondary structure of a box H/ACA small nucleolar RNA (snoRNA). Schematic representation of a box H/ACA snoRNA (blue) containing several evolutionarily conserved elements, including a box H (ANANNA) and box ACA motif and two pseudouridylation pockets. Pseudouridylation pockets are shown base pairing to the complementary sequence on substrate RNA (gray). The position of the target uridine modified to pseudouridine (Ψ) on substrate RNA is indicated by red arrow.
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Predicted effect of a single nucleotide substitution on H/ACA small nucleolar RNA (snoRNA) secondary structure. Sequence and predicted secondary structure of SNORA71C (a) and a SNORA71C variant found in head and neck cancer, SNORA71 60A>G (b). The position of the substituted nucleotide is indicated with an arrowhead. The nucleotide substitution appears to alter the predicted structure of the pseudouridylation pocket within SNORA71C (highlighted in green) and may likely inhibit base pairing to human 18S rRNA (blue, with position of pseudouridine highlighted in red). The box H and box ACA elements are boxed and shown in orange. Secondary structure predictions were obtained using RNAfold and visual inspection.
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Potential novel and emerging roles of H/ACA small nucleolar RNAs (snoRNAs). Schematic representation of the expanding functions of (a) H/ACA snoRNAs, and emerging roles of (b) H/ACA snoRNA derivatives and (c) noncoding RNAs (ncRNAs) with H/ACA snoRNA features. (a) Evidence that subsets of H/ACA snoRNAs are associated with chromatin, independent of H/ACA snoRNP proteins, indicates that H/ACA snoRNAs may play a role in chromatin remodeling. (b) The identification of H/ACA snoRNA derivatives, namely H/ACA snoRNA‐like microRNA (miRNA) and H/ACA snoRNA‐derived RNAs (sdRNA), suggests a potential role for H/ACA snoRNA derivatives in post‐transcriptional gene regulation. (c) H/ACA snoRNA‐related lncRNAs may play a role in transcriptional and post‐transcriptional gene expression regulation.
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Evolutionarily conserved and emerging novel substrates of H/ACA small nucleolar RNAs (snoRNAs). Schematic representation of the evolutionarily conserved and well‐characterized role of H/ACA snoRNAs in modifying ribosomal RNA (rRNA) and their putative role in modifying emerging novel RNA substrates. rRNA pseudouridine modifications (red) guided by evolutionarily conserved H/ACA small nucleolar ribonucleoproteins (snoRNPs) on human 18S and 28S rRNA (gray) are shown. rRNA pseudouridine modifications play an important role in modulating specific aspects of ribosome function, particularly translation fidelity and specificity. Emerging evidence indicates that additional RNA species including messenger RNAs (mRNAs), long noncoding RNAs (lncRNAs), and small nucleolar RNAs (snoRNAs) may also be subject to pseudouridine modifications by dyskerin and H/ACA snoRNAs that may likely affect the fate and function of substrate RNAs.
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Pseudouridine, an isomer of uridine, is implicated in stabilizing ribosomal RNA (rRNA). (a) Pseudouridine (Ψ) is an isomer of uridine (U) and is the only nucleotide to possess a carbon–carbon (C–C) glycosidic bond (C5, highlighted with a red arrowhead). Isomerization of uridine to pseudouridine involves the detachment of the uracil base at position N1 (red arrowhead) and rotation (180°) through the N3–C6 axis. The newly synthesized pseudouridine possesses an additional hydrogen bond donor site, highlighted in orange. (b) 3D model of human 28S and 5S rRNA (gray) with the position of pseudouridine residues (red) within H69 of 28S rRNA highlighted (in box). Pseudouridine residues within H69, as highlighted in the secondary structure depiction, appear to play a conserved role in stabilizing rRNA.
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RNA in Disease and Development > RNA in Disease
RNA Processing > RNA Editing and Modification
Translation > Translation Regulation

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