SnoRNA

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Associate Editor(s)-in-Chief:  Henry A. Hoff

Small nucleolar RNAs (snoRNAs) are a class of small RNA molecules that guide chemical modifications (methylation or pseudouridylation) of ribosomal RNAs (rRNAs) and other RNA genes (tRNAs  and other  small nuclear RNAs (snRNAs)). They are classified under snRNA in MeSH. SnoRNAs are commonly referred to as guide RNAs but should not be confused with the guide RNAs (gRNA) that direct RNA editing in trypanosomes.

"Small nucleolar RNAs (snoRNAs) are 60–300-nucleotide-long RNAs located in the nucleolus or in Cajal bodies. They constitute one of the most abundant classes of ncRNAs [9]. Predominantly intronic, 300 different snoRNA sequences are located in the human genome. They are classified into two categories, those containing boxes C and D; and, those containing boxes H and ACA. snoRNAs are generated after splicing, debranching, and trimming of mRNA introns. Subsequently, mature snoRNAs associate with proteins to form small nucleolar ribonucleoproteins (snoRNPs). These complexes are exported into the nucleolus to participate in rRNA processing [5]."[1]

Tiny "RNAs with a modal length of 18 nt [...] map within -60 to +120 nt of transcription start sites (TSSs) in human, chicken and Drosophila. These transcription initiation RNAs (tiRNAs) are derived from sequences on the same strand as the TSS and are preferentially associated with G+C-rich promoters. The 5' ends of tiRNAs show peak density 10-30 nt downstream of TSSs, indicating that they are processed. tiRNAs are generally, although not exclusively, associated with highly expressed transcripts and sites of RNA polymerase II binding."[2]

"With exception of U3 all box C/D snoRNAs presented in this study are intron-encoded, as it is the general pathway for the biogenesis of this class of snoRNAs (22)."[3]

"Box C/D snoRNAs [...] contain conserved Box C (UGAUGA) and Box D (CUGA) elements located closely to the 5′- and 3′-ends, respectively. Internal copies of these elements are termed Box C′ and Box D′ (20,21)."[3]

Five "principal motif-based classes of D. melanogaster promoters were proposed15, which could be further grouped into three general functional classes16."[4]

"Type I consists of the tissue-specific promoters, which are similar to the low-CpG class in mammals with respect to motif composition, stage of development at which they are expressed and tissue specificity, and they are characterized by a high enrichment for a TATA box at an appropriate distance from an initiator element (Inr element). Type II promoters are associated with ‘housekeeping’ genes and genes that are regulated at the level of individual cells; they have either a DNA recognition element (DRE) or a combination of novel motifs15. Finally, type III promoters have an Inr element only or an Inr element plus a downstream promoter element (DPE). These promoters are preferentially associated with developmentally regulated genes, the expression of which is precisely coordinated across different cells in a tissue or anatomical structure16."[4]

## Contents

* 1 snoRNA guided modifications
* 2 snoRNA guide families
* 2.1 C/D box
* 2.2 H/ACA box
* 2.3 Composite H/ACA and C/D box
* 3 snoRNA targets
* 4 Target modifications
* 5 Genomic organisation
* 6 Other functions of snoRNA
* 7 References
* 8 External links

## snoRNA guided modifications

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After transcription, nascent rRNA molecules (termed pre-rRNA) are required to undergo a series of processing steps in order to generate the mature rRNA molecule. Prior to cleavage by exo- and endonucleases the pre-rRNA undergoes a complex pattern of nucleoside modifications. These include methylations and pseudouridylations, guided by snoRNAs.

* Methylation is the attachment or substitution of a methyl group onto various substrates. The rRNA of humans contain approximately 115 methyl group modifications. The majority of these are 2'O-ribose-methylations ( where the methyl group is attached to the ribose group) [5].

* Pseudouridylation is the conversion (isomerisation) of the nucleoside uridine to a different isomeric form pseudouridine(Ψ). Mature human rRNAs contain approximately 95 Ψ modifications[5].

Each snoRNA molecule acts as a guide for only one (or two) individual modifications in a target RNA. In order to carry out modification, each snoRNA associates with at least four protein molecules in an RNA/protein complex referred to as a small nucleolar ribonucleoprotein (snoRNP). The proteins associated with each RNA depend on the type of snoRNA molecule (see snoRNA guide families below). The snoRNA molecule contains an antisense element (a stretch of 10-20 nucleotides) which are base complementary to the sequence surrounding the base (nucleotide) targeted for modification in the pre-RNA molecule. This enables the snoRNP to recognise and bind to the target RNA. Once the snoRNP has bound to the target site the associated proteins are in the correct physical location to catalyse the chemical modification of the target base.

## snoRNA guide families

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"Small nucleolar RNAs (snoRNAs) are noncoding RNAs involved in the processing and modification of ribosomal RNAs. They are grouped in two distinct families, the box C/D family, which catalyzes methylation of 2′-hydroxyls of the pre-rRNA precursor, and the box H/ACA family, which catalyzes the modification of uridines into pseudouridines in various RNAs (reviewed in Refs. [24] and [40])."[6]

The two different types of rRNA modification (methylation and pseudouridylation) are directed by two different families of snoRNPs. These families of snoRNAs are referred to as antisense C/D box and H/ACA box snoRNAs based on the presence of conserved sequence motifs in the snoRNA. There are exceptions but as a general rule C/D box members guide methylation and H/ACA members guide pseudouridylation. The members of each family may vary in biogenesis, structure and function but each family is classified by the following generalised characteristics. For more detail see review [7].

### C/D box

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File:RF00071.jpgExample of a C/D box snoRNA secondary structure taken from the Rfam database. This example is  SNORD73 (RF00071).

C/D box snoRNAs contain two short conserved sequence motifs, C (UGAUGA) and D (CUGA) located near the 5' and 3' ends of the snoRNA respectively. Short regions (~ 5 nucleotides) located  upstream of the C box and downstream of the D box are usually base complementary and form a stem-box structure which brings the C and D box motifs into close proximity. This stem-box structure has been shown to be essential for correct snoRNA synthesis and nucleolar localization [8]. Many C/D box snoRNA also contain an additional less well conserved copy of the C and D motifs (referred to as C' and D') located in the central portion of the snoRNA molecule. A conserved region of 10-21 nucleotides upstream of the D box is complementary to the methylation site of the target RNA and enables the snoRNA to form and RNA duplex with the RNA [9]. The nucleotide to be modified in the target RNA is usually located at the 5th position upstream from the D box (or D' box) [10] [11]. Box C/D snoRNAs associate with four evolutionary conserved and essential proteins ( Fibrillarin (Nop1p), Nop56p, Nop58p and Snu13 ) which make up the core C/D box snoRNP [7].

### H/ACA box

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File:RF00265.jpgExample of a H/ACA box snoRNA secondary structure taken from the Rfam database. This example is  SNORA69 (RF00265).

H/ACA box snoRNAs have a common secondary structure consisting of a two hairpins and two single stranded regions termed a hairpin-hinge-hairpin-tail structure [7]. H/ACA snoRNAs also contain conserved sequence motifs known as H box (consensus ANANNA) and the ACA box (ACA). Both motifs are usually located in the single stranded regions of the secondary structure. The H motif is located in the hinge and the ACA motif is located in the tail region, 3 nucleotides from the 3' end of the sequence [12]. The hairpin regions contain internal bulges known as recognition loops in which the antisense guide sequences (bases complementary to the target sequence) are located. This recognition sequence is bipartite (constructed from the two different arms of the loop region) and forms complex  pseudo-knots with the target RNA. H/ACA box snoRNAs associate with four evolutionary conserved and essential proteins ( dyskerin (Cbf5p), Gar1p, Nhp2p and Nop10p) which make up the core of the H/ACA box snoRNP [7].

### Composite H/ACA and C/D box

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An unusual guide snoRNA U85 was identified that functions in both 2'-O-ribose methylation and pseudouridylation of small nuclear RNA (snRNA) U5 [13]. This composite snoRNA contains both C/D and H/ACA box domains and associates with the proteins specific to each class of snoRNA (fibrillaring and Gar1p respectively. More composite snoRNAs have now been characterised [14].

These composite snoRNAs have been found to accumulate in a subnuclear organelle called the Cajal body and are referred to as  Cajal body specific RNAs. This is in contrast to the majority of C/D box or H/ACA box snoRNAs which localise to the nucleolus. These Cajal body specific RNAs and are proposed to be involved in the modification of RNA polymerase II transcribed spliceosomal RNAs U1, U2, U4, U5 and U12[14]. Not all snoRNAs that have been localised to Cajal bodies are composite C/D and H/ACA box snoRNAs.

## snoRNA targets

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The targets for newly identified snoRNAs are predicted on the basis of sequence complementarity between putative target RNAs and the antisense elements or recognition loops in the snoRNA sequence. However, there are an increasing number of 'orphan' guides without any known RNA targets, which suggests that there might be more proteins or transcripts involved in rRNA than previously and/or that some snoRNAs have different functions not concerning rRNA.[15]

## Target modifications

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The precise effect of the methylation and pseudouridylation modifications on the function of the mature RNAs is not yet known. The modifications do not appear to be essential but are known to subtly enhance the RNA folding and interaction with ribosomal proteins. In support of their importance, target site modifications are exclusively located within conserved and functionally important domains of the mature RNA and are commonly conserved amongst distant eukaryotes [7].

1. 2'-O-methylated ribose causes an increase in the 3'-endo conformation
2. Pseudouridine (psi/Ψ) adds another option for H-bonding.
3. Heavily methylated RNA is protected from hydrolysis. rRNA acts as a ribozyme by catalyzing its own hydrolysis and splicing.

## Genomic organisation

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The majority of snoRNA genes are encoded in the introns of proteins involved in ribosome synthesis or translation, and are synthesized by RNA polymerase II, but can also be transcribed from their own promoters by RNA polymerase II or III.

## Other functions of snoRNA

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Recently, it has been found that snoRNAs can have functions not related to rRNA. One such function is the regulation of alternative splicing of the trans gene transcript, which is done by the snoRNA HBII-52.[16]

## References

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1. ↑ Yannick Delpu, Dorian Larrieu, Marion Gayral, Dina Arvanitis, Marlène Dufresne, Pierre Cordelier, Jérôme Torrisani (2016). Gerda Egger and Paola Arimondo, ed. Noncoding RNAs, In: Drug Discovery in Cancer Epigenetics. sciencedirect. pp. 305–326. ISBN 978-0-12-802208-5. Retrieved 2018-05-16.CS1 maint: Multiple names: authors list (link)
2. ↑ RJ Taft, EA Glazov, N Cloonan, C Simons, S Stephen, GJ Faulkner, T, Lassmann, AR Forrest, SM Grimmond, K Schroder, K Irvine, T Arakawa, M Nakamura, A Kubosaki, K Hayashida, C Kawazu, M Murata, H Nishiyori, S Fukuda, J Kawai, CO Daub, DA Hume, H Suzuki, V Orlando, P Carninci, Y Hayashizaki, JS Mattick (May 2009). "Tiny RNAs associated with transcription start sites in animals". Nature Genetcs. 41 (5): 572–8. doi:10.1038/ng.312. Retrieved 2018-05-16.CS1 maint: Multiple names: authors list (link)
3. ↑ 3.0 3.1 Markus Brameier, Astrid Herwig, Richard Reinhardt, Lutz Walter, Jens Gruber (1 January 2011). "Human box C/D snoRNAs with miRNA like functions: expanding the range of regulatory RNAs". Nucleic Acids Research. 39 (2): 675–686. doi:10.1093/nar/gkq776. Retrieved 2018-05-16.CS1 maint: Multiple names: authors list (link)
4. ↑ 4.0 4.1 Boris Lenhard, Albin Sandelin and Piero Carninci (April 2012). "Metazoan promoters: emerging characteristics and insights into transcriptional regulation" (PDF). Nature Reviews Genetics. 13: 233–245. Retrieved 2018-04-30.
5. ↑ 5.0 5.1 Maden BE, Hughes JM (1997). "Eukaryotic ribosomal RNA: the recent excitement in the nucleotide modification problem". Chromosoma. 105 (7–8): 391–400. PMID 9211966.
6. ↑ Kevin Roy and Guillaume F. Chanfreau (2012). "Eukaryotic RNases and their Partners in RNA Degradation and Biogenesis, Part A, In: The Enzymes". sciencedirect. Retrieved 2018-05-16.
7. ↑ 7.0 7.1 7.2 7.3 7.4 Bachellerie, JP (2002). "The expanding snoRNA world". Biochimie. 84: 775–790. doi:10.1016/S0300-9084(02)01402-5. PMID 12457565. Unknown parameter `|coauthors=` ignored (help)
8. ↑ Samarsky, DA (1998). "The snoRNA box C/D motif directs nucleolar targeting and also couples snoRNA synthesis and localization". EMBO. 17: 3747–3757. doi:10.1093/emboj/17.13.3747. PMID 9649444. Unknown parameter `|coauthors=` ignored (help)
9. ↑ Kiss-László Z, Henry Y, Kiss T (1998). "Sequence and structural elements of methylation guide snoRNAs essential for site-specific ribose methylation of pre-rRNA". EMBO J. 17 (3): 797–807. doi:10.1093/emboj/17.3.797. PMID 9451004.CS1 maint: Multiple names: authors list (link)
10. ↑ Cavaillé J, Nicoloso M, Bachellerie JP (1996). "Targeted ribose methylation of RNA in vivo directed by tailored antisense RNA guides". Nature. 383 (6602): 732–5. doi:10.1038/383732a0. PMID 8878486.CS1 maint: Multiple names: authors list (link)
11. ↑ Kiss-László Z, Henry Y, Bachellerie JP, Caizergues-Ferrer M, Kiss T (1996). "Site-specific ribose methylation of preribosomal RNA: a novel function for small nucleolar RNAs". Cell. 85 (7): 1077–88. PMID 8674114.CS1 maint: Multiple names: authors list (link)
12. ↑ Ganot P, Caizergues-Ferrer M, Kiss T (1997). "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): 941–56. PMID 9106664.CS1 maint: Multiple names: authors list (link)
13. ↑ Jády BE, Kiss T (2001). "A small nucleolar guide RNA functions both in 2'-O-ribose methylation and pseudouridylation of the U5 spliceosomal RNA". EMBO J. 20 (3): 541–51. doi:10.1093/emboj/20.3.541. PMID 11157760.
14. ↑ 14.0 14.1 Darzacq X, Jády BE, Verheggen C, Kiss AM, Bertrand E, Kiss T (2002). "Cajal body-specific small nuclear RNAs: a novel class of 2'-O-methylation and pseudouridylation guide RNAs". EMBO J. 21 (11): 2746–56. doi:10.1093/emboj/21.11.2746. PMID 12032087.CS1 maint: Multiple names: authors list (link)
15. ↑ Gingeras, Thomas R. (2007). "Origin of phenotypes: Genes and transcripts". Genome Research. 17 (6): 682–690. doi:10.1101/gr.6525007. PMID 17567989.
16. ↑ Kishore S, Stamm S (2006). "The snoRNA HBII-52 regulates alternative splicing of the serotonin receptor 2C". Science. 311 (5758): 230–231. doi:10.1126/science.1118265. PMID 16357227.

## External links

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* Small+Nucleolar+RNA at the US National Library of Medicine Medical Subject Headings (MeSH)
* Small+Nuclear+RNA at the US National Library of Medicine Medical Subject Headings (MeSH)
* Rfam database of RNA families
* snoRNAbase: human H/ACA and C/D box snoRNA database
* plant snoRNA database

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