BBAGRM-00708; No. of pages: 6; 4C: Biochimica et Biophysica Acta xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Biochimica et Biophysica Acta
Review
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The many faces of small nucleolar RNAs
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Tomaž Bratkovič a, Boris Rogelj b,⁎
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Article history: Received 28 February 2014 Received in revised form 7 April 2014 Accepted 8 April 2014 Available online xxxx
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Keywords: Orphan snoRNA Bifunctional snoRNA miRNA Alternative splicing Posttranscriptional modification
University of Ljubljana, Faculty of Pharmacy, Department of Pharmaceutical Biology, Aškerčeva 7, SI-1000 Ljubljana, Slovenia Jozef Stefan Institute, Department of Biotechnology, Jamova 39, SI-1000 Ljubljana, Slovenia
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Small nucleolar RNAs (snoRNAs) are a class of evolutionally conserved non-coding RNAs traditionally associated with nucleotide modifications in other RNA species. Acting as guides pairing with ribosomal (rRNA) and small nuclear RNAs (snRNAs), snoRNAs direct partner enzymes to specific sites for uridine isomerization or ribose methylation, thereby influencing stability, folding and protein-interacting properties of target RNAs. In recent years, however, numerous non-canonical functions have also been ascribed to certain members of the snoRNA group, ranging from regulation of mRNA editing and/or alternative splicing to posttranscriptional gene silencing by a yet poorly understood pathway that may involve microRNA-like mechanisms. While some of these intriguing snoRNAs (the so-called orphan snoRNAs) have no sequence complementarity to rRNA or snRNA, others apparently display dual functionality, performing both traditional and newly elucidated functions. Here, we review the effects elicited by non-canonical snoRNA activities. © 2014 Published by Elsevier B.V.
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1. Introduction
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Small nucleolar RNAs (snoRNAs) have long been recognized as components of ribonucleoproteins (RNPs) responsible for posttranscriptional modification of RNA targets, primarily ribosomal (rRNAs) and small nuclear RNAs (snRNAs) [1,2]. The role of snoRNAs is to provide a scaffold onto which partner proteins assemble, and to function as guides for specific recognition and tethering of target RNAs, thereby specifying the modification site. For most snoRNAs, targets have not been experimentally verified [3] due to redundancy; often, there are numerous copies of specific snoRNA genes, while some modified positions are predicted to be targeted by more than a single snoRNA [4,5]. Therefore, knockout approaches cannot easily be applied in functional studies, and antisense and ribozyme-based technologies are severely hampered by shielding of snoRNAs by partner proteins in snoRNPs [6]. Moreover, lack of a single nucleotide modification on target RNA produces no, or merely slight, phenotype changes and detrimental effects on cellular growth are only observed when numerous modifications are abolished simultaneously (e.g., [7–9]). Despite allegedly performing essential and universal functions, some snoRNAs are differentially expressed with regard to cell type [10], developmental status [11,12], or environmental factors [13–15], and deletion of imprinted genetic locus at 15q11–q13 containing
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Abbreviations: 5-HT2cR, serotonin receptor subtype 2c; CB, Cajal body; CJD, Creutzfeldt–Jakob disease; lncRNA, long non-coding RNA; miRNA, microRNA; psnoRNA, processed small nucleolar RNA; PWS, Prader–Willi syndrome; scaRNA, small Cajal RNA; sdRNA, small nucleolar RNA-derived RNA; SNORA, H/ACA-box small nucleolar RNA; SNORD, C/D-box small nucleolar RNA; TERC, telomerase RNA component ⁎ Corresponding author. Tel.: +386 14773411. E-mail addresses: [email protected] (T. Bratkovič), [email protected] (B. Rogelj).
several snoRNA genes is known to result in a disorder known as the Prader–Willi syndrome [16–19]. Such realizations stirred up a ‘gold rush’ in delineating alternative functions that are unlikely to be explained merely by rRNA or snRNA decoration. Here, we arbitrarily classify snoRNAs to canonical (guiding rRNA or snRNA modifications), orphan (displaying no sequence complementarity to known modified positions of canonical targets and therefore possibly directing the modification of other RNA species), and bifunctional snoRNAs (apparently performing both roles), and discuss the recently identified non-canonical functions of snoRNAs.
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2. Canonical snoRNAs
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Early studies of snoRNA function have uncovered a role in rRNA maturation [20–22], also explaining their evolutionary conservation from Archaea to higher eukaryotes [23]. Based on the structural properties, snoRNAs are classified into two families, C/D-box and H/ACA-box snoRNAs (Fig. 1), each being associated with a distinct set of partner proteins to form C/D or H/ACA snoRNPs, respectively. C/D-box snoRNAs (SNORDs) principally guide 2′-O-methylation of ribose rings, while H/ACA-box snoRNAs (SNORAs) define uridine nucleotides for conversion to pseudouridine isomers. Nucleotides to be modified are specified through Watson–Crick base pairing between the target RNA and the so-called antisense element of snoRNA. For details on biogenesis of snoRNAs and mode of action of canonical snoRNPs readers are referred to recent reviews [22,24]. Extensive posttranscriptional modification of rRNAs profoundly influences folding and dictates ribosome assembly and its interactions with components of translational machinery [25,26]. The same holds true for snRNAs and the assembly and function of snRNPs in the spliceosome
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http://dx.doi.org/10.1016/j.bbagrm.2014.04.009 1874-9399/© 2014 Published by Elsevier B.V.
Please cite this article as: T. Bratkovič, B. Rogelj, The many faces of small nucleolar RNAs, Biochim. Biophys. Acta (2014), http://dx.doi.org/10.1016/ j.bbagrm.2014.04.009
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A number of snoRNAs show no apparent complementarity to known modified positions in rRNAs or snRNAs and were therefore proposed to guide modification of other RNA species. Compelling evidence has been gathered for SNORD115 family of snoRNAs, which in humans and mice are expressed exclusively in the brain, to direct modification of serotonin receptor subtype 2c (5-HT2cR) pre-mRNA [41–43]. SNORD115 is embedded in introns of a large multicistronic transcript SNURF/ SNRPN, expressed from the paternal locus only, sections of which were found to be deleted in individuals with Prader–Willi syndrome (PWS). PWS is a developmental and cognitive disorder, characterized by low muscle tone, delayed or incomplete sexual maturity, mild mental retardation, behavioral problems, and compulsive eating, leading to morbid obesity if not controlled. Interestingly, obsessive–compulsive
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symptoms in affected individuals can be ameliorated with selective serotonin reuptake inhibitor therapy [44], indicating a defect in serotonin signaling. SNORD115 contains a conserved 18 nucleotide antisense element complementary to a segment of an alternatively spliced exon of 5-HT2cR pre-mRNA [16]. Moreover, the second intron of 5-HT2cR pre-mRNA harbors an H/ACA snoRNA [16], suggesting that the receptor's primary transcript itself might be directed to nucleolus for processing. In 1997 Burns et al. [45] discovered that 5-HT2cR transcripts undergo site specific adenosine-to-inosine (A-to-I) editing, leading to alternative translational products. Specifically, the amino acid sequence variation is confined to the second intracellular loop contacting G proteins. The resulting receptor variants display significant differences in signal transduction efficacy. Accordingly, mutant mice solely expressing the fully edited receptor isoform recapitulate many phenotypic traits of PWS [46]. Intriguingly, in 2005 Vitali et al. [41] showed that modification exerted by SNORD115 on the same 5-HT2cR pre-mRNA segment antagonizes editing by the nuclear enzyme ADAR2 (adenosine deaminase acting on RNA 2). Specifically, SNORD115 snoRNP is believed to prevent A-to-I editing through ribose methylation, thereby inactivating the exonic silencer of splicing. The alternatively spliced exon Vb is thus incorporated in the mature mRNA, giving rise to fully functional receptor. Soon after, Kishore and Stamm [42] presented evidence that exon Vb inclusion might be methylation-independent and proposed that SNORD115 snoRNP transiently associates with receptor pre-mRNA, directly masking the silencer of splicing. A further study revealed that the same snoRNA is actually processed to shorter RNAs (called processed snoRNAs (psnoRNAs)) which, instead of forming canonical snoRNPs, associate with heterogeneous nuclear ribonucleoproteins (hnRNPs) to affect splicing of multiple other pre-mRNAs [43]. In a mouse model of PWS lacking SNORD115 expression, however, only an increase in editing, but not a shift in splicing pattern of 5-HT2cR could be confirmed [47]. Some authors even warn against considering enhanced 5-HT2cR editing as the PWS disease mechanism altogether [48] due to the fact that the abnormal 5-HT2cR editing pattern cannot be consistently linked to the PWS phenotype. In addition to 47 repeats of SNORD115 genes human PWS locus at 15q11–q13 harbors 27 repeats of SNORD116, two copies of SNORD9, and single SNORD64 and SNORD107 genes, along with a number of protein-coding genes, giving rise to a huge polycistronic transcript in neurons. All the PWS locus snoRNAs are of intronic origin as is the case with most vertebrate snoRNAs. With the exception of SNORD9, predicted to guide the 2′-O-ribose methylation of U6 snRNA A53 [49], other PWS locus snoRNAs have no known targets. Recently, paternal
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[27,28]. In snRNAs, however, some modifications are snoRNAindependent (i.e., catalyzed by enzymes that do not require RNA guides). A subset of snoRNAs that pair with rRNAs does not direct pseudouridylation or 2′-O-ribose methylation, but rather acts as molecular chaperones [29–36]. They are essential for correct folding of the prerRNA that is subsequently nucleolitically processed into 18S, 5.8S and 28S rRNAs by trans-acting endonucleases. As their name suggests, snoRNAs are enriched in nucleolus, where the assembly of ribosomal subunits takes place. A group of snoRNAs, however, specifically localizes to Cajal bodies (CBs), dynamic subnuclear foci involved in RNA metabolism and snRNP as well as snoRNP biogenesis, and is thus referred to as small Cajal RNAs (scaRNAs) [37]. A common feature of scaRNAs is the Cajal body localization signal, the CAB-box (motif UGAG), that ensures accumulation in CBs. scaRNAs adhere to C/D-H/ACA classification, but some contain structural traits characteristic of both main classes of snoRNAs. Such chimeric scaRNAs associate with both sets of canonical snoRNA protein partners, suggesting a dual role (i.e., in guiding ribose methylation and pseudouridylation). To date, however, this was only confirmed for a single scaRNA, U85, that functions both in 2′-O-ribose methylation and pseudouridylation of the U5 spliceosomal RNA [38]. Another atypical scaRNA not involved in RNA methylation or pseudouridylation is the telomerase RNA component (TERC). TERC serves as a template for telomere synthesis by the telomerase protein component, thereby ensuring genome integrity. The CABbox and the 3′-H/ACA domain of TERC are thought to contribute to correct localization and processing of precursor RNA, and to telomerase RNP assembly [39,40].
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Fig. 1. Structural features of C/D-box and H/ACA-box snoRNA families. (A) C/D-box snoRNAs share a kink-turn (i.e., stem–bulge–stem) fold with characteristic 5′ C-box and 3′ D-box brought together by intramolecular base pairing, forming a large loop. Some family members contain additional copies of C- and/or D-boxes (denoted C′ and D′, respectively) located within the loop. Antisense element (ASE) encompassing 10–20 nts is located upstream of box D and/or box D′. Me denotes the site targeted for 2′-O-ribose methylation. (B) H/ACA snoRNAs are characterized by two stem–bulge–stem domains separated by a hinge region containing the H-box. The second conserved motif (ACA-box) is located at the 3′-terminus. One or both loops contain an ASE of bipartite nature composed of a stretch of 9 to 13 nucleotides in total, split between the two strands. Ψ represent the uracil nucleotide targeted for pseudouridylation. Target RNAs are depicted in gray. Figure adapted from Ref. [24].
Please cite this article as: T. Bratkovič, B. Rogelj, The many faces of small nucleolar RNAs, Biochim. Biophys. Acta (2014), http://dx.doi.org/10.1016/ j.bbagrm.2014.04.009
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There is ample evidence that snoRNA processing to short stable RNA species is a wide-spread phenomenon not limited to orphan snoRNAs. Using deep sequencing methods, snoRNA-derived RNAs (sdRNAs) have been identified in animals (human [65–71], rodents [67,72], Drosophila [67], and chicken [67]), plants [67], as well as in fission yeast [67] and protozoa [73]. Many sdRNAs display microRNA-like properties, such as dependence on Dicer processing (indeed, most H/ACA-box snoRNAs are substrate for Dicer as opposed to relatively few C/D-box snoRNAs [74]) and association with argonaute proteins [66–68,70,71], central components of RNA-induced silencing complex [75]. sdRNAs are not simply degradation products of snoRNAs as common processing patterns have been observed across snoRNAs, there are differences to the extent of processing of different snoRNAs in the same cell line, and most importantly, posttranstriptional gene silencing activity was confirmed for a number of miRNA-like sdRNAs (e.g. [68]). Not surprisingly, there are examples of RNAs previously considered canonical miRNAs that actually turned out to be H/ACA or C/D sdRNAs [66,68,71]. Abundance of data supports the hypothesis that snoRNAs and miRNAs have evolved from a common ancestral small RNA species or, possibly, that canonical miRNAs were evolutionally derived from a subset of snoRNAs that have lost their primary role to gain a new function (discussed in a recent review [76]). While orphan snoRNAs presumably do not carry out canonical functions, there are snoRNAs that seem to, in addition to guiding rRNA decoration, control intriguing cellular processes. Two recent papers report on independent forward genetic screens implicating different snoRNAs in promotion of oxidative stress [77] and regulation of cholesterol
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or partner interactions. This might also explain noted differences in snoRNA expression during development [11,62] and stress [14,15, 63,64]. Several brain-specific orphan snoRNAs (SNORD115, SNORD116, SNORA35, and rodent-specific C/D-box snoRNA MBII-48) are not uniformly expressed in the mouse brain, with higher levels being reported in the hippocampus and amygdala, areas associated with learning and memory. This observation led Rogelj et al. [13] to investigate hippocampal expression changes during contextual memory consolidation. Through the use of contextual fear conditioning, a Pavlovian method of learning that establishes association between stimuli and their aversive consequences, SNORD115 and MBII-48 were found up- and downregulated, respectively. The changes in expression levels were short-termed, detected 90 min but not 25 h after treatment. The results suggest a role for SNORD115 and MBII-48 in higher brain function, but the functional analysis remains hampered by lack of target RNA identification; potential differences in 5-HT2cR mRNA splicing pattern were examined, however, no changes accompanying SNORD115 upregulation were detected. Another orphan snoRNA (SNORD3A) appears to be involved in modulation of the endoplasmic reticulum (ER) unfolded protein response in prion disease [63]. Its expression was found upregulated in the blood of Creutzfeldt–Jakob disease (CJD) patients. Additionally, its upregulation in the brain was confirmed in two mice models of CJD (i.e., in mice with prion protein E200K mutation prone to develop spongiform encephalopathy and wild-type scrapie-infected mice in age and disease progression manner, respectively). Concomitantly, ATF6, a transcription factor required for elevated expression of chaperones, accumulated in the affected brains, but not in chaperone proteins. No further detailed mechanistic study was undertaken and thus it is not clear whether SNORD3A elicits the stress response, blocks production of chaperones to prevent ER function recovery, or its overexpression is merely an epiphenomenon of ER stress resulting from prion protein aggregation. Nevertheless, SNORD3A holds great potential as a disease marker, especially considering that CJD can only be confirmed postmortem through Western blotting or immunohistochemical analysis.
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microdeletions of the SNORD116 gene cluster were identified as the main genetic cause of PWS [17–19,50–52], although lack of SNORD115 expression likely contributes to the disease phenotype. Suggestions that the lack of expression of SNORD116/SNORD115 host genes might be the primary cause of PWS have also been made. Notably, the PWS locus exhibits some unusual properties; at snoRNA gene cluster allele-specific higherorder chromatin organization was observed and spliced SNORD116 and SNORD115 host genes accumulate near the site of transcription [53–55]. The SNORD116 host gene was implicated in control of diurnal energy expenditure of the brain by indirectly repressing a group of wellknown diurnally regulated genes that might explain the PWS phenotypic traits [55]. Furthermore, a class of long non-coding RNAs (lncRNAs), expressed from the PWS locus and containing a SNORD motif at 5′- and 3′-ends, was identified in human embryonic stem cells [56]. Such SNORD116-tract transcripts associate strongly with Fox family splicing regulators in the nucleus, potentially acting as sponges for these regulatory proteins and thereby suppressing their activity. Thus, lack of sno-lncRNAs in PWS might lead to increase in Fox levels and consequent abnormalities in pre-mRNA splicing, resulting in abnormal development. With regard to mature SNORD116, Shen et al. [57] used RNase protection analysis to demonstrate that SNORD116 intronic transcripts also give rise to shorter psnoRNAs, sharing a processing pattern to those of SNORD115. Importantly, they reported indications of specific processing events by confirming that not all C/D-box snoRNAs are cleaved. The physiological relevance of both psnoRNA sets is yet to be clarified. Bortolin–Cavaille and Cavaille [58] have argued against functional SNORD115/SNORD116 psnoRNAs, claiming that most represent mere endogenous RNA degradation products and/or cleaved fragments derived from imperfect pairing of the riboprobes and numerous SNORD115/SNORD116 variants. Nevertheless, it is tempting to speculate that SNORD116 or cognate psnoRNAs dictate splicing as SNORD116 family members were bioinformatically predicted to preferentially target exonic sequences of alternatively spliced primary transcripts [59]. 15q11–q13 locus snoRNAs are not a lone example of orphan snoRNAs clustered in imprinted locus. In humans, maternally expressed locus 14q32 harbors the C/D-box snoRNAs (denoted SNORD112–114) that share notable similarities with PWS locus snoRNAs in terms of gene organization [60]. Both loci harbor tandemly repeated snoRNA genes that are processed from common complex primary transcripts. Moreover, both snoRNA groups show similar tissue-specific expression, being most abundant in uterine mucous membrane and brain. In rodents, locus orthologous to human 14q32 gives rise to strictly brain specific snoRNAs with no significant homology to human counterparts, which contrasts the situation at PWS imprinted locus. Yet, in humans and in mice, both loci are developmentally regulated in neurons and display significant parenteral-specific chromatin decondensation [61]. Interestingly, when chromatin loosening was interrogated over diverse highly transcribed genetic loci in mice neurons, only PWS and 12qF1 (orthologous to 14q32 in human) loci were found fully decondensed at paternal and maternal alleles, respectively. The mere imprinting and transcription of non-coding RNAs or long transcripts were found insufficient for decondensation. This implies that snoRNA cluster genomic neighborhood is vital for chromatin remodeling. Furthermore, chromatin decondensation at imprinted snoRNA loci appears to be required for proper nucleolar size during neuronal maturation as Purkinje cells of mice lacking SNORD115/SNORD116 expression had significantly smaller nucleoli compared to wild-type littermates [61]. The authors reasoned that neuron-specific snoRNAs may be implicated in rRNA modification after all. Indeed, Kehr et al. [5] have recently reported bioinformatic prediction of rRNA targets for a number of orphan snoRNA families, including SNORD116, and suggested that undetected rRNA modifications take place only under certain conditions. The nucleotides presumed to be targeted lie next to highly structured pseudoknotted segments, indicating that modification might fine-tune rRNA fold and/
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Please cite this article as: T. Bratkovič, B. Rogelj, The many faces of small nucleolar RNAs, Biochim. Biophys. Acta (2014), http://dx.doi.org/10.1016/ j.bbagrm.2014.04.009
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Bioinformatic prediction of snoRNA targets is rather unreliable due to relatively short nucleotide stretches that constitute snoRNA antisense elements as well as tolerance for mismatches upon target pairing [5,84]. Thus, experimental identification of non-canonical snoRNA protein partners and/or RNA targets (or alternative ones in case of bifunctional snoRNAs) is the key to understanding the many faces of these non-coding RNAs. Approaches such as RNA pull-down and co-immunoprecipitation coupled with mass spectrometry will be of paramount importance. Several snoRNAs are expressed at different levels across various cell types [68,85] which can be attributed to regulation of host genes harboring snoRNAs. Additionally, biological (e.g., developmental stage [11,62] or genetic factors [63,64]) and environmental factors ([13–15]) may provoke differences in snoRNA expression, and possibly also their choice of partners. Therefore, designing experiments in a way to recapitulate biologically relevant situations will be crucial. Bifunctional snoRNAs are believed to be incorporated in more than a single RNP particle, each performing a distinct task [86]. Similar structural and functional plasticity was recently proposed for miRNA–argonaute complexes [87], whereby addition of various accessory proteins would explain the observed complexity of miRNPs, both in the mode of action and the extent of translational repression [75]. Alternative snoRNPs are likely to coexist, some at considerably lower levels than others, yet both being physiologically relevant. As the canonical snoRNP may, due to its ubiquity, mask other form(s), highly sensitive detection methods are needed. Advances in snoRNA knockdown, such as the use of 2′-methyloxylethyl modified phosphorothioate backbone-containing RNA–DNA chimeric antisense oligonucleotides enabling highly specific and efficient depletion of snoRNAs [88], should also facilitate functional studies.
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to be occupied by transcription factor SREBP1, one of the main regulators of cholesterol uptake and synthesis [83], providing a potential direct link between SNORD60 expression and cellular cholesterol regulating machinery at transcriptional level.
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homeostasis [78], respectively. In both cases promoter trap mutagenesis in CHO cells coupled with phenotypic screening led the researches to identification of loss of function mutation in genes harboring intronic snoRNAs. Unexpectedly, they showed that loss of specific snoRNAs and not the spliced exonic transcripts is responsible for the observed traits. Furthermore, there were no indications that any of these snoRNAs might serve as precursor of miRNAs, implying a separate mechanism of action. Promoter trap mutagenesis enables unbiased forward genetic screening as it relies on random genomic integration of retroviral vector harboring promoterless neomycin-resistance conferring cassette. Thus, a gene is inactivated only when the provirus is inserted downstream of a functional endogenous promoter, essentially hijacking it to express aminoglycoside 3′-phosphotransferase, a neomycin-inactivating enzyme [79]. In the first study, Michel et al. [77] screened transduced geneticin-resistant CHO cells for resistance to palmitate-induced apoptosis. The selected mutant cell line endured not only palmitate but also hydrogen peroxide treatment as well, indicating that it can withstand a wide range of oxidative stress. The causative mutation was traced to gene rpl13a encoding 60S ribosomal protein L13a along with four intronic snoRNAs (SNORD32A, -33, -34, and -35A). In contrast to the mutant cell line, palmitate exposure induced upregulation of three snoRNAs (SNORD32A, -33, and -35A; but not the mature rpl13a mRNA), in wild-type CHO cells and murine myoblasts. Ectopic expression of the intact murine rpl13a genomic locus (but not the one with intronic snoRNAs removed) in palmitate-resistant CHO cells rescued the mutant phenotype. Similarly, knockdown in murine myoblasts of all three snoRNAs using antisense oligonucleotides brought about palmitate resistance. The effect was SNORD32A/33/35A-specific and required that all three snoRNAs be knocked down concomitantly. No differences in the extent of ribose methylation at the predicted rRNA modification sites for any of the rpl13a snoRNAs in wild-type and mutant CHO cells under basal or palmitate-treated conditions were detected, suggesting an additional non-canonical role in oxidative stress propagation. This is further supported by the observation that murine myoblasts, when exposed to lipotoxic palmitate, show increased cytoplasmic levels of rpl13a snoRNAs, whereas their nuclear levels are unchanged. There is compelling evidence that these snoRNAs work in concert as mediators of oxidative stress, however, the mechanism by which they elicit cellular death remains elusive. The mere fact that they reside in the cytosol is compatible with a potential role in regulation of translation. miRNAs have previously been identified as trans acting factors that promote sequestration of mRNAs to processing bodies and stress granules, cytoplasmic RNP foci inaccessible to translational machinery [75,80,81]. Considering evolutional linkage of miRNAs and snoRNAs, it is feasible that rpl13a snoRNAs act in a similar manner, recruiting specific mRNAs to processing bodies, stress granules, or related submicroscopic structures [82]. In the second study, Brandis et al. [78] performed a positive selection of transduced geneticin-resistant CHO cells for resistance to amphotericin B (a cholesterol-binding toxin) following low-density lipoprotein (LDL) treatment to identify mutants with deficiency in cholesterol trafficking from plasma membrane to ER. A mutant cell line was recovered that displayed increased rate of de novo cholesterol synthesis and decrease in plasma membrane cholesterol esterification, which was attributed to defects in sensing cellular cholesterol levels. The researchers found a single insertional mutation residing in SNORD60 host gene (SNORD60hg). When the mutant cell line was complemented with murine SNORD60hg (that, as opposed to hamster ortholog, has no open reading frames) the mutant phenotype was rescued. In addition to the unexpected role in regulating cholesterol homeostasis, SNORD60 was confirmed to associate with canonical snoRNP proteins, presumably to guide 28S rRNA G4340 2′-O-methylation. Yet, no reduction of methylation at the predicted rRNA target site could be associated with SNORD60 insufficiency. Thus, the SNORD60 non-canonical mode of action awaits elucidation. Of note, in HepG2 cells SNORD60hg was previously shown
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This work was supported by the Slovenian Research Agency [grant 397 numbers J3-2356, J3-4026, J3-5502 and P4-0127]. 398 References
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Contents lists available at ScienceDirect
Biochimica et Biophysica Acta
Review
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The many faces of small nucleolar RNAs
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Tomaž Bratkovič a, Boris Rogelj b,⁎
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Article history: Received 28 February 2014 Received in revised form 7 April 2014 Accepted 8 April 2014 Available online xxxx
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Keywords: Orphan snoRNA Bifunctional snoRNA miRNA Alternative splicing Posttranscriptional modification
University of Ljubljana, Faculty of Pharmacy, Department of Pharmaceutical Biology, Aškerčeva 7, SI-1000 Ljubljana, Slovenia Jozef Stefan Institute, Department of Biotechnology, Jamova 39, SI-1000 Ljubljana, Slovenia
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Small nucleolar RNAs (snoRNAs) are a class of evolutionally conserved non-coding RNAs traditionally associated with nucleotide modifications in other RNA species. Acting as guides pairing with ribosomal (rRNA) and small nuclear RNAs (snRNAs), snoRNAs direct partner enzymes to specific sites for uridine isomerization or ribose methylation, thereby influencing stability, folding and protein-interacting properties of target RNAs. In recent years, however, numerous non-canonical functions have also been ascribed to certain members of the snoRNA group, ranging from regulation of mRNA editing and/or alternative splicing to posttranscriptional gene silencing by a yet poorly understood pathway that may involve microRNA-like mechanisms. While some of these intriguing snoRNAs (the so-called orphan snoRNAs) have no sequence complementarity to rRNA or snRNA, others apparently display dual functionality, performing both traditional and newly elucidated functions. Here, we review the effects elicited by non-canonical snoRNA activities. © 2014 Published by Elsevier B.V.
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Small nucleolar RNAs (snoRNAs) have long been recognized as components of ribonucleoproteins (RNPs) responsible for posttranscriptional modification of RNA targets, primarily ribosomal (rRNAs) and small nuclear RNAs (snRNAs) [1,2]. The role of snoRNAs is to provide a scaffold onto which partner proteins assemble, and to function as guides for specific recognition and tethering of target RNAs, thereby specifying the modification site. For most snoRNAs, targets have not been experimentally verified [3] due to redundancy; often, there are numerous copies of specific snoRNA genes, while some modified positions are predicted to be targeted by more than a single snoRNA [4,5]. Therefore, knockout approaches cannot easily be applied in functional studies, and antisense and ribozyme-based technologies are severely hampered by shielding of snoRNAs by partner proteins in snoRNPs [6]. Moreover, lack of a single nucleotide modification on target RNA produces no, or merely slight, phenotype changes and detrimental effects on cellular growth are only observed when numerous modifications are abolished simultaneously (e.g., [7–9]). Despite allegedly performing essential and universal functions, some snoRNAs are differentially expressed with regard to cell type [10], developmental status [11,12], or environmental factors [13–15], and deletion of imprinted genetic locus at 15q11–q13 containing
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Abbreviations: 5-HT2cR, serotonin receptor subtype 2c; CB, Cajal body; CJD, Creutzfeldt–Jakob disease; lncRNA, long non-coding RNA; miRNA, microRNA; psnoRNA, processed small nucleolar RNA; PWS, Prader–Willi syndrome; scaRNA, small Cajal RNA; sdRNA, small nucleolar RNA-derived RNA; SNORA, H/ACA-box small nucleolar RNA; SNORD, C/D-box small nucleolar RNA; TERC, telomerase RNA component ⁎ Corresponding author. Tel.: +386 14773411. E-mail addresses: [email protected] (T. Bratkovič), [email protected] (B. Rogelj).
several snoRNA genes is known to result in a disorder known as the Prader–Willi syndrome [16–19]. Such realizations stirred up a ‘gold rush’ in delineating alternative functions that are unlikely to be explained merely by rRNA or snRNA decoration. Here, we arbitrarily classify snoRNAs to canonical (guiding rRNA or snRNA modifications), orphan (displaying no sequence complementarity to known modified positions of canonical targets and therefore possibly directing the modification of other RNA species), and bifunctional snoRNAs (apparently performing both roles), and discuss the recently identified non-canonical functions of snoRNAs.
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2. Canonical snoRNAs
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Early studies of snoRNA function have uncovered a role in rRNA maturation [20–22], also explaining their evolutionary conservation from Archaea to higher eukaryotes [23]. Based on the structural properties, snoRNAs are classified into two families, C/D-box and H/ACA-box snoRNAs (Fig. 1), each being associated with a distinct set of partner proteins to form C/D or H/ACA snoRNPs, respectively. C/D-box snoRNAs (SNORDs) principally guide 2′-O-methylation of ribose rings, while H/ACA-box snoRNAs (SNORAs) define uridine nucleotides for conversion to pseudouridine isomers. Nucleotides to be modified are specified through Watson–Crick base pairing between the target RNA and the so-called antisense element of snoRNA. For details on biogenesis of snoRNAs and mode of action of canonical snoRNPs readers are referred to recent reviews [22,24]. Extensive posttranscriptional modification of rRNAs profoundly influences folding and dictates ribosome assembly and its interactions with components of translational machinery [25,26]. The same holds true for snRNAs and the assembly and function of snRNPs in the spliceosome
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http://dx.doi.org/10.1016/j.bbagrm.2014.04.009 1874-9399/© 2014 Published by Elsevier B.V.
Please cite this article as: T. Bratkovič, B. Rogelj, The many faces of small nucleolar RNAs, Biochim. Biophys. Acta (2014), http://dx.doi.org/10.1016/ j.bbagrm.2014.04.009
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A number of snoRNAs show no apparent complementarity to known modified positions in rRNAs or snRNAs and were therefore proposed to guide modification of other RNA species. Compelling evidence has been gathered for SNORD115 family of snoRNAs, which in humans and mice are expressed exclusively in the brain, to direct modification of serotonin receptor subtype 2c (5-HT2cR) pre-mRNA [41–43]. SNORD115 is embedded in introns of a large multicistronic transcript SNURF/ SNRPN, expressed from the paternal locus only, sections of which were found to be deleted in individuals with Prader–Willi syndrome (PWS). PWS is a developmental and cognitive disorder, characterized by low muscle tone, delayed or incomplete sexual maturity, mild mental retardation, behavioral problems, and compulsive eating, leading to morbid obesity if not controlled. Interestingly, obsessive–compulsive
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symptoms in affected individuals can be ameliorated with selective serotonin reuptake inhibitor therapy [44], indicating a defect in serotonin signaling. SNORD115 contains a conserved 18 nucleotide antisense element complementary to a segment of an alternatively spliced exon of 5-HT2cR pre-mRNA [16]. Moreover, the second intron of 5-HT2cR pre-mRNA harbors an H/ACA snoRNA [16], suggesting that the receptor's primary transcript itself might be directed to nucleolus for processing. In 1997 Burns et al. [45] discovered that 5-HT2cR transcripts undergo site specific adenosine-to-inosine (A-to-I) editing, leading to alternative translational products. Specifically, the amino acid sequence variation is confined to the second intracellular loop contacting G proteins. The resulting receptor variants display significant differences in signal transduction efficacy. Accordingly, mutant mice solely expressing the fully edited receptor isoform recapitulate many phenotypic traits of PWS [46]. Intriguingly, in 2005 Vitali et al. [41] showed that modification exerted by SNORD115 on the same 5-HT2cR pre-mRNA segment antagonizes editing by the nuclear enzyme ADAR2 (adenosine deaminase acting on RNA 2). Specifically, SNORD115 snoRNP is believed to prevent A-to-I editing through ribose methylation, thereby inactivating the exonic silencer of splicing. The alternatively spliced exon Vb is thus incorporated in the mature mRNA, giving rise to fully functional receptor. Soon after, Kishore and Stamm [42] presented evidence that exon Vb inclusion might be methylation-independent and proposed that SNORD115 snoRNP transiently associates with receptor pre-mRNA, directly masking the silencer of splicing. A further study revealed that the same snoRNA is actually processed to shorter RNAs (called processed snoRNAs (psnoRNAs)) which, instead of forming canonical snoRNPs, associate with heterogeneous nuclear ribonucleoproteins (hnRNPs) to affect splicing of multiple other pre-mRNAs [43]. In a mouse model of PWS lacking SNORD115 expression, however, only an increase in editing, but not a shift in splicing pattern of 5-HT2cR could be confirmed [47]. Some authors even warn against considering enhanced 5-HT2cR editing as the PWS disease mechanism altogether [48] due to the fact that the abnormal 5-HT2cR editing pattern cannot be consistently linked to the PWS phenotype. In addition to 47 repeats of SNORD115 genes human PWS locus at 15q11–q13 harbors 27 repeats of SNORD116, two copies of SNORD9, and single SNORD64 and SNORD107 genes, along with a number of protein-coding genes, giving rise to a huge polycistronic transcript in neurons. All the PWS locus snoRNAs are of intronic origin as is the case with most vertebrate snoRNAs. With the exception of SNORD9, predicted to guide the 2′-O-ribose methylation of U6 snRNA A53 [49], other PWS locus snoRNAs have no known targets. Recently, paternal
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[27,28]. In snRNAs, however, some modifications are snoRNAindependent (i.e., catalyzed by enzymes that do not require RNA guides). A subset of snoRNAs that pair with rRNAs does not direct pseudouridylation or 2′-O-ribose methylation, but rather acts as molecular chaperones [29–36]. They are essential for correct folding of the prerRNA that is subsequently nucleolitically processed into 18S, 5.8S and 28S rRNAs by trans-acting endonucleases. As their name suggests, snoRNAs are enriched in nucleolus, where the assembly of ribosomal subunits takes place. A group of snoRNAs, however, specifically localizes to Cajal bodies (CBs), dynamic subnuclear foci involved in RNA metabolism and snRNP as well as snoRNP biogenesis, and is thus referred to as small Cajal RNAs (scaRNAs) [37]. A common feature of scaRNAs is the Cajal body localization signal, the CAB-box (motif UGAG), that ensures accumulation in CBs. scaRNAs adhere to C/D-H/ACA classification, but some contain structural traits characteristic of both main classes of snoRNAs. Such chimeric scaRNAs associate with both sets of canonical snoRNA protein partners, suggesting a dual role (i.e., in guiding ribose methylation and pseudouridylation). To date, however, this was only confirmed for a single scaRNA, U85, that functions both in 2′-O-ribose methylation and pseudouridylation of the U5 spliceosomal RNA [38]. Another atypical scaRNA not involved in RNA methylation or pseudouridylation is the telomerase RNA component (TERC). TERC serves as a template for telomere synthesis by the telomerase protein component, thereby ensuring genome integrity. The CABbox and the 3′-H/ACA domain of TERC are thought to contribute to correct localization and processing of precursor RNA, and to telomerase RNP assembly [39,40].
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Fig. 1. Structural features of C/D-box and H/ACA-box snoRNA families. (A) C/D-box snoRNAs share a kink-turn (i.e., stem–bulge–stem) fold with characteristic 5′ C-box and 3′ D-box brought together by intramolecular base pairing, forming a large loop. Some family members contain additional copies of C- and/or D-boxes (denoted C′ and D′, respectively) located within the loop. Antisense element (ASE) encompassing 10–20 nts is located upstream of box D and/or box D′. Me denotes the site targeted for 2′-O-ribose methylation. (B) H/ACA snoRNAs are characterized by two stem–bulge–stem domains separated by a hinge region containing the H-box. The second conserved motif (ACA-box) is located at the 3′-terminus. One or both loops contain an ASE of bipartite nature composed of a stretch of 9 to 13 nucleotides in total, split between the two strands. Ψ represent the uracil nucleotide targeted for pseudouridylation. Target RNAs are depicted in gray. Figure adapted from Ref. [24].
Please cite this article as: T. Bratkovič, B. Rogelj, The many faces of small nucleolar RNAs, Biochim. Biophys. Acta (2014), http://dx.doi.org/10.1016/ j.bbagrm.2014.04.009
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There is ample evidence that snoRNA processing to short stable RNA species is a wide-spread phenomenon not limited to orphan snoRNAs. Using deep sequencing methods, snoRNA-derived RNAs (sdRNAs) have been identified in animals (human [65–71], rodents [67,72], Drosophila [67], and chicken [67]), plants [67], as well as in fission yeast [67] and protozoa [73]. Many sdRNAs display microRNA-like properties, such as dependence on Dicer processing (indeed, most H/ACA-box snoRNAs are substrate for Dicer as opposed to relatively few C/D-box snoRNAs [74]) and association with argonaute proteins [66–68,70,71], central components of RNA-induced silencing complex [75]. sdRNAs are not simply degradation products of snoRNAs as common processing patterns have been observed across snoRNAs, there are differences to the extent of processing of different snoRNAs in the same cell line, and most importantly, posttranstriptional gene silencing activity was confirmed for a number of miRNA-like sdRNAs (e.g. [68]). Not surprisingly, there are examples of RNAs previously considered canonical miRNAs that actually turned out to be H/ACA or C/D sdRNAs [66,68,71]. Abundance of data supports the hypothesis that snoRNAs and miRNAs have evolved from a common ancestral small RNA species or, possibly, that canonical miRNAs were evolutionally derived from a subset of snoRNAs that have lost their primary role to gain a new function (discussed in a recent review [76]). While orphan snoRNAs presumably do not carry out canonical functions, there are snoRNAs that seem to, in addition to guiding rRNA decoration, control intriguing cellular processes. Two recent papers report on independent forward genetic screens implicating different snoRNAs in promotion of oxidative stress [77] and regulation of cholesterol
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or partner interactions. This might also explain noted differences in snoRNA expression during development [11,62] and stress [14,15, 63,64]. Several brain-specific orphan snoRNAs (SNORD115, SNORD116, SNORA35, and rodent-specific C/D-box snoRNA MBII-48) are not uniformly expressed in the mouse brain, with higher levels being reported in the hippocampus and amygdala, areas associated with learning and memory. This observation led Rogelj et al. [13] to investigate hippocampal expression changes during contextual memory consolidation. Through the use of contextual fear conditioning, a Pavlovian method of learning that establishes association between stimuli and their aversive consequences, SNORD115 and MBII-48 were found up- and downregulated, respectively. The changes in expression levels were short-termed, detected 90 min but not 25 h after treatment. The results suggest a role for SNORD115 and MBII-48 in higher brain function, but the functional analysis remains hampered by lack of target RNA identification; potential differences in 5-HT2cR mRNA splicing pattern were examined, however, no changes accompanying SNORD115 upregulation were detected. Another orphan snoRNA (SNORD3A) appears to be involved in modulation of the endoplasmic reticulum (ER) unfolded protein response in prion disease [63]. Its expression was found upregulated in the blood of Creutzfeldt–Jakob disease (CJD) patients. Additionally, its upregulation in the brain was confirmed in two mice models of CJD (i.e., in mice with prion protein E200K mutation prone to develop spongiform encephalopathy and wild-type scrapie-infected mice in age and disease progression manner, respectively). Concomitantly, ATF6, a transcription factor required for elevated expression of chaperones, accumulated in the affected brains, but not in chaperone proteins. No further detailed mechanistic study was undertaken and thus it is not clear whether SNORD3A elicits the stress response, blocks production of chaperones to prevent ER function recovery, or its overexpression is merely an epiphenomenon of ER stress resulting from prion protein aggregation. Nevertheless, SNORD3A holds great potential as a disease marker, especially considering that CJD can only be confirmed postmortem through Western blotting or immunohistochemical analysis.
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microdeletions of the SNORD116 gene cluster were identified as the main genetic cause of PWS [17–19,50–52], although lack of SNORD115 expression likely contributes to the disease phenotype. Suggestions that the lack of expression of SNORD116/SNORD115 host genes might be the primary cause of PWS have also been made. Notably, the PWS locus exhibits some unusual properties; at snoRNA gene cluster allele-specific higherorder chromatin organization was observed and spliced SNORD116 and SNORD115 host genes accumulate near the site of transcription [53–55]. The SNORD116 host gene was implicated in control of diurnal energy expenditure of the brain by indirectly repressing a group of wellknown diurnally regulated genes that might explain the PWS phenotypic traits [55]. Furthermore, a class of long non-coding RNAs (lncRNAs), expressed from the PWS locus and containing a SNORD motif at 5′- and 3′-ends, was identified in human embryonic stem cells [56]. Such SNORD116-tract transcripts associate strongly with Fox family splicing regulators in the nucleus, potentially acting as sponges for these regulatory proteins and thereby suppressing their activity. Thus, lack of sno-lncRNAs in PWS might lead to increase in Fox levels and consequent abnormalities in pre-mRNA splicing, resulting in abnormal development. With regard to mature SNORD116, Shen et al. [57] used RNase protection analysis to demonstrate that SNORD116 intronic transcripts also give rise to shorter psnoRNAs, sharing a processing pattern to those of SNORD115. Importantly, they reported indications of specific processing events by confirming that not all C/D-box snoRNAs are cleaved. The physiological relevance of both psnoRNA sets is yet to be clarified. Bortolin–Cavaille and Cavaille [58] have argued against functional SNORD115/SNORD116 psnoRNAs, claiming that most represent mere endogenous RNA degradation products and/or cleaved fragments derived from imperfect pairing of the riboprobes and numerous SNORD115/SNORD116 variants. Nevertheless, it is tempting to speculate that SNORD116 or cognate psnoRNAs dictate splicing as SNORD116 family members were bioinformatically predicted to preferentially target exonic sequences of alternatively spliced primary transcripts [59]. 15q11–q13 locus snoRNAs are not a lone example of orphan snoRNAs clustered in imprinted locus. In humans, maternally expressed locus 14q32 harbors the C/D-box snoRNAs (denoted SNORD112–114) that share notable similarities with PWS locus snoRNAs in terms of gene organization [60]. Both loci harbor tandemly repeated snoRNA genes that are processed from common complex primary transcripts. Moreover, both snoRNA groups show similar tissue-specific expression, being most abundant in uterine mucous membrane and brain. In rodents, locus orthologous to human 14q32 gives rise to strictly brain specific snoRNAs with no significant homology to human counterparts, which contrasts the situation at PWS imprinted locus. Yet, in humans and in mice, both loci are developmentally regulated in neurons and display significant parenteral-specific chromatin decondensation [61]. Interestingly, when chromatin loosening was interrogated over diverse highly transcribed genetic loci in mice neurons, only PWS and 12qF1 (orthologous to 14q32 in human) loci were found fully decondensed at paternal and maternal alleles, respectively. The mere imprinting and transcription of non-coding RNAs or long transcripts were found insufficient for decondensation. This implies that snoRNA cluster genomic neighborhood is vital for chromatin remodeling. Furthermore, chromatin decondensation at imprinted snoRNA loci appears to be required for proper nucleolar size during neuronal maturation as Purkinje cells of mice lacking SNORD115/SNORD116 expression had significantly smaller nucleoli compared to wild-type littermates [61]. The authors reasoned that neuron-specific snoRNAs may be implicated in rRNA modification after all. Indeed, Kehr et al. [5] have recently reported bioinformatic prediction of rRNA targets for a number of orphan snoRNA families, including SNORD116, and suggested that undetected rRNA modifications take place only under certain conditions. The nucleotides presumed to be targeted lie next to highly structured pseudoknotted segments, indicating that modification might fine-tune rRNA fold and/
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Bioinformatic prediction of snoRNA targets is rather unreliable due to relatively short nucleotide stretches that constitute snoRNA antisense elements as well as tolerance for mismatches upon target pairing [5,84]. Thus, experimental identification of non-canonical snoRNA protein partners and/or RNA targets (or alternative ones in case of bifunctional snoRNAs) is the key to understanding the many faces of these non-coding RNAs. Approaches such as RNA pull-down and co-immunoprecipitation coupled with mass spectrometry will be of paramount importance. Several snoRNAs are expressed at different levels across various cell types [68,85] which can be attributed to regulation of host genes harboring snoRNAs. Additionally, biological (e.g., developmental stage [11,62] or genetic factors [63,64]) and environmental factors ([13–15]) may provoke differences in snoRNA expression, and possibly also their choice of partners. Therefore, designing experiments in a way to recapitulate biologically relevant situations will be crucial. Bifunctional snoRNAs are believed to be incorporated in more than a single RNP particle, each performing a distinct task [86]. Similar structural and functional plasticity was recently proposed for miRNA–argonaute complexes [87], whereby addition of various accessory proteins would explain the observed complexity of miRNPs, both in the mode of action and the extent of translational repression [75]. Alternative snoRNPs are likely to coexist, some at considerably lower levels than others, yet both being physiologically relevant. As the canonical snoRNP may, due to its ubiquity, mask other form(s), highly sensitive detection methods are needed. Advances in snoRNA knockdown, such as the use of 2′-methyloxylethyl modified phosphorothioate backbone-containing RNA–DNA chimeric antisense oligonucleotides enabling highly specific and efficient depletion of snoRNAs [88], should also facilitate functional studies.
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to be occupied by transcription factor SREBP1, one of the main regulators of cholesterol uptake and synthesis [83], providing a potential direct link between SNORD60 expression and cellular cholesterol regulating machinery at transcriptional level.
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homeostasis [78], respectively. In both cases promoter trap mutagenesis in CHO cells coupled with phenotypic screening led the researches to identification of loss of function mutation in genes harboring intronic snoRNAs. Unexpectedly, they showed that loss of specific snoRNAs and not the spliced exonic transcripts is responsible for the observed traits. Furthermore, there were no indications that any of these snoRNAs might serve as precursor of miRNAs, implying a separate mechanism of action. Promoter trap mutagenesis enables unbiased forward genetic screening as it relies on random genomic integration of retroviral vector harboring promoterless neomycin-resistance conferring cassette. Thus, a gene is inactivated only when the provirus is inserted downstream of a functional endogenous promoter, essentially hijacking it to express aminoglycoside 3′-phosphotransferase, a neomycin-inactivating enzyme [79]. In the first study, Michel et al. [77] screened transduced geneticin-resistant CHO cells for resistance to palmitate-induced apoptosis. The selected mutant cell line endured not only palmitate but also hydrogen peroxide treatment as well, indicating that it can withstand a wide range of oxidative stress. The causative mutation was traced to gene rpl13a encoding 60S ribosomal protein L13a along with four intronic snoRNAs (SNORD32A, -33, -34, and -35A). In contrast to the mutant cell line, palmitate exposure induced upregulation of three snoRNAs (SNORD32A, -33, and -35A; but not the mature rpl13a mRNA), in wild-type CHO cells and murine myoblasts. Ectopic expression of the intact murine rpl13a genomic locus (but not the one with intronic snoRNAs removed) in palmitate-resistant CHO cells rescued the mutant phenotype. Similarly, knockdown in murine myoblasts of all three snoRNAs using antisense oligonucleotides brought about palmitate resistance. The effect was SNORD32A/33/35A-specific and required that all three snoRNAs be knocked down concomitantly. No differences in the extent of ribose methylation at the predicted rRNA modification sites for any of the rpl13a snoRNAs in wild-type and mutant CHO cells under basal or palmitate-treated conditions were detected, suggesting an additional non-canonical role in oxidative stress propagation. This is further supported by the observation that murine myoblasts, when exposed to lipotoxic palmitate, show increased cytoplasmic levels of rpl13a snoRNAs, whereas their nuclear levels are unchanged. There is compelling evidence that these snoRNAs work in concert as mediators of oxidative stress, however, the mechanism by which they elicit cellular death remains elusive. The mere fact that they reside in the cytosol is compatible with a potential role in regulation of translation. miRNAs have previously been identified as trans acting factors that promote sequestration of mRNAs to processing bodies and stress granules, cytoplasmic RNP foci inaccessible to translational machinery [75,80,81]. Considering evolutional linkage of miRNAs and snoRNAs, it is feasible that rpl13a snoRNAs act in a similar manner, recruiting specific mRNAs to processing bodies, stress granules, or related submicroscopic structures [82]. In the second study, Brandis et al. [78] performed a positive selection of transduced geneticin-resistant CHO cells for resistance to amphotericin B (a cholesterol-binding toxin) following low-density lipoprotein (LDL) treatment to identify mutants with deficiency in cholesterol trafficking from plasma membrane to ER. A mutant cell line was recovered that displayed increased rate of de novo cholesterol synthesis and decrease in plasma membrane cholesterol esterification, which was attributed to defects in sensing cellular cholesterol levels. The researchers found a single insertional mutation residing in SNORD60 host gene (SNORD60hg). When the mutant cell line was complemented with murine SNORD60hg (that, as opposed to hamster ortholog, has no open reading frames) the mutant phenotype was rescued. In addition to the unexpected role in regulating cholesterol homeostasis, SNORD60 was confirmed to associate with canonical snoRNP proteins, presumably to guide 28S rRNA G4340 2′-O-methylation. Yet, no reduction of methylation at the predicted rRNA target site could be associated with SNORD60 insufficiency. Thus, the SNORD60 non-canonical mode of action awaits elucidation. Of note, in HepG2 cells SNORD60hg was previously shown
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This work was supported by the Slovenian Research Agency [grant 397 numbers J3-2356, J3-4026, J3-5502 and P4-0127]. 398 References
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