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Frontiers in Biology

Front. Biol.    2018, Vol. 13 Issue (1) : 1-10
RNA-dependent pseudouridylation catalyzed by box H/ACA RNPs
Meemanage D. De Zoysa, Yi-Tao Yu()
University of Rochester Medical Center, Department of Biochemistry and Biophysics, Center for RNA Biology, 601 Elmwood Avenue, Rochester, NY14642, USA
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BACKGROUND: Pseudouridine (Y) is the most abundant post-transcriptionally modified nucleotide found in RNA. Y is clustered in functionally important and evolutionary conserved regions of RNAs in all three domains of life. Pseudouridylation is catalyzed by two distinct mechanisms: an RNA-independent and an RNA-dependent mechanism. The former involves a group of stand-alone protein enzymes, and the latter involves a family of complex enzymes called box H/ACA RNPs, each of which consists of one RNA (box H/ACA RNA) and a set of four core proteins. Over the years, the mechanism of RNA-dependent pseudouridylation has been extensively studied. The crystal structures of partial and complete box H/ACA RNP have been solved. However, the detailed picture of RNA-dependent pseudouridylation is still not entirely clear.

OBJECTIVE: In this work, we review what is known about box H/ACA RNP and the mechanism by which box H/ACA RNP catalyzes RNA-dependent pseudouridylation. We also discuss some examples of the dual nature and redundancy of box H/ACA RNPs that deviate from the usual mechanism.

METHODS: A methodical literature search was performed using the Pubmed central search engine and International Digital Publishing Forum (EPUB) using the following keywords: “pseudouridylation,” “pseudouridine,” and “box H/ACA RNP.” The necessary information was extracted and cited.

RESULTS: A detailed introduction is made including the discovery, mechanism and crystal structure of box H/ACA RNP. Three sequence/structural requirements for box H/ACA RNA-guided pseudouridylation are discussed and the exceptions to those rules are explored.

CONCLUSION: Over the years, box H/ACA RNP-catalyzed pseudouridylation has been extensively studied, generating fruitful results. However, a detailed picture regarding the mechanism of this reaction is still to be deciphered. More work is needed to fully understand box H/ACA RNP-catalyzed pseudouridylation.

Corresponding Author(s): Yi-Tao Yu   
Just Accepted Date: 19 January 2018   Issue Date: 26 March 2018
 Cite this article:   
Meemanage D. De Zoysa,Yi-Tao Yu. RNA-dependent pseudouridylation catalyzed by box H/ACA RNPs[J]. Front. Biol., 2018, 13(1): 1-10.
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Meemanage D. De Zoysa
Yi-Tao Yu
Fig.1  Pseudouridylation (U-to-Y Isomerization). The nucleotide pseudouridylation reaction is schematized. The N1-C1' bond in uridine is broken. The uracil base is lifted up and turned 180° around the C6-N3 axis. Upon reformation of the C5-C1' bond, Y is generated. “a” and “d” represent hydrogen bond acceptor and donor, respectively.
Fig.2  Box H/ACA RNP, a highly complex pseudouridylase that catalyzes RNA-dependent RNA pseudouridylation. The components of the RNP, including a box H/ACA RNA and four core proteins (Cbf5, Nhp2, Nop10 and Gar1), are shown. The two hairpins, the hinge region and the 3′ ACA tail of the box H/ACA RNA are indicated. The upper and lower stems, as well as the internal loop (or pseudouridylation pocket) of each hairpin are also indicated. Also depicted are the substrate RNA, which forms base-pairing interactions with the pseudouridylation pocket sequences, and the target uridines, which are to be pseudouridylated (Ys, the arrows).
Fig.3  Box H/ACA RNA-guided RNA pseudouridylation under normal and stress conditions. Shown is the S. cerevisiae snR81 box H/ACA RNA, which guides the pseudouridylation of U2 snRNA at position 42 (the 5′ pocket) and 25 S rRNA at position 1051 (the 3′ pocket) under normal and starvation conditions. Under starvation conditions, the 3′ pocket of snR81 loosens its specificity to also guide U2 pseudouridylation at a novel site, position 93. The substrate RNAs (U2 snRNA and 25S rRNA), which form base-pairing interactions with the sequences of the pseudouridylation pockets, and the target nucleotides to be pseudouridylated (Ys, the arrows) are also shown. The H and ACA boxes of snR81 are indicated (gray boxes) as well.
Fig.4  Intricate box H/ACA RNA-substrate network. Several mammalian box H/ACA RNAs, including ACA19, ACA42 and ACA67, are schematized. According to computational predictions, the 5′ hairpin of ACA19 folds into three alternative structures, forming three distinct pseudouridylation pockets that target three different sites, U866 and U863 of 18S rRNA and U3709 of 28S rRNA. However, experimental results indicate that the 5′ pocket of ACA19 only targets U3709 of 28S rRNA (Xiao et al., 2009). U866 and U863 of 18S rRNA are the targets of ACA28 (its 3′ pocket) and ACA24 (its 5′ pocket), respectively (indicated) (Xiao et al., 2009). Based on computational predictions, ACA42 and ACA67 possess almost identical pseudouridylation pockets, targeting the same sites: the 5′ pocket of ACA42 and the 5′ pocket of ACA67 both target U572 of 18S rRNA, and the ACA42 3′ pocket and the ACA67 3′ pocket both target U109 of 18S rRNA. But, in reality, the 5′ pocket of ACA42 fails to guide U572-to-Y572 conversion (Xiao et al., 2009). Interestingly, small nucleotide changes can turn a non-functional pseudouridylation pocket into a functional pocket.
Fig.5  Redundancy between stand-alone pseudouridine synthases and box H/ACA RNP pseudouridylases. Vertebrate U2 RNA is schematized and its branch site recognition region sequence is shown. Pus7 (stand-alone protein enzyme) and the 5′ pocket of pugU2-34/44 (a box H/ACA RNP also known as SCARNA8 or U92 scaRNP) both target U34 (equivalent to U35 in Drosophila) of U2. Pus1 (stand-alone protein enzyme) and pugU2-34/44 (or pugU2-43/44 in pombe) both target U43 (equivalent to U44 in Drosophila) of U2 (Deryusheva and Gall, 2017).
1 Baker D L, Youssef O A, Chastkofsky M I R, Dy D A, Terns R M, Terns M P (2005). RNA-guided RNA modification: functional organization of the archaeal H/ACA RNP. Genes Dev, 19(10): 1238–1248 pmid: 15870259
2 Balakin A G, Smith L, Fournier M J (1996). The RNA world of the nucleolus: two major families of small RNAs defined by different box elements with related functions. Cell, 86(5): 823–834 pmid: 8797828
3 Basak A, Query C C (2014). A pseudouridine residue in the spliceosome core is part of the filamentous growth program in yeast. Cell Reports, 8(4): 966–973 pmid: 25127136
4 Becker H F, Motorin Y, Planta R J, Grosjean H (1997). The yeast gene YNL292w encodes a pseudouridine synthase (Pus4) catalyzing the formation of psi55 in both mitochondrial and cytoplasmic tRNAs. Nucleic Acids Res, 25(22): 4493–4499 pmid: 9358157
5 Bortolin M L, Ganot P, Kiss T (1999). Elements essential for accumulation and function of small nucleolar RNAs directing site-specific pseudouridylation of ribosomal RNAs. EMBO J, 18(2): 457–469 pmid: 9889201
6 Branlant C, Krol A, Machatt M A, Pouyet J, Ebel J P, Edwards K, Kössel H (1981). Primary and secondary structures of Escherichia coli MRE 600 23S ribosomal RNA. Comparison with models of secondary structure for maize chloroplast 23S rRNA and for large portions of mouse and human 16S mitochondrial rRNAs. Nucleic Acids Res, 9(17): 4303–4324 pmid: 6170936
7 Carlile T M, Rojas-Duran M F, Zinshteyn B, Shin H, Bartoli K M, Gilbert W V (2014). Pseudouridine profiling reveals regulated mRNA pseudouridylation in yeast and human cells. Nature, 515(7525): 143–146 pmid: 25192136
8 Charette M, Gray M W (2000). Pseudouridine in RNA: what, where, how, and why. IUBMB Life, 49(5): 341–351 pmid: 10902565
9 Charpentier B, Muller S, Branlant C (2005). Reconstitution of archaeal H/ACA small ribonucleoprotein complexes active in pseudouridylation. Nucleic Acids Res, 33(10): 3133–3144 pmid: 15933208
10 Cohn W E (1959). 5-Ribosyl uracil, a carbon-carbon ribofuranosyl nucleoside in ribonucleic acids. Biochim Biophys Acta, 32: 569–571 pmid: 13811055
11 Deryusheva S, Gall J G (2013). Novel small Cajal-body-specific RNAs identified in Drosophila: probing guide RNA function. RNA, 19(12): 1802–1814 pmid: 24149844
12 Deryusheva S, Gall J G (2017). Dual nature of pseudouridylation in U2 snRNA: Pus1p-dependent and Pus1p-independent activities in yeasts and higher eukaryotes. RNA, 23(7): 1060–1067 pmid: 28432181
13 Dönmez G, Hartmuth K, Lührmann R (2004). Modified nucleotides at the 5′ end of human U2 snRNA are required for spliceosomal E-complex formation. RNA, 10(12): 1925–1933 pmid: 15525712
14 Duan J, Li L, Lu J, Wang W, Ye K (2009). Structural mechanism of substrate RNA recruitment in H/ACA RNA-guided pseudouridine synthase. Mol Cell, 34(4): 427–439 pmid: 19481523
15 Ganot P, Bortolin M L, Kiss T (1997a). Site-specific pseudouridine formation in preribosomal RNA is guided by small nucleolar RNAs. Cell, 89(5): 799–809 pmid: 9182768
16 Ganot P, Caizergues-Ferrer M, Kiss T (1997b). The family of box ACA small nucleolar RNAs is defined by an evolutionarily conserved secondary structure and ubiquitous sequence elements essential for RNA accumulation. Genes Dev, 11(7): 941–956 pmid: 9106664
17 Ge J, Yu Y T (2013). RNA pseudouridylation: new insights into an old modification. Trends Biochem Sci, 38(4): 210–218 pmid: 23391857
18 Girard J P, Lehtonen H, Caizergues-Ferrer M, Amalric F, Tollervey D, Lapeyre B (1992). GAR1 is an essential small nucleolar RNP protein required for pre-rRNA processing in yeast. EMBO J, 11(2): 673–682
pmid: 1531632
19 Grosjean H (2005). Modification and editing of RNA: historical overview and important facts to remember. In: H. Grosjean, ed. Fine-Tuning of RNA Functions by Modification and Editing. Berlin: Springer Berlin Heidelberg, pp. 1–22
20 Hamma T, Reichow S L, Varani G, Ferré-D’Amaré A R (2005). The Cbf5-Nop10 complex is a molecular bracket that organizes box H/ACA RNPs. Nat Struct Mol Biol, 12(12): 1101–1107 pmid: 16286935
21 Henras A, Henry Y, Bousquet-Antonelli C, Noaillac-Depeyre J, Gélugne J P, Caizergues-Ferrer M (1998). Nhp2p and Nop10p are essential for the function of H/ACA snoRNPs. EMBO J, 17(23): 7078–7090 pmid: 9843512
22 Hopper A K, Phizicky E M (2003). tRNA transfers to the limelight. Genes Dev, 17(2): 162–180 pmid: 12533506
23 Hüttenhofer A, Kiefmann M, Meier-Ewert S, O’Brien J, Lehrach H, Bachellerie J P, Brosius J (2001). RNomics: an experimental approach that identifies 201 candidates for novel, small, non-messenger RNAs in mouse. EMBO J, 20(11): 2943–2953 pmid: 11387227
24 Jack K, Bellodi C, Landry D M, Niederer R O, Meskauskas A, Musalgaonkar S, Kopmar N, Krasnykh O, Dean A M, Thompson S R, Ruggero D, Dinman J D (2011). rRNA pseudouridylation defects affect ribosomal ligand binding and translational fidelity from yeast to human cells. Mol Cell, 44(4): 660–666 pmid: 22099312
25 Jiang W, Middleton K, Yoon H J, Fouquet C, Carbon J (1993). An essential yeast protein, CBF5p, binds in vitro to centromeres and microtubules. Mol Cell Biol, 13(8): 4884–4893 pmid: 8336724
26 Khanna M, Wu H, Johansson C, Caizergues-Ferrer M, Feigon J (2006). Structural study of the H/ACA snoRNP components Nop10p and the 3′ hairpin of U65 snoRNA. RNA, 12(1): 40–52 pmid: 16373493
27 King T H, Liu B, McCully R R, Fournier M J (2003). Ribosome structure and activity are altered in cells lacking snoRNPs that form pseudouridines in the peptidyl transferase center. Mol Cell, 11(2): 425–435 pmid: 12620230
28 Li H (2008). Unveiling substrate RNA binding to H/ACA RNPs: one side fits all. Curr Opin Struct Biol, 18(1): 78–85 pmid: 18178425
29 Li L, Ye K (2006a). Crystal structure of an H/ACA box ribonucleoprotein particle. Nature, 443(7109): 302–307 pmid: 16943774
30 Li L, Ye K (2006b). Crystal structure of an H/ACA box ribonucleoprotein particle. Nature, 443(7109): 302–307 pmid: 16943774
31 Li S, Duan J, Li D, Yang B, Dong M, Ye K (2011). Reconstitution and structural analysis of the yeast box H/ACA RNA-guided pseudouridine synthase. Genes Dev, 25(22): 2409–2421 pmid: 22085967
32 Li X, Zhu P, Ma S, Song J, Bai J, Sun F, Yi C (2015). Chemical pulldown reveals dynamic pseudouridylation of the mammalian transcriptome. Nat Chem Biol, 11(8): 592–597 pmid: 26075521
33 Liang B, Xue S, Terns R M, Terns M P, Li H (2007). Substrate RNA positioning in the archaeal H/ACA ribonucleoprotein complex. Nat Struct Mol Biol, 14(12): 1189–1195 pmid: 18059286
34 Liang B, Zhou J, Kahen E, Terns R M, Terns M P, Li H (2009a). Structure of a functional ribonucleoprotein pseudouridine synthase bound to a substrate RNA. Nat Struct Mol Biol, 16(7): 740–746 pmid: 19478803
35 Liang X H, Liu Q, Fournier M J (2009b). Loss of rRNA modifications in the decoding center of the ribosome impairs translation and strongly delays pre-rRNA processing. RNA, 15(9): 1716–1728 pmid: 19628622
36 Lovejoy A F, Riordan D P, Brown P O (2014). Transcriptome-wide mapping of pseudouridines: pseudouridine synthases modify specific mRNAs in S. cerevisiae. PLoS One, 9(10): e110799 pmid: 25353621
37 Ma X, Zhao X, Yu Y T (2003). Pseudouridylation (Y) of U2 snRNA in S. cerevisiae is catalyzed by an RNA-independent mechanism. EMBO J, 22(8): 1889–1897 pmid: 12682021
38 Manival X, Charron C, Fourmann J B, Godard F, Charpentier B, Branlant C (2006). Crystal structure determination and site-directed mutagenesis of the Pyrococcus abyssi aCBF5-aNOP10 complex reveal crucial roles of the C-terminal domains of both proteins in H/ACA sRNP activity. Nucleic Acids Res, 34(3): 826–839 pmid: 16456033
39 Massenet S, Mougin A, Branlant C (1998). Posttranscriptional Modifications in the U Small Nuclear RNAs. In: Grosjean H, Benne R, eds. Modification and Editing of RNA. Washington D. C.: ASM Press
40 Meier U T (2005). The many facets of H/ACA ribonucleoproteins. Chromosoma, 114(1): 1–14 pmid: 15770508
41 Mitchell J R, Wood E, Collins K (1999). A telomerase component is defective in the human disease dyskeratosis congenita. Nature, 402: 551
42 Ni J, Tien A L, Fournier M J (1997). Small nucleolar RNAs direct site-specific synthesis of pseudouridine in ribosomal RNA. Cell, 89(4): 565–573 pmid: 9160748
43 Nurse K, Wrzesinski J, Bakin A, Lane B G, Ofengand J (1995). Purification, cloning, and properties of the tRNA psi 55 synthase from Escherichia coli. RNA, 1(1): 102–112
pmid: 7489483
44 Ofengand J, Fournier M J (1998). The Pseudouridine Residues of rRNA: Number, Location, Biosynthesis, and Function. In: Grosjean H, Benne R., eds. Modification and Editing of RNA. Washington D. C.: ASM Press
45 Piekna-Przybylska D, Przybylski P, Baudin-Baillieu A, Rousset J P, Fournier M J (2008). Ribosome performance is enhanced by a rich cluster of pseudouridines in the A-site finger region of the large subunit. J Biol Chem, 283(38): 26026–26036 pmid: 18611858
46 Rashid R, Liang B, Baker D L, Youssef O A, He Y, Phipps K, Terns R M, Terns M P, Li H (2006). Crystal structure of a Cbf5-Nop10-Gar1 complex and implications in RNA-guided pseudouridylation and dyskeratosis congenita. Mol Cell, 21(2): 249–260 pmid: 16427014
47 Reddy R, Busch H (1988). Small Nuclear RNAs: RNA Sequences, Structure, and Modifications. In: Birnstiel M L, ed. Structure and Function of Major and Minor Small Nuclear Ribonucleoprotein Particles. Berlin: Springer Berlin Heidelber, pp. 1–37
48 Reichow S L, Hamma T, Ferré-D’Amaré A R, Varani G (2007). The structure and function of small nucleolar ribonucleoproteins. Nucleic Acids Res, 35(5): 1452–1464 pmid: 17284456
49 Rozhdestvensky T S, Tang T H, Tchirkova I V, Brosius J, Bachellerie J P, Hüttenhofer A (2003). Binding of L7Ae protein to the K-turn of archaeal snoRNAs: a shared RNA binding motif for C/D and H/ACA box snoRNAs in Archaea. Nucleic Acids Res, 31(3): 869–877 pmid: 12560482
50 Schattner P, Barberan-Soler S, Lowe T M (2006). A computational screen for mammalian pseudouridylation guide H/ACA RNAs. RNA, 12(1): 15–25 pmid: 16373490
51 Schattner P, Decatur W A, Davis C A, Ares M Jr, Fournier M J, Lowe T M (2004). Genome-wide searching for pseudouridylation guide snoRNAs: analysis of the Saccharomyces cerevisiae genome. Nucleic Acids Res, 32(14): 4281–4296 pmid: 15306656
52 Schwartz S, Bernstein D A, Mumbach M R, Jovanovic M, Herbst R H, León-Ricardo B X, Engreitz J M, Guttman M, Satija R, Lander E S, Fink G, Regev A (2014). Transcriptome-wide mapping reveals widespread dynamic-regulated pseudouridylation of ncRNA and mRNA. Cell, 159(1): 148–162 pmid: 25219674
53 Sprinzl M, Vassilenko K S (2005). Compilation of tRNA sequences and sequences of tRNA genes. Nucleic Acids Res, 33(Database issue): D139–D140 pmid: 15608164
54 Terns M, Terns R (2006). Noncoding RNAs of the H/ACA family. Cold Spring Harb Symp Quant Biol, 71(0): 395–405 pmid: 17381322
55 Torchet C, Badis G, Devaux F, Costanzo G, Werner M, Jacquier A (2005). The complete set of H/ACA snoRNAs that guide rRNA pseudouridylations in Saccharomyces cerevisiae. RNA, 11(6): 928–938 pmid: 15923376
56 Vitali P, Royo H, Seitz H, Bachellerie J P, Hüttenhofer A, Cavaillé J (2003). Identification of 13 novel human modification guide RNAs. Nucleic Acids Res, 31(22): 6543–6551 pmid: 14602913
57 Watkins N J, Gottschalk A, Neubauer G, Kastner B, Fabrizio P, Mann M, Lührmann R (1998). Cbf5p, a potential pseudouridine synthase, and Nhp2p, a putative RNA-binding protein, are present together with Gar1p in all H BOX/ACA-motif snoRNPs and constitute a common bipartite structure. RNA, 4(12): 1549–1568 pmid: 9848653
58 Wu G, Adachi H, Ge J, Stephenson D, Query C C, Yu Y T (2016). Pseudouridines in U2 snRNA stimulate the ATPase activity of Prp5 during spliceosome assembly. EMBO J, 35(6): 654–667 pmid: 26873591
59 Wu G, Xiao M, Yang C, Yu Y T (2011). U2 snRNA is inducibly pseudouridylated at novel sites by Pus7p and snR81 RNP. EMBO J, 30(1): 79–89 pmid: 21131909
60 Wu G, Yu A T, Kantartzis A, Yu Y T (2011). Functions and mechanisms of spliceosomal small nuclear RNA pseudouridylation. Wiley Interdiscip Rev RNA, 2(4): 571–581 pmid: 21957045
61 Xiao M, Yang C, Schattner P, Yu Y T (2009). Functionality and substrate specificity of human box H/ACA guide RNAs. RNA, 15(1): 176–186 pmid: 19033376
62 Yang C, McPheeters D S, Yu Y T (2005). y35 in the branch site recognition region of U2 small nuclear RNA is important for pre-mRNA splicing in Saccharomyces cerevisiae. J Biol Chem, 280(8): 6655–6662 pmid: 15611063
63 Ye K (2007). H/ACA guide RNAs, proteins and complexes. Curr Opin Struct Biol, 17(3): 287–292 pmid: 17574834
64 Yu A T, Ge J, Yu Y T (2011). Pseudouridines in spliceosomal snRNAs. Protein Cell, 2(9): 712–725 pmid: 21976061
65 Yu Y T, Meier U T (2014). RNA-guided isomerization of uridine to pseudouridine--pseudouridylation. RNA Biol, 11(12): 1483–1494 pmid: 25590339
66 Yu Y T, Shu M D, Steitz J A (1998). Modifications of U2 snRNA are required for snRNP assembly and pre-mRNA splicing. EMBO J, 17(19): 5783–5795 pmid: 9755178
67 Yu Y T, Terns R M, Terns M P (2005). Mechanisms and functions of RNA-guided RNA modification. In: Grosjean H. ed. Fine-Tuning of RNA Functions by Modification and Editing. Berlin: Springer Berlin Heidelberg, pp. 223–262
68 Zebarjadian Y, King T, Fournier M J, Clarke L, Carbon J (1999). Point mutations in yeast CBF5 can abolish in vivo pseudouridylation of rRNA. Mol Cell Biol, 19(11): 7461–7472 pmid: 10523634
69 Zhao X, Li Z H, Terns R M, Terns M P, Yu Y T (2002). An H/ACA guide RNA directs U2 pseudouridylation at two different sites in the branchpoint recognition region in Xenopus oocytes. RNA, 8(12): 1515–1525
pmid: 12515384
70 Zhao X, Yu Y T (2004). Pseudouridines in and near the branch site recognition region of U2 snRNA are required for snRNP biogenesis and pre-mRNA splicing in Xenopus oocytes. RNA, 10(4): 681–690 pmid: 15037777
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