review article regulatory role of small nucleolar rnas in...

Review ArticleRegulatory Role of Small Nucleolar RNAs in Human Diseases

Grigory A Stepanov1 Julia A Filippova12 Andrey B Komissarov34 Elena V Kuligina1

Vladimir A Richter1 and Dmitry V Semenov1

1 Institute of Chemical Biology and Fundamental Medicine Siberian Branch of Russian Academy of SciencesLavrentiev Avenue 8 Novosibirsk 630090 Russia2Novosibirsk State University Pirogova Street 2 Novosibirsk 630090 Russia3Research Institute of Influenza Prof Popova Street 1517 Saint Petersburg 197376 Russia4Saint Petersburg State University Universitetskaya Embankment 7-9 Saint Petersburg 199034 Russia

Correspondence should be addressed to Grigory A Stepanov stepanovganibochnscru

Received 21 November 2014 Accepted 8 April 2015

Academic Editor Thean-Hock Tang

Copyright copy 2015 Grigory A Stepanov et al This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

Small nucleolar RNAs (snoRNAs) are appreciable players in gene expression regulation in human cells The canonical function ofbox CD and box HACA snoRNAs is posttranscriptional modification of ribosomal RNAs (rRNAs) namely 21015840-O-methylationand pseudouridylation respectively A series of independent studies demonstrated that snoRNAs as well as other noncodingRNAs serve as the source of various short regulatory RNAs Some snoRNAs and their fragments can also participate in theregulation of alternative splicing and posttranscriptional modification of mRNA Alterations in snoRNA expression in humancells can affect numerous vital cellular processes SnoRNA level in human cells blood serum and plasma presents a promisingtarget for diagnostics and treatment of human pathologies Here we discuss the relation between snoRNAs and oncologicalneurodegenerative and viral diseases and also describe changes in snoRNA level in response to artificial stress and some drugs

1 Introduction

Small nucleolar RNAs (snoRNAs) represent a class of regula-tory RNAs responsible for posttranscriptional maturation ofribosomal RNAs (rRNAs) Small nucleolar RNAs are dividedinto two families based on their structure andmain functionbox CD snoRNAs and box HACA snoRNAs Box CDRNAs are responsible for 21015840-O-methylation while the latterfamily guides pseudouridylation of nucleotides [1 2]

Eukaryotic box CD RNAs are typically 70ndash120 nt inlength and contain two conserved elements boxes b (PuU-GAUGA) and D (CUGA) located at the 51015840- and 31015840-termini of the RNA molecule respectively (Figure 1(a))These sequence elements form so-called ldquokink-turnrdquo (stem-bulge-stem) structure that serves as the scaffold for theassembly of a small nucleolar ribonucleoprotein (snoRNP)including the following proteins Nop1p (also known asfibrillarin) Nop56p Nop58p and Snu13p (155 kDa) [3ndash6]Methyltransferase fibrillarin serves as the key component

of snoRNPs it catalyzes the transfer of a methyl groupfrom S-adenosylmethionine (SAM) to 21015840-O-position of thetarget nucleotide The methylation guide sequence exhibitscomplementarity to the region of the target RNA it is 10ndash21 ntlong and located upstream of the box DD1015840 motifs The basein the target RNA paired to the fifth nucleotide upstream ofthe box DD1015840 sequence is to be methylated [1 7]

Box HACA family snoRNAs share hallmark secondarystructure called ldquohairpin-hinge-hairpin-tailrdquo that includestwo hairpin domains linked with a single-stranded region(hinge) and 31015840-terminus region (tail) [2] Boxes H and ACAare located in a close vicinity of the hairpin in the hingeand tail regions respectively (Figure 1(b)) Box H representsa conserved ANANNA (N stands for any nucleotide) motifwhile box ACA is a trinucleotide located 3 nt before the31015840-terminus Each hairpin consists of internal and externalloops A 9-13-nt-long guide sequence is located on bothstrands of the inner loop During interaction with the targetRNAmolecule the complementary sequences of box HACA

Hindawi Publishing CorporationBioMed Research InternationalVolume 2015 Article ID 206849 10 pageshttpdxdoiorg1011552015206849

2 BioMed Research International

(a)

DC

O B

O O

O

O B

O O

O

SAM

SAH

Box CD RNA

H

Target

3998400

5998400

3998400

5998400

CH3

D998400

C998400

⋆

(b)

TargetNU

ACABox HACA RNA

O U

O OH

O

O

O

O

OH

3998400

5998400

3998400

5998400

HΨ

⋆

Figure 1 (a) Box CD snoRNAs share two conserved elements boxesb (PuUGAUGA) andD (CUGA) located at the 51015840- and 31015840-termini of theRNAmolecule respectively Often box CD snoRNAs also have an additional copy of internally located C1015840 orD1015840 boxes A complex of box CDsnoRNA with nucleolar proteins Nop1p (fibrillarin) Nop56p Nop58p and Snu13p (155 kDa) catalyzes site-specific 21015840-O-methylation of thenucleotide in target RNA S-Adenosylmethionine (SAM) serves as the donor of themethyl group and is converted to S-adenosylhomocysteine(SAH) (b) Box HACA snoRNAs have ldquohairpin-hinge-hairpin-tailrdquo structure with boxes H (ANANNA) and ACA located within the single-stranded (hinge) and 31015840-terminus (tail) regions respectively Pseudouridylation complex includes dyskerin (the pseudouridine synthase)GAR1 NHP2 and NOP10 proteins Box HACA snoRNP catalyzes site-specific isomerization of uridine (U) to pseudouridine (Ψ) in targetRNA SnoRNA with target RNA in square brackets designates snoRNP enzyme-substrate complex

RNAflank twonucleotides including a uridine residue whichis further subjected to UΨ isomerization Thus the three-dimensional structure of the conserved motif enables theaccess of pseudouridylation enzymes to the substrate uridineThe distance between the target nucleotide and HACA boxin rRNA-snoRNA duplex is 14-15 nt long [2 8]

Similar elements boxes C and D as well as boxes H andACA can be found in primary structures of small Cajalbody-specific RNAs (scaRNAs) These RNAs guide 21015840-O-methylation and pseudouridylation of small nuclear RNAs(snRNAs) [9 10]

It has been shown that numerous box CD and boxHACA RNAs have no identified targets among rRNAsor snRNAs Such snoRNAs referred to as ldquoorphan snoR-NAsscaRNAsrdquo may have some other regulatory functionaside from 21015840-O-methylation and pseudouridylation of RNAnucleotides [11ndash13] Series of studies of snoRNA expressionprofiles in mammalian cells have demonstrated that thelevel of many ldquoorphanrdquo box CD and box HACA RNAsvaries among different tissues [14ndash17] The variation ofsnoRNA expression profiles suggests that such RNAs havetissue-specific functions For example two brain-specific box

CD RNAs SNORD115 (HBII-52) and SNORD116 (HBII-85) were shown to be processed into smaller RNAs thatcan affect the outcome of alternative splicing of variouspre-mRNAs by preventing the formation of particular pre-mRNA splicing variants [18] SNORD115 is also involved inthe regulation of serotonin receptor 5-HT2CR mRNA levelin brain cells through alternative splicing and control ofposttranscriptional nucleotide modification (adenosine-to-inosine editing) of the target mRNA [19 20]

Along with SNORD115 and SNORD116 a number ofother human snoRNAs can generate smaller fragments asit has been demonstrated by high-throughput sequencingand RNase protection experiments [21ndash23] Short fragmentsderived from box CD snoRNA SNORD88C (HBII-180C)hold complementarity to fibroblast growth receptor-3(FGFR-3) pre-mRNA Being expressed from artificialldquosnoMENrdquo vector SNORD88C (HBII-180C) is capableof suppressing target gene mRNA and protein level in asequence-dependent manner through base pairing withpre-mRNA regulatory elements [24 25] Bioinformaticanalysis showed that about a half of all box CD RNAs areprocessed into small molecules that are conserved among

BioMed Research International 3

multiple cell lines [26] Box HACA snoRNAs are usuallyprocessed into 20ndash24 nt fragments while box CD-derivedRNAs are sim17ndash19 or gt24 nt long These fragments are termedsnoRNA-derived RNAs (sdRNAs) and considered to be anovel class of regulatory RNAs Most of sdRNAs preserveconserved CD or HACA box pairs [21 27 28] Moreoverseveral sdRNAs were found to interact with Ago familyproteins the key components of RISC complexes [29 30]It was shown that a number of box CD RNA-derivedfragments can exhibit miRNA activity [28] However themechanism underlying the biogenesis of such snoRNAderivatives that resemble microRNAs still remains unknownIt has been shown that processing of box CD RNAs intosdRNAs was Dicer-independent while production of boxHACA-derived sdRNAs required Dicer [29 31] ThussnoRNAs can serve as a source of short regulatory RNAspecies involved in the control of processing and translationof various mRNAs

Each of the functions described above may be implicatedin the initiation and progression of pathology The studyof snoRNA function will have significant diagnostic andtherapeutic valueThis review deals with the latest data on therelationship between snoRNAs and socially important dis-eases such as oncological and neurodegenerative disordersChanges in snoRNA level in mammalian cells subjected tostress and drugs are also described

2 snoRNAs and Cancer

The defects in ribosome maturation and function can causedisruption of vital processes and lead to diseases and trans-formation of normal cells into tumor cells [32ndash34] SincesnoRNAs are involved in the regulation of posttranscriptionalmodification of ribosomal RNAs it is fair to assume thatsnoRNA level can affect physiological condition of cellstissues and organs Thus the change in snoRNA expres-sion level may lead to various diseases Hence the studiesaimed at evaluating snoRNA expression levels in humanand mammalian cells might underpin the development ofdiagnostic approaches and generation of novel therapeuticagents

Research in this field is mostly focused on the involve-ment of human snoRNAs in oncological diseases In mam-malians the majority of snoRNAs are encoded within theintrons of protein coding or noncoding genes so-calledldquohost-genesrdquo (reviewed in [35 36])Therefore an alteration ofsnoRNA expression may result from the oncogenic processesaccompanied by changes in transcriptional activity of thehost-gene or aberrations of nuclear maturation of the pol IItranscript In that case the snoRNA cellular level of whichrisesdrops rapidly may not play a key role in the pathologybut the alteration itself may indicate tumor progressionand reflect metastatic potential [37] On the other handsnoRNA the expression of which is positively or negativelycorrelated with tumor cells proliferation and invasion mayhave considerable impact on carcinogenesis and thus shouldbe treated as an oncogenewhen its expression goes far beyondthe ldquonormal levelrdquo [38]

21 The Role of snoRNAs in Oncotransformation of Mam-malian Cells Specific increase in the expression level ofseveral box CD RNAs was detected in murine and humanbreast cancer cells [39] Both breast cancer primary culturesand breast cancer cell lines (MCF-7 and ZR-75-1) exhibitedincreased level of U22 U3 U8 U94 and U97 box CDsnoRNAs compared to normal and untransformed (MCF-10A) human cells Change in snoRNA expression level isaccompanied by an increase in fibrillarin the core componentof snoRNPs with its level correlating with the expressionof Myc oncogene High level of fibrillarin was observed notonly in breast cancer cells but also in prostate and manyother human cancers Targeted repression of fibrillarin andother proteins of themethyltransferase complex (NOP56 andNOP58) not only led to the decrease in box CD snoRNAlevel but also inhibited cancer cell growth and decreasedoncogenicity [39] siRNA-mediated knockdown of fibrillarinin cancer cells enhanced induction of tumor suppressor p53protein Meanwhile increased fibrillarin expression resultedin significantly compromised p53-dependent response tostress in cancer cells Earlier it has been demonstrated thatdisrupted nucleolar activity such as blocked transcriptionof rRNA genes leads to p53 protein stabilization due tothe binding between MDM2 (negative regulator of p53) andribosomal proteins (RPL5 RPL11 and RPL23) [40]Thus thepresented data elucidate the role of nucleolar componentsincluding snoRNAs and snoRNP proteins in survival ofcancer cells by modulation of p53 expression

Small nucleolar box HACA RNA SNORA42 which isoverexpressed in nonsmall cell lung carcinoma (NSCLC) wasidentified as a lung cancer oncogene [38] siRNA knockdownof SNORA42 results in reduced cancer cell growth (H460and H1944 cells) inhibited H460 and H1944 cell colonyformation and compromised tumorigenicity in animal mod-els Specific SNORA42 suppression in cancer cells leads toapoptosis in a p53-dependent manner On the contraryoverexpression of SNORA42 activates cancer cell growthTheexpression level of SNORA42 in lung tumor tissue specimenwas found to be inversely correlated with the survival ofNSCLC patients [38]

ACA11 is a peculiar snoRNA encoded within an intronof WHSC1 that exhibits the structure of a box HACARNA and is predominantly localized in the nucleolus [41]However it has been demonstrated that it does not associatewith dyskerin and other components of the pseudouridy-lation machinery typical of HACA snoRNPs Instead itbinds to the proteins implicated in RNA processing RNAsplicing factors (SF3B1 SF3B2 and SFPQ) ATP-dependentRNA helicase A (DHX9) RNA-specific adenosine deaminase(ADAR) and the members of the heterogeneous nuclearribonucleoprotein family ACA11 is highly expressed inmultiple myeloma colon esophageal and bladder cancersACA11 overexpression was found to induce downregulationof ribosomal protein genes and snRNA involved in oxidativestress regulation resulting in resistance to chemotherapy andenhancing multiple myeloma cell proliferation [41]

Studies in mouse models have uncovered that adeno-associated virus integrates with high-frequency on chromo-some 12 near Meg3 gene locus [42] This region is rich in


orphan snoRNA and microRNA genes The integration ofthe viral genome causes aberrations in host-gene expressionleading to hepatocellular carcinoma The syntenic regionin humans is proposed to encode tumor suppressor genesThe expression of the noncoding Meg3 transcript is severelysuppressed in various cancer cell lines and tumor types whilethe deletion of the corresponding genome locus leads toaggressive tumors [43] Meg3 RNA upregulates p53 levels bydownregulating Mdm2 levels and promotes angiogenesis byincreasing Vegfa and Vegfr1 levels [44 45]

Two other genes ZFAS1 and GAS5 which host snoRNAswithin their introns have been associated with numeroustypes of cancers [37 46ndash49] GAS5 locus contains 10 boxbD RNAs that guide modification of various nucleotides in18S and 28S rRNAs The expression of two GAS5-associatedsnoRNAs U44 and U47 was found upregulated in colorectaltumors compared to benign colon tissues [46]Meanwhile inbreast cancer head and neck squamous cell carcinoma (SCC)low expression level of U44 directly correlated with poorsurvival of patients [37 47] ZFAS1 contains three box bDRNAs SNORD12 SNORD12B and SNORD12C that guide21015840-O-methylation of G3878 in 28S rRNA ZFAS1 locus andthese snoRNAs were shown to be strongly downregulated inbreast ductal carcinoma [49]

SnoRNA expression level was found decreased in acutemyeloid leukemia (AML) and acute lymphoblastic leukemia(ALL) cells compared to normal cells [50] Underexpressionhas been reported for another class of ncRNAs microRNAsin several types of cancers [50 51] However a few snoRNAsare overexpressed in some AML cases Specific overexpres-sion has been reported for several orphan box CD RNAsSNORD112-114 encoded within the DLK1-Dio3 locus ofchromosome 14 SNORD114-1 has been shown to promotecell cycle progression through G0G1 to S phase transition[50] Overexpression of SNORD114-1 activates proliferationin K562 cell line while targeted suppression of the boxCD RNA leads to the induction of cell death The dataimplicate that some of these box CD RNAs participate in thedevelopment of leukemia

One of the mechanisms regulating overall level ofsnoRNA in cancer cells may be the methylation of the CpGislands located close to snoRNAgenesTheDNAmethylationstatus of CpG islands within 2 kb from 51015840-termini of 49snoRNA genes was analysed in HCT-116 colorectal cancercells [52] Hypermethylation of the CpG islands located nearthe 51015840-termini of host-genes for SNORD123 SNORA70Cand SNORA59B was established to be specific for cancercells compared to normal human cells Further analysisenabled us to reveal similar DNA methylation profile closeto these snoRNA host-genes in melanoma lymphoma andleukemia cell lines lung breast prostate ovary and kidneycancers as well as the primary cultures of blood cells inpatients with ALL Furthermore the expression of these boxCD and HACA snoRNAs in HCT-116 and SW48 cells wasdownregulated compared to the cells lacking CpG islandmethylation near SNORD123 SNORA70C and 59B snoRNAhost-genes The result obtained suggests the existence ofepigenetic control mechanism for the regulation of snoRNAexpression which might be common for various cancer cells

The expression of other noncoding RNA genes is also knownto be regulated by changing themethylation status in adjacentchromosome regions For example CpG island methylationin cancer cells can result in the repression of microRNAs thatare reported to be tumor suppressors [53]

Martens-Uzunova et al demonstrated that some box CDand boxHACA snoRNAs as well as several tRNAs are over-expressed in prostate cancer cells during the premetastaticstages [54] The data claim that snoRNAs are capable ofactive participation in tumor progression Ribosomal RNAbiogenesis is known to be more robust in cancer cells thanin normal cells [55] Therefore it can be assumed that theincrease in snoRNAs level is necessary for the accelerationof rRNA maturation ribosome assembling and proteinsynthesis during tumorigenesis It should be noted that therelationship between the deregulation of snoRNA expressionand rRNA biogenesis in diseases still remains elusive Furtherstudies in snoRNA research area should be addressed to thisissue

22 Oncodiagnostic Value of snoRNAs In a recent study Liaoet al have profiled the expression signatures of 352 snoR-NAs in NSCLC [56] Six snoRNAsmdashSNORD33 SNORD66SNORD73B SNORD76 SNORD78 and SNORA42mdashwereestablished to be overexpressed both in adenocarcinoma(AC) and SCC [56] All 6 snoRNAs are present in a stableform in human blood plasma and their level can be accu-rately measured by RT-qPCR A new diagnostic system with811 sensitivity and 958 specificity was proposed basedon simultaneous assessment of three snoRNAs (SNORD33SNORD66 and SNORD76) blood plasma levels Accordingto the data presented the usage of the three diagnostic genesallows us not only to detect NSCLC but also to distinguishit from chronic obstructive pulmonary disease However thelevels of SNORD33 SNORD66 and SNORD76 do not reflectthe stage of malignancy or histological origin [56]

A homozygous 2 bp (TT) deletion in U50 snoRNAgene encoded within the intron of U50HG (SNHG5) wasfound in prostate cancer cell lines [57] The same but oftenheterozygous 2-nt mutation in U50HG (SNHG5) gene ispresent in breast cancer cells [58] The deletion leads to thereduced expression of U50 snoRNA In both cases the returnto the wild-type expression level of the snoRNA results ininhibited cancer cell growthThemutation was detected withdiagnostically significant frequencies in blood cells of maleswith prostate cancer and females with breast cancer [57 58]The data allowed identifying U50 box CD RNA as a tumorsuppressor

Expression profile of snoRNA and scaRNA genes wasanalyzed with quantitative RT-PCR in leukemic cells ofdifferent originmdashAML T-ALL and pre-B ALL Burkittrsquoslymphomaleukemia and a solid tumor (HeLa cell line) [59]Box CD and box HACA snoRNA expression profiles werefound to vary within different types and subtypes of cancerwith different leukemia subtypes sharing the most similarityThat difference in snoRNA levels enables us to use snoRNAand scaRNA patterns for characterization and classificationof cancer types [59] Diagnostically useful differences insnoRNA expression profiles were also reported for different


subtypes of T-cell lymphoma [60] Elevated level of box CDRNA HBII-239 and its microRNA derivative miRNA-768-3pin peripheral T-cell lymphoma was detected in cases withfavorable outcomes

In conclusion the data reported suggest that there aremeaningful changes in box CD and box HACA snoRNAlevels in human cells and body fluids during the developmentof oncological diseases Small nucleolar RNAswere suggestedboth as biomarkers of oncological diseases and as targetsfor cancer therapy Other ncRNAs first of all circulatingin human blood plasma microRNAs have been consideredto be perspective minimally invasive markers of diseases[61ndash66] Thus small nucleolar RNAs supplement the setof therapeutically and diagnostically significant regulatoryRNAs and the fundamental knowledge of snoRNA structureand biological functions can be applied to the developmentof new therapeutic approaches for cancer treatment

3 snoRNAs and Human NeurodegenerativeDisorder

The relation between box CD RNAs and neurodegenerativedisease development has been also described [67 68] In aseries of independent studies the genetic disorder Prader-Willi syndrome (PWS) was shown to be caused by the lossof paternal gene expression from a maternally imprintedregion 15q11ndashq13 on chromosome 15 The disease is featuredby mental retardation low height obesity and muscle hypo-tonia Locus 15q11ndashq13 contains numerous copies of two boxCD RNAsmdashSNORD115 (HBII-52) and SNORD116 (HBII-85) [16] Box CD RNA SNORD115 may have an impact on5-HT2CR serotonin receptor mRNA level in brain [19 20]The loss of the SNORD116 snoRNAs can be a significantcontribution to the etiology of PWS [16 69 70]

The deletion of PWS critical region that contains theSNURF-SNRPN locus as it has been demonstrated in mousemodel of PWS leads to the changes in splicing patterns of sev-eral pre-mRNAs [18]The data also indicates that SNORD115as well as SNORD116 undergoes specific hydrolysis formingsmaller fragments processed snoRNAs referred to as ldquopsnoR-NAsrdquo [18 22] These processed species of SNORD115 but notthe full-length snoRNA were suggested to affect the outcomeof alternative splicing of the pre-mRNAs [18] HoweverBortolin-Cavaille and Cavaille provided evidence againstthe existence of abundant processed variants of SNORD115and SNORD116 (psnoRNAs) in human or mouse brainconcluding that PWS-encoded snoRNAs represent canonicalbox CD snoRNAs [71]

A recent study revealed that the change in box CD RNAlevel also takes place in brain cells during abnormal fetaldevelopment caused by maternal alcohol consumption dur-ing pregnancy [72] Mousemodel experiments demonstratedthat along with the change in DNA methylation patternbrain tissue also exhibited changes in expression levels ofsome microRNAs and snoRNAs Particularly the increase inSNORD115 and the decrease in SNORD116 snoRNA levelswere demonstrated [72] It has been previously reported thatthe upregulation of SNORD115 due to the duplication ofthe region of mouse chromosome 7 that mirrors the human

chromosome 15q11ndash13 duplication results in abnormal braindevelopment The observed change in SNORD115 level led tovarious psychic and behavioral aberrations typical of autism[73]

4 snoRNAs and Viral Diseases

Viral infection leads to the transcriptional activation of avast group of genes that are related to the innate immuneresponse genes [74 75] The activity of the products of suchgenes is aimed at suppressing the processes of viral devel-opment particularly replication and transcription of viralgenome translation of viral mRNAs and virus assembly [76]Noncoding RNA genes have been found among the groupof genes that are overexpressed during activation of antiviralresponse but their role has not been clearly established yet[77 78] Recently the first data on upregulation of the seriesof snoRNA genes in virus-infected human cells have beenobtained [79] On the one hand snoRNAcan act asmediatorsof host antiviral response on the other hand the activity ofregulatory RNAs can be utilized by viruses to evade innateimmunity and complete their life cycle [80]

The first evidence of the existence of snoRNA encodedin viral genomes was obtained from the studies on her-pesviruses A box CD RNA termed as v-snoRNA1 (viralsmall nucleolar RNA1) has been found in B lymphocytesinfected with Epstein-Barr virus (EBV) [81] This RNA was65 nt long and encoded within the viral genome Despite thefact that the viral box CD RNA has CD and C1015840D1015840 pairsof boxes and contains short regions (9ndash11 nt) complementaryto human 18S and 28S rRNAs the further analysis did notreveal 21015840-O-methylation of potential rRNA target nucleotidesin infected cells [81] Apart from the full-length box CDRNA a 24-nt RNA that represents a 31015840-terminal fragment(41st to 64th nt) of the viral box CD RNA v-snoRNA124ppwas found in cells infected with EBV In EBV genome v-snoRNA1 is encoded in the antisense direction to 31015840-UTRof DNA polymerase gene (BALF5) It has been shown thatv-snoRNA124pp is able to interact with BALF5 mRNA andinduce specific hydrolysis of target mRNA in the regionof complementarity The levels of the viral box CD RNAand its shortened form increase 30-fold in cells during thelytic phase of infection It has also been established that thelevel of BALF5 mRNA in infected cells is controlled by theviral microRNA miR-BART2 during transition from latentto lytic phase [82] Therefore it is reasonable to assumethat activation of viral box CD RNA expression and itsprocessing to short regulatory form enables a more rapiddecrease in a target mRNA level Bioinformatic analysishas demonstrated that a cognate box CD RNA is encodedwithin the genome of another 120574-herpesvirus rhesus monkeyLymphocryptovirus [81] The presence of box CD RNA inviral genome indicates that viruses are able to utilize snoRNA-dependent mechanisms for the regulation of their life cycle

Many RNA viruses especially (+)ssRNA viruses encodetheir own RNA processing machinery capable of RNAcleavage and modification Among RNA viruses there aremembers of the order Nidovirales comprising such well-known human pathogens as coronaviruses that uniquely


encode within their genome an endonuclease designated asNendoU Endonuclease NendoU bears striking homology tocellular XendoU poly(U)-specific endoribonuclease A fromXenopus laevis involved in snoRNA processing (eg U16and U86 snoRNA maturation) [83] XendoU is known tobe broadly conserved among Metazoa but its homologuesin human and most laboratory animals remain hypotheticalSevere acute respiratory syndrome coronavirus (SARS-CoV)NendoU is a component of the replicase-transcriptase com-plex but whether its role is critically important for the virallife cycle remains to be determined

Vast majority of noncoding RNAs are subjected to dif-ferential regulation in response to virus infection yet theexamples of changes in expression of snoRNAs in infectedcells are very limited Recently the analysis of lung tran-scriptome in mice infected with SARS-CoV or influenza Avirus has revealed differential expression of 30 small RNAsoverlapping with annotated snoRNAs Two putative snoR-NAs differentially regulated by respiratory virus infectionwere found in GAS5 locus [84] Intriguing GAS5 intronicsnoRNAs U44 U76 and U78 were found to be upregulatedin human cells infected with chikungunya virus [79] It canbe speculated that GAS5 intronic snoRNAs may be involvedin the regulation of T-cell growth [85]

The hypothesis that viruses are able to involve hostsnoRNAs in the regulation of stability and functionality oftheir RNAs is supported by the studies demonstrating thatviral RNAs contain a variety of modified nucleotides [86 87]Moreover it has been established that viruses are capable ofutilizing other pathways in order to regulate the modificationof their ownmRNAs and evade host immune system [88ndash90]In order to determine the role of snoRNAs in viral infectionsfurther research is needed

5 Change in snoRNA Level in MammalianCells Subjected to Stress and Drugs

Changes in the level of snoRNAs circulating in body fluidswere shown to be induced by different stress factors At thescale of the whole organism any trauma is considered to bestress causing shift in homeostasis Two box CD snoRNAsU48 and U38 were found to be significantly overexpressedin serum of patients with anterior cruciate ligament (ACL)injury [91] Moreover U38 snoRNA expression level wasreliably elevated in patients with cartilage damage associatedwith ACL injury The snoRNA U38 may therefore serve asa biomarker for early diagnostics of osteoarthritis followingjoint injury

Changes of snoRNA level can also occur in mammaliancells exposed to chemical stress factors It has been demon-strated that Chinese hamster ovary (CHO) cells containincreased level of three box CD snoRNAsmdashU32a U33 andU35a when exposed to fatty acids [92] These snoRNAs areencoded within different introns of the ribosomal proteinL13a (RPL13a) Under such conditions box CD snoRNAsaccumulate in cytoplasm but not nuclei thus suggesting anew cytoplasmic function of small nucleolar RNAs Fattyacids are known to be toxic to mammalian cells Lipo-toxicity is characterized by initiation of oxidative stress

endoplasmic reticulum (ER) dysfunction and can furtherlead to proinflammatory processes and apoptotic cell death[93 94] First it has been demonstrated that RPL13a islargely involved in activation of palmitate-induced cell deathSaturated fatty acids (myristate palmitate and stearate)unlike less toxic unsaturated fatty acids (palmitoleate andoleate) have been reported to induce U32a U33 and U35asnoRNA overexpression [92] Despite the upregulation ofsnoRNA therewas no detectable change in 21015840-O-methylationlevel of rRNAs Specific downregulation of the reportedbox CD RNAs protected cells from lipotoxicity It is alsonotable that the suppression of U32a U33 and U35a boxCD RNA genes in cells resulted in inhibited accumulationof H2O2-derived reactive oxygen species thus implicating

the participation of these snoRNAs in a commonmechanismof cellular response to oxidative stress In vivo experimentsshowed that administration of lipopolysaccharides inducesU32a U33 and U35a snoRNA expression in mouse liver[92] Thus small nucleolar RNAs are capable of participatingin the regulation of cellular response to external stress andcontrolling activation of apoptosis

Tamoxifen is one of the major drugs used for thehormonotherapy of breast cancer It serves as an estrogenreceptor antagonist and induces breast cancer cell death byapoptosis [95] However there are breast cancer types notsusceptible to tamoxifen Global analysis of the transcriptomein tamoxifen-sensitive and tamoxifen-resistant breast cancercells revealed differences in snoRNA pattern between the twotypes of cancer cells [96] Such data suggest that small nucleo-lar RNAs play a prominent role in sustaining drug-resistancein cancer cells where targeted regulation of snoRNA expres-sion may increase their sensitivity to the therapy

Tenofovir disoproxil fumarate (TDF) is a nucleotide-derived inhibitor targeted to HIV reverse transcriptase It isallowed for administration to HIV-infected patients as partof complex antiretroviral therapy Patients under tenofovirtreatment are known to experience bone tissue loss In arecent study Grigsby et al have profiled gene expression inprimary murine osteoclasts [97] The research demonstratedthat TDF treatment causes downregulation of three genesmdashGNAS GOT2 and SNORD32a It was proposed that beingcombined with other cellular malfunctions change in thesnoRNA level induced by the drug administration can leadto aberrant rRNA biogenesis and induce cell death [97]

The data presented suggests that alterations in snoRNAexpression profile canmodulate the sensitivity of human cellsto drugs

6 Conclusion

RNA posttranscriptional modification and control of mRNAstability and translation are important parts of gene expres-sion regulation in human cells Small nucleolar RNAs andtheir functional fragments play a considerable role in theseprocesses they guide modification of rRNA and snRNAnucleotides influence alternative splicing of complementarypre-mRNAs and control translation and stability of mRNAsthrough RISC-dependent pathway Disruption of snoRNAexpression can be caused by both external factors and


intracellular signal cascades and result in physiologicalchanges on a cellular level organ dysfunctions and variousdiseases The structure of snoRNAs their expression patternand localization within cells have regulatory significance andare considered diagnostic markers of pathology The insightinto snoRNA expression and the mechanisms of their func-tioning will provide new possibilities for the developmentof diagnostic systems and novel therapeutic approaches forhuman diseases

Abbreviations

snoRNAs Small nucleolar RNAsrRNAs Ribosomal RNAssnoRNP Small nucleolar ribonucleoproteinSAM S-AdenosylmethionineSAH S-AdenosylhomocysteinescaRNAs Small Cajal body-specific RNAssnRNAs Small nuclear RNAssdRNAs SnoRNA-derived RNAsNSCLC Nonsmall cell lung carcinomaSCC Squamous cell carcinomaAML Acute myeloid leukemiaALL Acute lymphoblastic leukemiaAC AdenocarcinomaPWS Prader-Willi syndromepsnoRNAs Processed snoRNAsv-snoRNA1 Viral small nucleolar RNA1EBV Epstein-Barr virusSARS-CoV Severe acute respiratory syndrome

coronavirusACL Anterior cruciate ligamentCHO Chinese hamster ovaryER Endoplasmic reticulumTDF Tenofovir disoproxil fumarateHIV human immunodeficiency virus

Conflict of Interests

The authors declare that they have no competing interests

Acknowledgment

The work was supported by Russian Foundation for BasicResearch Grants 14-04-31468 14-34-50408 and 13-04-01058

References

[1] J Cavaille M Nicoloso and J-P Bachellerie ldquoTargeted ribosemethylation of RNA in vivo directed by tailored antisense RNAguidesrdquo Nature vol 383 no 6602 pp 732ndash735 1996

[2] P Ganot M-L Bortolin and T Kiss ldquoSite-specific pseu-douridine formation in preribosomal RNA is guided by smallnucleolar RNAsrdquo Cell vol 89 no 5 pp 799ndash809 1997

[3] D J Klein T M Schmeing P B Moore and T A SteitzldquoThe kink-turn a new RNA secondary structure motifrdquo EMBOJournal vol 20 no 15 pp 4214ndash4221 2001

[4] L B Szewczak J S Gabrielsen S J Degregorio S A Strobeland J A Steitz ldquoMolecular basis for RNA kink-turn recognition

by the h155K small RNP proteinrdquo RNA vol 11 no 9 pp 1407ndash1419 2005

[5] N Spackova K Reblova and J Sponer ldquoStructural dynamicsof the box CD RNA kink-turn and its complex with proteinsthe role of the A-minor 0 interaction long-residency waterbridges and structural ion-binding sites revealed by molecularsimulationsrdquo Journal of Physical Chemistry B vol 114 no 32 pp10581ndash10593 2010

[6] A K Henras C Dez and Y Henry ldquoRNA structure andfunction in CD and HACA s(no)RNPsrdquo Current Opinion inStructural Biology vol 14 no 3 pp 335ndash343 2004

[7] J Lin S Lai R Jia et al ldquoStructural basis for site-specific ribosemethylation by box CD RNA protein complexesrdquo Nature vol469 no 7331 pp 559ndash563 2011

[8] L Lui and T Lowe ldquoSmall nucleolar RNAs and RNA-guidedpost-transcriptional modificationrdquo Essays in Biochemistry vol54 no 1 pp 53ndash77 2013

[9] X Darzacq B E Jady C Verheggen A M Kiss E Bertrandand T Kiss ldquoCajal body-specific small nuclear RNAs a novelclass of 21015840-O-methylation and pseudouridylation guide RNAsrdquoEMBO Journal vol 21 no 11 pp 2746ndash2756 2002

[10] P Richard X Darzacq E Bertrand B E Jady C Verheggenand T Kiss ldquoA common sequence motif determines the Cajalbody-specific localization of box HACA scaRNAsrdquo EMBOJournal vol 22 no 16 pp 4283ndash4293 2003

[11] A Fedorov J Stombaugh M W Harr S Yu L Nasalean andV Shepelev ldquoComputer identification of snoRNA genes usinga Mammalian Orthologous Intron Databaserdquo Nucleic AcidsResearch vol 33 no 14 pp 4578ndash4583 2005

[12] P S Bazeley V Shepelev Z Talebizadeh et al ldquosnoTARGETshows that human orphan snoRNA targets locate close toalternative splice junctionsrdquo Gene vol 408 no 1-2 pp 172ndash1792008

[13] A Huttenhofer J Cavaille and J-P Bachellerie ldquoExperimentalRNomics a global approach to identifying small nuclear RNAsand their targets in different model organismsrdquo Methods inMolecular Biology vol 265 pp 409ndash428 2004

[14] B Rogelj ldquoBrain-specific small nucleolar RNAsrdquo Journal ofMolecular Neuroscience vol 28 no 2 pp 103ndash110 2006

[15] A Huttenhofer M Kiefmann S Meier-Ewert et al ldquoRnomicsan experimental approach that identifies 201 candidates fornovel small non-messenger RNAs in mouserdquo The EMBOJournal vol 20 no 11 pp 2943ndash2953 2001

[16] J Cavaille K Buiting M Kiefmann et al ldquoIdentificationof brain-specific and imprinted small nucleolar RNA genesexhibiting an unusual genomic organizationrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 97 no 26 pp 14311ndash14316 2000

[17] J C Castle C D Armour M Lower et al ldquoDigital genome-wide ncRNA expression including SnoRNAs across 11 humantissues using polya-neutral amplificationrdquo PLoS ONE vol 5 no7 Article ID e11779 2010

[18] S Kishore A Khanna Z Zhang et al ldquoThe snoRNA MBII-52 (SNORD 115) is processed into smaller RNAs and regulatesalternative splicingrdquo Human Molecular Genetics vol 19 no 7pp 1153ndash1164 2010

[19] S Kishore and S Stamm ldquoThe snoRNA HBII-52 regulatesalternative splicing of the serotonin receptor 2Crdquo Science vol311 no 5758 pp 230ndash232 2006

[20] P Vitali E Basyuk E LeMeur et al ldquoADAR2-mediated editingof RNA substrates in the nucleolus is inhibited by CD small


nucleolar RNAsrdquoThe Journal of Cell Biology vol 169 no 5 pp745ndash753 2005

[21] R J Taft E A Glazov T Lassmann Y Hayashizaki P Carninciand J S Mattick ldquoSmall RNAs derived from snoRNAsrdquo RNAvol 15 no 7 pp 1233ndash1240 2009

[22] M Shen E Eyras J Wu et al ldquoDirect cloning of double-stranded RNAs from RNase protection analysis reveals pro-cessing patterns of CD box snoRNAs and provides evidencefor widespread antisense transcript expressionrdquo Nucleic AcidsResearch vol 39 no 22 pp 9720ndash9730 2011

[23] M Falaleeva and S Stamm ldquoProcessing of snoRNAs as a newsource of regulatory non-coding RNAs snoRNA fragmentsform a new class of functional RNAsrdquo BioEssays vol 35 no 1pp 46ndash54 2013

[24] M Ono K Yamada F Avolio et al ldquoAnalysis of human smallnucleolar RNAs (snoRNA) and the development of snoRNAmodulator of gene expression vectorsrdquoMolecular Biology of theCell vol 21 no 9 pp 1569ndash1584 2010

[25] M Ono M S Scott K Yamada F Avolio G J Barton andA I Lamond ldquoIdentification of humanmiRNA precursors thatresemble boxCD snoRNAsrdquoNucleic Acids Research vol 39 no9 pp 3879ndash3891 2011

[26] M S Scott M Ono K Yamada A Endo G J Barton and AI Lamond ldquoHuman box CD snoRNA processing conservationacross multiple cell typesrdquoNucleic Acids Research vol 40 no 8pp 3676ndash3688 2012

[27] M S Scott F Avolio M Ono A I Lamond and G JBarton ldquoHumanmiRNA precursors with box HACA snoRNAfeaturesrdquo PLoS Computational Biology vol 5 no 9 Article IDe1000507 2009

[28] M Brameier A Herwig R Reinhardt L Walter and JGruber ldquoHuman box CD snoRNAs with miRNA like func-tions expanding the range of regulatory RNAsrdquo Nucleic AcidsResearch vol 39 no 2 pp 675ndash686 2011

[29] C Ender A Krek M R Friedlander et al ldquoA human snoRNAwith microRNA-like functionsrdquo Molecular Cell vol 32 no 4pp 519ndash528 2008

[30] A M Burroughs Y Ando M J L de Hoon et al ldquoDeep-sequencing of human argonaute-associated small RNAs pro-vides insight into miRNA sorting and reveals argonaute associ-ation with RNA fragments of diverse originrdquo RNA Biology vol8 no 1 pp 158ndash177 2011

[31] D Langenberger M V Cakir S Hoffmann and P F StadlerldquoDicer-processed small RNAs rules and exceptionsrdquo Journalof Experimental Zoology Part B Molecular and DevelopmentalEvolution vol 320 no 1 pp 35ndash46 2013

[32] J Badhai A-S Frojmark E J Davey J Schuster and N DahlldquoRibosomal protein S19 and S24 insufficiency cause distinctcell cycle defects in Diamond-Blackfan anemiardquo Biochimica etBiophysica ActamdashMolecular Basis of Disease vol 1792 no 10pp 1036ndash1042 2009

[33] N Hariharan and M A Sussman ldquoStressing on the nucleolusin cardiovascular diseaserdquo Biochimica et Biophysica ActamdashMolecular Basis of Disease vol 1842 no 6 pp 798ndash801 2014

[34] P A Trainor and A E Merrill ldquoRibosome biogenesis in skele-tal development and the pathogenesis of skeletal disordersrdquoBiochimica et BiophysicaActa vol 1842 no 6 pp 769ndash778 2014

[35] J-P Bachellerie J Cavaille andAHuttenhofer ldquoThe expandingsnoRNA worldrdquo Biochimie vol 84 no 8 pp 775ndash790 2002

[36] D Tollervey and T Kiss ldquoFunction and synthesis of smallnucleolar RNAsrdquo Current Opinion in Cell Biology vol 9 no 3pp 337ndash342 1997

[37] H E Gee F M Buffa C Camps et al ldquoThe small-nucleolarRNAs commonly used for microRNA normalisation correlatewith tumour pathology and prognosisrdquo British Journal ofCancer vol 104 no 7 pp 1168ndash1177 2011

[38] Y-P Mei J-P Liao J Shen et al ldquoSmall nucleolar RNA 42 actsas an oncogene in lung tumorigenesisrdquoOncogene vol 31 no 22pp 2794ndash2804 2012

[39] H Su T Xu S Ganapathy et al ldquoElevated snoRNA biogenesisis essential in breast cancerrdquo Oncogene vol 33 no 11 pp 1348ndash1358 2014

[40] Y Zhang and H Lu ldquoSignaling to p53 ribosomal proteins findtheir wayrdquo Cancer Cell vol 16 no 5 pp 369ndash377 2009

[41] L Chu M Y Su L B Maggi Jr et al ldquoMultiple myeloma-associated chromosomal translocation activates orphansnoRNA ACA11 to suppress oxidative stressrdquo Journal of ClinicalInvestigation vol 122 no 8 pp 2793ndash2806 2012

[42] A Donsante D G Miller Y Li et al ldquoAAV vector integrationsites in mouse hepatocellular carcinomardquo Science vol 317 no5837 article 477 2007

[43] Y Zhou X Zhang andA Klibanski ldquoMEG3 noncoding RNA atumor suppressorrdquo Journal of Molecular Endocrinology vol 48no 3 pp R45ndashR53 2012

[44] Y Zhou Y Zhong Y Wang et al ldquoActivation of p53 by MEG3non-coding RNArdquoThe Journal of Biological Chemistry vol 282no 34 pp 24731ndash24742 2007

[45] F E Gordon C L Nutt P Cheunsuchon et al ldquoIncreasedexpression of angiogenic genes in the brains of mouse meg3-null embryosrdquo Endocrinology vol 151 no 6 pp 2443ndash24522010

[46] J Krell A E Frampton R Mirnezami et al ldquoGrowth arrest-specific transcript 5 associated snoRNA levels are related to p53expression and DNA damage in colorectal cancerrdquo PLoS ONEvol 9 no 6 Article ID e98561 2014

[47] M Mourtada-Maarabouni M R Pickard V L Hedge FFarzaneh and G T Williams ldquoGAS5 a non-protein-codingRNA controls apoptosis and is downregulated in breast cancerrdquoOncogene vol 28 no 2 pp 195ndash208 2009

[48] M R Pickard M Mourtada-Maarabouni and G T WilliamsldquoLong non-coding RNA GAS5 regulates apoptosis in prostatecancer cell linesrdquo Biochimica et Biophysica Acta vol 1832 no10 pp 1613ndash1623 2013

[49] M E Askarian-Amiri J Crawford J D French et al ldquoSNORD-host RNA Zfas1 is a regulator of mammary development and apotential marker for breast cancerrdquo RNA vol 17 no 5 pp 878ndash891 2011

[50] W Valleron E Laprevotte E-F Gautier et al ldquoSpecificsmall nucleolar RNA expression profiles in acute leukemiardquoLeukemia vol 26 no 9 pp 2052ndash2060 2012

[51] A Gaur D A Jewell Y Liang et al ldquoCharacterization ofmicroRNA expression levels and their biological correlates inhuman cancer cell linesrdquo Cancer Research vol 67 no 6 pp2456ndash2468 2007

[52] H J Ferreira H Heyn C Moutinho and M Esteller ldquoCpGisland hypermethylation-associated silencing of small nucleolarRNAs in human cancerrdquo RNA Biology vol 9 no 6 pp 881ndash8902012

[53] P Lopez-Serra and M Esteller ldquoDNA methylation-associatedsilencing of tumor-suppressor microRNAs in cancerrdquo Onco-gene vol 31 no 13 pp 1609ndash1622 2012

[54] E S Martens-Uzunova S E Jalava N F Dits et al ldquoDiagnosticand prognostic signatures from the small non-coding RNA


transcriptome in prostate cancerrdquo Oncogene vol 31 no 8 pp978ndash991 2012

[55] S Belin A Beghin E Solano-Gonzalez et al ldquoDysregulationof ribosome biogenesis and translational capacity is associatedwith tumor progression of human breast cancer cellsrdquo PLoSONE vol 4 no 9 Article ID e7147 2009

[56] J Liao L Yu Y Mei et al ldquoSmall nucleolar RNA signatures asbiomarkers for non-small-cell lung cancerrdquo Molecular Cancervol 9 article 198 2010

[57] X-Y Dong C Rodriguez P Guo et al ldquoSnoRNA U50 is acandidate tumor-suppressor gene at 6q143 with a mutationassociated with clinically significant prostate cancerrdquo HumanMolecular Genetics vol 17 no 7 pp 1031ndash1042 2008

[58] X-Y Dong P Guo J Boyd et al ldquoImplication of snoRNA U50in human breast cancerrdquo Journal of Genetics and Genomics vol36 no 8 pp 447ndash454 2009

[59] K J Teittinen A Laiho A Uusimaki J-P Pursiheimo AGyenesei and O Lohi ldquoExpression of small nucleolar RNAs inleukemic cellsrdquo Cellular Oncology (Dordrecht) vol 36 no 1 pp55ndash63 2013

[60] W Valleron L Ysebaert L Berquet et al ldquoSmall nucleolar RNAexpression profiling identifies potential prognostic markers inperipheral T-cell lymphomardquo Blood vol 120 no 19 pp 3997ndash4005 2012

[61] S Hirajima S Komatsu D Ichikawa et al ldquoClinical impactof circulating miR-18a in plasma of patients with oesophagealsquamous cell carcinomardquo British Journal of Cancer vol 108no 9 pp 1822ndash1829 2013

[62] C Wu C Wang X Guan et al ldquoDiagnostic and prognosticimplications of a serummiRNApanel in oesophageal squamouscell carcinomardquo PLoSONE vol 9 no 3 Article ID e92292 2014

[63] T A Farazi J I Hoell P Morozov and T Tuschl ldquoMicroRNAsin human cancerrdquo Advances in Experimental Medicine andBiology vol 774 pp 1ndash20 2013

[64] E Zandberga V Kozirovskis A Abols D Andrejeva GPurkalne and A Line ldquoCell-free microRNAs as diagnosticprognostic and predictive biomarkers for lung cancerrdquo GenesChromosomes and Cancer vol 52 no 4 pp 356ndash369 2013

[65] Y Yang X Gu M Zhou J Xiang and Z Chen ldquoSerummicroRNAs a new diagnostic method for colorectal cancerrdquoBioscience Reports vol 1 no 4 pp 495ndash498 2013

[66] C Yang C Wang X Chen et al ldquoIdentification of sevenserum microRNAs from a genome-wide serum microRNAexpression profile as potential noninvasive biomarkers formalignant astrocytomasrdquo International Journal of Cancer vol132 no 1 pp 116ndash127 2013

[67] C M Doe D Relkovic A S Garfield et al ldquoLoss of theimprinted snoRNA mbii-52 leads to increased 5htr2c pre-RNA editing and altered 5HT

2119862R-mediated behaviourrdquoHuman

Molecular Genetics vol 18 no 12 pp 2140ndash2148 2009[68] P Sridhar H H Gan and T Schlick ldquoA computational screen

for CD box snoRNAs in the human genomic region associ-ated with Prader-Willi and Angelman syndromesrdquo Journal ofBiomedical Science vol 15 no 6 pp 697ndash705 2008

[69] A L Duker B C Ballif E V Bawle et al ldquoPaternallyinherited microdeletion at 15q112 confirms a significant rolefor the SNORD116 CD box snoRNA cluster in Prader-Willisyndromerdquo European Journal of Human Genetics vol 18 no 11pp 1196ndash1201 2010

[70] T Sahoo D del Gaudio J R German et al ldquoPrader-Williphenotype caused by paternal deficiency for the HBII-85 CD

box small nucleolar RNA clusterrdquo Nature Genetics vol 40 no6 pp 719ndash721 2008

[71] M-L Bortolin-Cavaille and J Cavaille ldquoThe SNORD115(HMBII-52) and SNORD116 (HMBII-85) gene clusters atthe imprinted Prader-Willi locus generate canonical box CDsnoRNAsrdquo Nucleic Acids Research vol 40 no 14 pp 6800ndash6807 2012

[72] B I Laufer K Mantha M L Kleiber E J Diehl S M FAddison and S M Singh ldquoLong-lasting alterations to DNAmethylation and ncRNAs could underlie the effects of fetal alco-hol exposure in micerdquo DMM Disease Models and Mechanismsvol 6 no 4 pp 977ndash992 2013

[73] J Nakatani K Tamada F Hatanaka et al ldquoAbnormal behaviorin a chromosome-engineered mouse model for human 15q11-13duplication seen in autismrdquo Cell vol 137 no 7 pp 1235ndash12462009

[74] S D Der A Zhou B R G Williams and R H SilvermanldquoIdentification of genes differentially regulated by interferon 120572120573 or 120574 using oligonucleotide arraysrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 95 no26 pp 15623ndash15628 1998

[75] G Trinchieri ldquoType I interferon friend or foerdquo Journal ofExperimental Medicine vol 207 no 10 pp 2053ndash2063 2010

[76] A J Sadler and B R G Williams ldquoInterferon-inducibleantiviral effectorsrdquoNature Reviews Immunology vol 8 no 7 pp559ndash568 2008

[77] L M Sedger ldquoMicroRNA control of interferons and interferoninduced anti-viral activityrdquoMolecular Immunology vol 56 no4 pp 781ndash793 2013

[78] M Hecker M Thamilarasan D Koczan et al ldquoMicroRNAexpression changes during interferon-beta treatment in theperipheral blood of multiple sclerosis patientsrdquo InternationalJournal of Molecular Sciences vol 14 no 8 pp 16087ndash161102013

[79] T Saxena B Tandon S Sharma et al ldquoCombined miRNA andmRNA signature identifies key molecular players and pathwaysinvolved in chikungunya virus infection in human cellsrdquo PLoSONE vol 8 no 11 Article ID e79886 2013

[80] B R Cullen ldquoMicroRNAs as mediators of viral evasion of theimmune systemrdquoNature Immunology vol 14 no 3 pp 205ndash2102013

[81] R Hutzinger R Feederle J Mrazek et al ldquoExpression and pro-cessing of a small nucleolar RNA from the Epstein-Barr virusgenomerdquo PLoS Pathogens vol 5 no 8 Article ID e10005472009

[82] S Barth T Pfuhl A Mamiani et al ldquoEpstein-Barr virus-encoded microRNA miR-BART2 down-regulates the viralDNA polymerase BALF5rdquo Nucleic Acids Research vol 36 no2 pp 666ndash675 2008

[83] F Renzi E Caffarelli P Laneve I Bozzoni M Brunori and BVallone ldquoThe structure of the endoribonuclease XendoU fromsmall nucleolar RNA processing to severe acute respiratorysyndrome coronavirus replicationrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 103 no33 pp 12365ndash12370 2006

[84] X Peng L Gralinski M T Ferris et al ldquoIntegrative deepsequencing of themouse lung transcriptome reveals differentialexpression of diverse classes of small RNAs in response torespiratory virus infectionrdquo mBio vol 2 no 6 Article IDe00198-11 2011

[85] G T Williams M Mourtada-Maarabouni and F Farzaneh ldquoAcritical role for non-coding RNA GAS5 in growth arrest and


rapamycin inhibition in human T-lymphocytesrdquo BiochemicalSociety Transactions vol 39 no 2 pp 482ndash486 2011

[86] S J Plotch and R M Krug ldquoSegments of influenza viruscomplementary RNA synthesized in vitrordquo Journal of Virologyvol 25 no 2 pp 579ndash586 1978

[87] P Narayan D F Ayers F M Rottman P A Maroney andT W Nilsen ldquoUnequal distribution of N6-methyladenosine ininfluenza virus mRNAsrdquoMolecular and Cellular Biology vol 7no 4 pp 1572ndash1575 1987

[88] S Daffis K J Szretter J Schriewer et al ldquo21015840-O methylationof the viral mRNA cap evades host restriction by IFIT familymembersrdquo Nature vol 468 no 7322 pp 452ndash456 2010

[89] D Guilligay J Kadlec T Crepin et al ldquoComparative structuraland functional analysis of Orthomyxovirus polymerase cap-snatching domainsrdquo PLoS ONE vol 9 no 1 Article ID e849732014

[90] S ReichDGuilligay A Pflug et al ldquoStructural insight into cap-snatching and RNA synthesis by influenza polymeraserdquoNaturevol 516 no 7531 pp 361ndash366 2014

[91] L Zhang M Yang P Marks et al ldquoSerum non-coding RNAsas biomarkers for osteoarthritis progression after ACL injuryrdquoOsteoarthritis and Cartilage vol 20 no 12 pp 1631ndash1637 2012

[92] C I Michel C L Holley B S Scruggs et al ldquoSmall nucleolarRNAs U32a U33 and U35a are critical mediators of metabolicstressrdquo Cell Metabolism vol 14 no 1 pp 33ndash44 2011

[93] R H Unger ldquoLipid overload and overflow metabolic traumaand the metabolic syndromerdquo Trends in Endocrinology andMetabolism vol 14 no 9 pp 398ndash403 2003

[94] N M Borradaile X Han J D Harp S E Gale D S Ory andJ E Schaffer ldquoDisruption of endoplasmic reticulum structureand integrity in lipotoxic cell deathrdquo Journal of Lipid Researchvol 47 no 12 pp 2726ndash2737 2006

[95] R E McDaniel P Y Maximov and V C Jordan ldquoEstrogen-mediated mechanisms to control the growth and apoptosisof breast cancer cells a translational research success storyrdquoVitamins amp Hormones vol 93 pp 1ndash49 2013

[96] K J Huber-Keener X Liu Z Wang et al ldquoDifferential geneexpression in tamoxifen-resistant breast cancer cells revealed bya new analytical model of RNA-seq datardquo PLoS ONE vol 7 no7 Article ID e41333 2012

[97] I F Grigsby L Pham R Gopalakrishnan LMMansky and KC Mansky ldquoDownregulation of Gnas Got2 and Snord32a fol-lowing tenofovir exposure of primary osteoclastsrdquo Biochemicaland Biophysical Research Communications vol 391 no 3 pp1324ndash1329 2010

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anatomy Research International

PeptidesInternational Journal of


Hindawi Publishing Corporation httpwwwhindawicom

International Journal of

Volume 2014

Zoology


Molecular Biology International

GenomicsInternational Journal of


The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014


BioinformaticsAdvances in

Marine BiologyJournal of



Signal TransductionJournal of


BioMed Research International

Evolutionary BiologyInternational Journal of



Biochemistry Research International

ArchaeaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014


Genetics Research International


Advances in

Virolog y

Hindawi Publishing Corporationhttpwwwhindawicom

Nucleic AcidsJournal of

Volume 2014

Stem CellsInternational



Enzyme Research



Microbiology


(a)

DC

O B

O O

O

O B

O O

O

SAM

SAH

Box CD RNA

H

Target

3998400

5998400

3998400

5998400

CH3

D998400

C998400

⋆

(b)

TargetNU

ACABox HACA RNA

O U

O OH

O

O

O

O

OH

3998400

5998400

3998400

5998400

HΨ

⋆

Figure 1 (a) Box CD snoRNAs share two conserved elements boxesb (PuUGAUGA) andD (CUGA) located at the 51015840- and 31015840-termini of theRNAmolecule respectively Often box CD snoRNAs also have an additional copy of internally located C1015840 orD1015840 boxes A complex of box CDsnoRNA with nucleolar proteins Nop1p (fibrillarin) Nop56p Nop58p and Snu13p (155 kDa) catalyzes site-specific 21015840-O-methylation of thenucleotide in target RNA S-Adenosylmethionine (SAM) serves as the donor of themethyl group and is converted to S-adenosylhomocysteine(SAH) (b) Box HACA snoRNAs have ldquohairpin-hinge-hairpin-tailrdquo structure with boxes H (ANANNA) and ACA located within the single-stranded (hinge) and 31015840-terminus (tail) regions respectively Pseudouridylation complex includes dyskerin (the pseudouridine synthase)GAR1 NHP2 and NOP10 proteins Box HACA snoRNP catalyzes site-specific isomerization of uridine (U) to pseudouridine (Ψ) in targetRNA SnoRNA with target RNA in square brackets designates snoRNP enzyme-substrate complex

RNAflank twonucleotides including a uridine residue whichis further subjected to UΨ isomerization Thus the three-dimensional structure of the conserved motif enables theaccess of pseudouridylation enzymes to the substrate uridineThe distance between the target nucleotide and HACA boxin rRNA-snoRNA duplex is 14-15 nt long [2 8]

Similar elements boxes C and D as well as boxes H andACA can be found in primary structures of small Cajalbody-specific RNAs (scaRNAs) These RNAs guide 21015840-O-methylation and pseudouridylation of small nuclear RNAs(snRNAs) [9 10]

It has been shown that numerous box CD and boxHACA RNAs have no identified targets among rRNAsor snRNAs Such snoRNAs referred to as ldquoorphan snoR-NAsscaRNAsrdquo may have some other regulatory functionaside from 21015840-O-methylation and pseudouridylation of RNAnucleotides [11ndash13] Series of studies of snoRNA expressionprofiles in mammalian cells have demonstrated that thelevel of many ldquoorphanrdquo box CD and box HACA RNAsvaries among different tissues [14ndash17] The variation ofsnoRNA expression profiles suggests that such RNAs havetissue-specific functions For example two brain-specific box

CD RNAs SNORD115 (HBII-52) and SNORD116 (HBII-85) were shown to be processed into smaller RNAs thatcan affect the outcome of alternative splicing of variouspre-mRNAs by preventing the formation of particular pre-mRNA splicing variants [18] SNORD115 is also involved inthe regulation of serotonin receptor 5-HT2CR mRNA levelin brain cells through alternative splicing and control ofposttranscriptional nucleotide modification (adenosine-to-inosine editing) of the target mRNA [19 20]

Along with SNORD115 and SNORD116 a number ofother human snoRNAs can generate smaller fragments asit has been demonstrated by high-throughput sequencingand RNase protection experiments [21ndash23] Short fragmentsderived from box CD snoRNA SNORD88C (HBII-180C)hold complementarity to fibroblast growth receptor-3(FGFR-3) pre-mRNA Being expressed from artificialldquosnoMENrdquo vector SNORD88C (HBII-180C) is capableof suppressing target gene mRNA and protein level in asequence-dependent manner through base pairing withpre-mRNA regulatory elements [24 25] Bioinformaticanalysis showed that about a half of all box CD RNAs areprocessed into small molecules that are conserved among













































6 Conclusion




Abbreviations





Acknowledgment


References



















































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology













































6 Conclusion




Abbreviations





Acknowledgment


References



















































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology



Abbreviations





Acknowledgment


References



















































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology






























































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology

review article regulatory role of small nucleolar rnas in...

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