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Review
. 2014;11(12):1483-94.
doi: 10.4161/15476286.2014.972855.

RNA-guided Isomerization of Uridine to Pseudouridine--Pseudouridylation

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Free PMC article
Review

RNA-guided Isomerization of Uridine to Pseudouridine--Pseudouridylation

Yi-Tao Yu et al. RNA Biol. .
Free PMC article

Abstract

Box H/ACA ribonucleoproteins (RNPs), each consisting of one unique guide RNA and 4 common core proteins, constitute a family of complex enzymes that catalyze, in an RNA-guided manner, the isomerization of uridines to pseudouridines (Ψs) in RNAs, a reaction known as pseudouridylation. Over the years, box H/ACA RNPs have been extensively studied revealing many important aspects of these RNA modifying machines. In this review, we focus on the composition, structure, and biogenesis of H/ACA RNPs. We explain the mechanism of how this enzyme family recognizes and specifies its target uridine in a substrate RNA. We discuss the substrates of box H/ACA RNPs, focusing on rRNA (rRNA) and spliceosomal small nuclear RNA (snRNA). We describe the modification product Ψ and its contribution to RNA function. Finally, we consider possible mechanisms of the bone marrow failure syndrome dyskeratosis congenita and of prostate and other cancers linked to mutations in H/ACA RNPs.

Keywords: DC, dyskeratosis congenita; H/ACA; HH, hoyeraal-hreidarsson syndrome; PIKK, phosphatidylinositol 3-kinase-related kinase; PUA, pseudouridylase and archaeosine transglycosylase; RNA modification; RNA-guided; RNP, ribonucleoprotein; SMN, survival of motor neuron protein; SSD, SHQ1 specific domain; U, uridine; X-DC, X-linked dyskeratosis congenita; dyskeratosis congenita; prostate cancer; pseudouridine; rRNA; rRNA, ribosomal RNA; ribonucleoproteins; sca, small Cajal body; snRNA, small nuclear RNA; sno, small nucleolar; snoRNA; snoRNA, small nucleolar RNA; spliceosomal small nuclear RNA; tRNA, transfer RNA; ψ, pseudouridine, 5-ribosyluracil.

Figures

Figure 1.
Figure 1.
Pseudouridylation, guide RNA, and guide mechanism. (A) Chemical structure of uridine (U) and pseudouridine (Ψ). The 180° rotation of the base frees up the N-glycosidic nitrogen in U as an additional hydrogen donor in Ψ (red). The numbering of base and ribose positions for potential nucleophilic attacks by a conserved aspartate of the Ψ-synthase is indicated. Note the aspartate is highlighted in yellow in the dark green catalytic domain of the Ψ-synthase (Fig. 2, inset). (B) Schematic of an H/ACA guide RNA hybridized to a substrate RNA (blue) in its 3′ pseudouridylation pocket. The hinge region and ACA conserved sequence elements responsible for the H/ACA name are highlighted (red; N = any nucleotide). (C) Example of the pseudouridylation pocket of the yeast H/ACA RNA snR81 hybridized to its substrate RNA (blue). Perfect Watson-Crick base-pairs between the guide sequence and the substrate RNA result in constitutive pseudouridylation at the target site (left panel, constitutive pseudouridylation). In contrast, if the guide sequence forms imperfect base-pairs (there are 2 mismatches) with the substrate RNA, pseudouridylation occurs only under stress (nutrient-deprivation) conditions (right panel, inducible pseudouridylation).
Figure 2.
Figure 2.
H/ACA RNPs. Schematic of the different classes of H/ACA RNPs defined by the H/ACA RNAs. One set of the 4 core proteins assembles with each hairpin of every H/ACA RNA. Guide sequences of the RNAs are indicated (thickening of lines) and the snoRNAs and scaRNAs that are the focus of this review are highlighted (bold). The functions, targets, and importance, where known, are listed underneath. The approximate number of species within each class of H/ACA RNA (which in most cases is still growing) is specified in parentheses. Inset: model of the structure of a single hairpin of a human H/ACA RNP. The color code of the core proteins is the same as in the schematic. The RNA is in gray and the ACA triplet at the bottom of the molecule is in purple. The catalytic aspartate of the green Ψ-synthase is highlighted (yellow). Archaeal and bacterial structures served as basis for the model.140
Figure 3.
Figure 3.
Schematic of the surprisingly complex biogenesis of H/ACA RNPs. Details of the at least 4-step process are described in the text. The approximate size and sites of interactions of the proteins is drawn to scale. Inset: Surface rendering of the structures of yeast NAP57 alone and in complex with the SHQ1 specific domain (SSD; pdb: 3uai). Amino acid positions equivalent to those mutated in human NAP57 in patients with dyskeratosis congenita are highlighted (orange). Note many of these positions cluster in the C-terminal segment (CTS, knob on the left) that serves as handle for the SSD, although they are generally poorly visible in this surface rendering.

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