RNA Modification PDF
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ISBN:978-0-12-811777-4 ISSN:1874-6047 ForinformationonallAcademicPresspublications visitourwebsiteathttps://www.elsevier.com/books-and-journals Publisher:ZoeKruze AcquisitionEditor:KirstenShankland EditorialProjectManager:NaomiRobertson ProductionProjectManager:SuryaNarayananJayachandran CoverDesigner:VickyPearson TypesetbySPiGlobal,India CONTRIBUTORS PaulF.Agris TheRNAInstitute,StateUniversityofNewYork,Albany,NY,UnitedStates JuanD.Alfonzo DepartmentofMicrobiology,OhioStateBiochemistryProgram,TheCenterforRNA Biology,TheOhioStateUniversity,Columbus,OH,UnitedStates PeterA.Beal UniversityofCalifornia,Davis,CA,UnitedStates GuillaumeF.Chanfreau UniversityofCalifornia,LosAngeles,CA,UnitedStates MeemanageD.DeZoysa UniversityofRochesterMedicalCenter,CenterforRNABiology,Rochester,NY, UnitedStates EmilyEruysal TheRNAInstitute,StateUniversityofNewYork,Albany,NY,UnitedStates BrianD.Gregory UniversityofPennsylvania;CellandMolecularBiologyGraduateProgram;Genomicsand ComputationalBiologyGraduateProgram,UniversityofPennsylvania,Philadelphia,PA, UnitedStates AnthonyK.Henras LaboratoiredeBiologieMol(cid:1)eculaireEucaryote,CentredeBiologieInt(cid:1)egrative,Universit(cid:1)e deToulouse,CNRS,UPS,Toulouse,France YvesHenry LaboratoiredeBiologieMol(cid:1)eculaireEucaryote,CentredeBiologieInt(cid:1)egrative,Universit(cid:1)e deToulouse,CNRS,UPS,Toulouse,France Ya-MingHou ThomasJeffersonUniversity,Philadelphia,PA,UnitedStates OdileHumbert LaboratoiredeBiologieMol(cid:1)eculaireEucaryote,CentredeBiologieInt(cid:1)egrative,Universit(cid:1)e deToulouse,CNRS,UPS,Toulouse,France OlgaKolaj-Robin InstitutdeG(cid:1)en(cid:1)etiqueetdeBiologieMol(cid:1)eculaireetCellulaire(IGBMC);CentreNationalde RechercheScientifique(CNRS)UMR7104;InstitutNationaldeSant(cid:1)eetdeRecherche M(cid:1)edicale(INSERM)U964;Universit(cid:1)edeStrasbourg,Illkirch,France IsaoMasuda ThomasJeffersonUniversity,Philadelphia,PA,UnitedStates ix x Contributors RyumaMatsubara ThomasJeffersonUniversity,Philadelphia,PA,UnitedStates KatherineM.McKenney DepartmentofMicrobiology,OhioStateBiochemistryProgram,TheCenterforRNA Biology,TheOhioStateUniversity,Columbus,OH,UnitedStates AmithiNarendran TheRNAInstitute,StateUniversityofNewYork,Albany,NY,UnitedStates C(cid:1)eliaPlisson-Chastang LaboratoiredeBiologieMol(cid:1)eculaireEucaryote,CentredeBiologieInt(cid:1)egrative,Universit(cid:1)e deToulouse,CNRS,UPS,Toulouse,France YvesRomeo LaboratoiredeBiologieMol(cid:1)eculaireEucaryote,CentredeBiologieInt(cid:1)egrative,Universit(cid:1)e deToulouse,CNRS,UPS,Toulouse,France MaryAnneT.Rubio DepartmentofMicrobiology,OhioStateBiochemistryProgram,TheCenterforRNA Biology,TheOhioStateUniversity,Columbus,OH,UnitedStates KathrynSarachan TheRNAInstitute,StateUniversityofNewYork,Albany,NY,UnitedStates BertrandS(cid:1)eraphin InstitutdeG(cid:1)en(cid:1)etiqueetdeBiologieMol(cid:1)eculaireetCellulaire(IGBMC);CentreNationalde RechercheScientifique(CNRS)UMR7104;InstitutNationaldeSant(cid:1)eetdeRecherche M(cid:1)edicale(INSERM)U964;Universit(cid:1)edeStrasbourg,Illkirch,France JoannaI.Sulkowska CenterofNewTechnologies,UniversityofWarsaw,Warsaw,Poland RyuichiTakase ThomasJeffersonUniversity,Philadelphia,PA,UnitedStates LeeE.Vandivier UniversityofPennsylvania;CellandMolecularBiologyGraduateProgram,Universityof Pennsylvania,Philadelphia,PA,UnitedStates VilleY.P.V€are TheRNAInstitute,StateUniversityofNewYork,Albany,NY,UnitedStates YuruWang UniversityofCalifornia,Davis,CA,UnitedStates Yi-TaoYu UniversityofRochesterMedicalCenter,CenterforRNABiology,Rochester,NY, UnitedStates YuxuanZheng UniversityofCalifornia,Davis,CA,UnitedStates PREFACE The field of RNA modifications has been experiencing a renaissance in recent years. Decades ago, some of the earliest studies focusing on RNA modificationsrevealedtheirroleininfluencingthedecodingofgeneticmes- sengerRNAsbytransferRNAs(tRNAs).WhileRNAmodificationswere initiallyidentifiedinthesetRNAsandinribosomalRNAs(rRNAs)because oftheirhighabundance,theadventofmodernsequencingtechnologieshas enabled researchers to investigate the global extent of RNA modifications on the transcriptome. These recent studies have revealed a large variety of modifications and of modification sites in all major classes of cellular RNAs. The enzymes that catalyze the addition of chemical modifications toRNAareasdiverseasthechemicalgroupsthatareaddedtoRNAs.These enzymes range from single protein chains to large ribonucleoprotein complexes,inwhichthepresenceofanRNAguidetargetsthemodification enzymetoitsRNAsubstrates.ThespecificityofRNA-modifyingenzymes is essential, as misguided RNA modifications can negatively impact the process of genetic decoding during translation. Moreover, the presence of RNA modifications has a major influence on the metabolic fate of these modified RNAs, as these modifications can promote their correct folding, nucleocytoplasmic trafficking, translation, or turnover. Finally, RNA modifications can provide recognition sites for proteins that interact with modified RNAs. This volume of The Enzymes highlights some of the most recent advances in the field of RNA modifications and attempts toprovideacomprehensivereviewofthestructure,function,andspecificity of RNA-modifying enzymes as well as a survey of the role of these modi- fications on RNA metabolism. Throughout these chapters, it will become apparent that these modifications providekey functional groups,as disrup- tion of RNA modification reactions due to mutations in RNA-modifying enzymes results in a variety of inherited diseases, highlighting the impor- tance of these modifications in cellular metabolism. I thank all the authors who generously contributed to this volume of TheEnzymes.IwouldalsoliketoexpressmygratitudetoNaomiRobertson at Elsevier for handling and copyediting this volume. GUILLAUME F. CHANFREAU xi CHAPTER ONE The Importance of Being Modified: The Role of RNA Modifications in Translational Fidelity Paul F. Agris1, Amithi Narendran, Kathryn Sarachan, Ville Y.P. V€are, Emily Eruysal TheRNAInstitute,StateUniversityofNewYork,Albany,NY,UnitedStates 1Correspondingauthor:e-mailaddress:[email protected] Contents 1. Introduction 2 1.1 UniversalGeneticCode 2 1.2 PosttranscriptionalRNAModification 4 1.3 RNAModificationandtheAccuracyandEfficiencyofTranslation 6 2. HumanMitochondrialtRNAMetDecodesthe1:3DegenerateCodonBox 9 2.1 HumanMitochondrialandCytoplasmictRNAMet 9 2.2 PosttranscriptionalModificationofMitochondrialtRNAMet 10 2.3 OtherHumanMitochondrialtRNAMetProperties 14 2.4 HumanMitochondrialtRNADisease 15 2.5 Summary 16 3. tRNADecodingoftheTwofold,2:2,DegenerateCodonBox 17 3.1 tRNALysTwofoldDegenerateCodonsAAAandAAG 17 3.2 WobblePositionUridine-34Modifications 18 3.3 ModificationsofAdenosine-37,30-AdjacenttotheAnticodon 22 3.4 Summary 24 4. tRNADecodingofCodonFourfoldDegeneracy 25 4.1 SingletRNAReadsAllFourCodonsoftheProkaryoteFourfoldDegenerate CodonBox 25 4.2 EukaryotetRNAsThatWobbleinReadingFourfoldDegenerateCodons 27 4.3 RolesofBothWobblePositions-34and-37ModificationsinReading FourfoldDegenerateCodons 28 4.4 Summary 30 5. ThreeAminoAcidsAreEncodedbySixSynonymousCodonsEach 30 5.1 SixfoldDegeneracyandReadingoftheArginineCodons 30 5.2 Modification-DependenttRNAReadingoftheArginineCodons 32 5.3 TheModification2-ThiocytidineModulatesInosineReadingofA,U,andC 33 5.4 tRNAArgSpeciesDecodingaTwofoldDegenerateCodonBox 35 5.5 Summary 37 TheEnzymes,Volume41 #2017ElsevierInc. 1 ISSN1874-6047 Allrightsreserved. http://dx.doi.org/10.1016/bs.enz.2017.03.005 2 PaulF.Agrisetal. 6. PosttranscriptionalModificationoftRNAIsRequiredforAccurateandEfficient Decoding 38 Acknowledgment 39 References 40 Abstract TheposttranscriptionalmodificationsoftRNA’santicodonstemandloop(ASL)domain representathirdlevel,athirdcode,totheaccuracyandefficiencyoftranslatingmRNA codonsintothecorrectaminoacidsequenceofproteins.ModificationsoftRNA’sASL domain are enzymatically synthesized and site specifically located at the anticodon wobble position-34 and 30-adjacent to the anticodon at position-37. Degeneracy of the64UniversalGeneticCodesandthelimitationinthenumberoftRNAspeciesrequire sometRNAstodecodemorethanonecodon.Thespecificmodificationchemistriesand theirimpactonthetRNA’sASLstructureanddynamicsenableonetRNAtodecodecog- nate and “wobble codons” or to expand recognition to synonymous codons, all the whilemaintainingthetranslationalreadingframe.Somemodifiednucleosides’chem- istriesprestructuretRNAtoreadthetwocodonsofaspecificaminoacidthatsharesa twofolddegeneratecodonbox,andotherchemistriesallowadifferenttRNAtorespond toallfourcodonsofafourfolddegeneratecodonbox.Thus,tRNAASLmodificationsare critical and mutations in genes for the modification enzymes and tRNA, the conse- quencesofwhichisalackofmodification,leadtomistranslationandhumandisease. By optimizing tRNA anticodon chemistries, structure, and dynamics in all organisms, modificationsensuretranslationalfidelityofmRNAtranscripts. 1. INTRODUCTION 1.1 Universal Genetic Code The Universal Genetic Code of 64 triplet codons encoded in DNA and transcribed into each messenger RNA (mRNA) is degenerate (Fig. 1). As a general rule, 61 codons represent the 20 amino acids during translation on the ribosome. Three codons are read by protein factors as translation stops. TransferRNAs(tRNAs)decodethe mRNA codons whilebringing thecognateaminoacidtotheribosomeforincorporationintothegrowing peptidechain.Theribosomeisoneofthemostcomplexofenzymes.With thebacterialandeukaryotedecodingoraminoacylsite(A-site)andthepep- tidyl transferase center (PTC) consisting almost completely of RNA [1,2], the ribosome is an RNA-based enzyme with large RNA substrates. Even themitochondrialribosome,whichismorehighlyproportionedofproteins, has an RNA-rich decoding and PTC [3]. In humans, the ribosome’s sub- strates include some 25,000 mRNAs for proteins of less than 100 amino ImportanceofRNABeingModified 3 Second U C A G xi6A37 U UUUUCU PPhhee Gm34 UUCCCU SSeerr 5xmU34 UUAAUC TTyyrr UUGGUC CCyyss CU m1G37 UUA Leu U34 UCA Ser U; 34 UAA Stop UGA Stop A UUG Leu 5m UCG Ser 5o UAG Stop UGG Trp G x x CUU Leu CCU Pro U34 CAU His CGU Arg U mm12GA3377 C CCUUCA LLeeuu CCCCCA PPrroo 5U; xm34 CCAACA HGilsn 5xmU34CCGGCA AArrgg 2sC32 CA ble) rst CUG Leu CCG Pro 5xo CAG Gln CGG Arg G wob Fi mt66AA3377 A AAAAUUUUGUCA lllMMllleeeeett 5fC34 AAAACCCCGCUA TTTThhhhrrrr xo5U; xm5U3434 AAAAAAAAGUCA AALLyyssssnn 52xmsU34 AAAAGGGGGUCA SSAAeerrggrr 5xmU34 UCAG Third ( m6A37 GGUUCU VVaall 5mU34 GGCCUC AAllaa 5mU34GGAAUC AAsspp U34GGGGUC GGllyy UC mm12GA3377 GGGUUGA VVaall 5oU; x34GGCCGA AAllaa 5oU; x34GGAAGA GGlluu 52xms GGGGGA GGllyy AG x x Fig.1 TheUniversalGeneticCode.Twofolddegeneratecodonsarehighlightedintan; threefold(Ile)ingray,fourfoldinyellow,andsixfoldinblue.ThesinglecodonsofMetand Trparehighlighted ingreen and orange,respectively, andthethreestop codons are highlightedinred.Thefigureisannotatedwiththeabbreviationsforthosemodified nucleosides found inthe anticodon domain of tRNAs responding to the codons and discussedinthisreview.Thechemicalstructuresandfullnamesofthemodifications arefoundinFig.3. acidsinlengthtomorethan20,000aminoacids[4];GTP;anumberofpro- tein factors; and some 40 transfer RNAs (tRNA) each aminoacylated with one specific amino acid. The ribosome’s enzymatic activity in translating mRNAcodonsintotheaminoacidsequencesisa“processive”mechanism ofaction.Theribosomesequentiallyandcovalentlylinksthegrowingpep- tidechaintotheaminoterminusoftheincomingaminoacidthatisboundto itsspecifictRNAthroughanesterbond.tRNAsareaminoacylatedattheir 0 universal 3-terminal adenosine by amino acid-specific, aminoacyl-tRNA synthetases.TheaminoacylatedtRNAisbroughttotheribosomebyapro- tein,elongationfactor,thatrecognizesthatthetRNAisaminoacylated,but is not engaged in codon recognition and specificity. CodonrecognitionbyaminoacylatedtRNA,acceptanceandaccommo- dationofthetRNAbytheribosome,peptidebondformation,translocation 4 PaulF.Agrisetal. of the peptidyl-tRNA from the decoding or aminoacyl site (A-site) to the peptidyl-site (P-site), and the movement of unacylated tRNA from the P-sitetotheexit(E-site)areprocessive.WithoutleavingthemRNAtem- plate, the ribosome progresses from codon to codon from the mRNA’s translational start sequence and first codon AUG for methionine to the 0 3- termination codons UAG, UAA, and UGA, and release sequences. The three nucleosides of each aminoacylated tRNA’s anticodon recognize athree-nucleotidemRNAcodonandbindtothecodoninasequence-and frame-specific manner to deliver the 20 common amino acids for protein synthesis. The aminoacylated tRNA is accepted at the A-site in response tothecomplementarymRNAcodon,andaproofreadingmechanismcon- sisting of some nine hydrogen bonds formed between the ribosomalRNA (rRNA), tRNA, and codon ensures a high fidelity in translation. Accurate interactionoftheanticodonwithcodonisverymuchdependentontheini- tial Watson–Crick(A●U;G●C)complementarityof thehydrogenbond- ingofthefirsttwobasepairs.Otherenzymeshavingprocessivemechanisms ofactionincludetheDNA-andRNApolymerases.Whileproteinsynthesis is accurate to 1 in 10,000 or 20,000 amino acids at a rate of 10–20 peptide bondsformedpersecond[5,6],DNA-andRNApolymeraseshaveerrorsof lessthan1in109at50–100sofbasepairspersecondincludingproofreading steps[7,8]and1in105atarateof8–85basespersecond[9,10],respectively, in vivo. tRNAhastobeconsideredoneofthemostuniqueofenzymesubstrates. The ribosome structure and its processive catalytic mechanism [2] require thetRNAsubstratestohaveauniformityinchemistryandstructure.Nev- ertheless, some 40 tRNA molecules, 22 within the human mitochondria, possess enough unique chemical diversity and structural malleability to be recognized by 20 aminoacyl-tRNA synthetases and to decode 61 mRNA codonsontheribosome.HowdotRNAsachieveuniformityofchemistry and structure and yet a necessary distinctiveness for protein synthesis? Although seemingly contradictory, tRNAs use posttranscriptional modifi- cation chemistriesto achieve both astablestructure mandatedby the ribo- someandtheoriginalityrequiredforproteinrecognitiondeterminantsand codon reading. 1.2 Posttranscriptional RNA Modification AllRNAsareinvolvedinactivitiesthatcontributedirectlyor indirectlyto theregulation,accuracy,andefficiencyofgeneexpressionthatisfulfilledin translatingthemRNAcodonsintotheaminoacidsequencesofproteins.As ImportanceofRNABeingModified 5 in translating one language into another, the accuracy of that translation is dependentnotonlyonaliteralword-to-wordequivalencybutalsooncon- text,frame,andpunctuation.Theenzymaticallysynthesized,sitespecifically positioned,posttranscriptionalmodificationsofRNA(Fig.2)couldbecon- sidered the punctuation marks in the translation of the genetic code. It is difficult to find among RNA species (mRNA; tRNA; ribosomal, rRNA; smallnuclear,snRNA;micro,miRNA;longnoncoding,lncRNA)onethat is not posttranscriptionally modified [11]. TheUniversalGeneticCodeforthe20aminoacids,thefirstcode,and the operational RNA code for the recognition of tRNA by its cognate aminoacyl-tRNA synthetase, the second code [12], did not take into accounttheposttranscriptionalmodificationsofRNA,forlittlewasknown about them at the time, except that they existed. The ubiquitously occur- ring,conservedmodifiednucleosidesconstituteayettobefullyappreciated third code in regulating translation, its accuracy, and efficiency [13]. Even Aminoacyl stem D stem and loop T stem and loop Extra loop Anticodon stem and loop 29 41 ψ 30 40 ψ 31 39 s2C ψ 32 38 33 37 t6A 34 m6A 36 i6A 35 ms2i6A f5C m2A τm5s2U m1G mnm5U mnm5s2U mcm5s2U ncm5U mcm5U cmo5U Fig. 2 tRNA and its anticodon stem and loop (ASL) domain. Left: General cloverleaf structure of a 76-nucleotide tRNA with the aminoacyl-accepting stem in green, dihydrouridine (D) stem and loop in black, ASL in red, extra loop in blue, and ribothymidine(T)stemandloopinplum.Right:AnenlargementoftheASLdomain,with theabbreviationsoftheimportantmodificationsdiscussedinthisreviewlisted.Adarker colorhueinplumrepresentsmoreimportantmodificationsites. 6 PaulF.Agrisetal. withmorethanhalfacenturyofresearch,morethan100differentposttran- scriptionalmodificationsofRNAsremainmostlyanundeterminedregulat- ing factor to translation [14,15]. The posttranscriptional modification of RNA, designatedastheepitranscriptome[16],nowusuallyrefersexclusively to mRNAs. mRNAs have a half-dozen different types of modifications identifiedtodate[17].Theserepresentsomeofthemostcommonofallmod- 0 ifications,the2-Omethylationsofthefourmajornucleosidesadenosine(Am), guanosine(Gm),cytosine(Cm),anduridine(Um);theisomerofuridinewith acarbon–carbonglycosidicbondpseudouridine(Ψ);andthebasemethylations N6-methyladenosine (m6A), 1-methyladenosine (m1A), 7-methylguanosine (m7G), 5-methylcytosine (m5C), and 5-hydroxymethylcytosine (hm5C) [18]. Though these are simple chemical alterations, their influence in regulatingtranslationappearstobetrulysignificant [19–21].Weareonlyjust beginning to understand the relevance of mRNA modifications to decoding [22]. Inrecentyears,thecodingregionsofmRNAhavebeenfoundpunctu- ated with posttranscriptional modifications [17]. Early in the study of mRNAbiochemistryitwasrecognizedthatmRNAhadmodifiednucleo- 0 sides in noncoding regions, such as the 5-CAP [23]. Some of the mRNA modificationsaretransientinthatmethyltransferases“write”amethylation and demethylases “erase” the methyl group while other proteins, as “readers,” recognize the “mark” and bind the RNA, affecting its structure and function [24]. Some have been proven to affect translation and gene expression [25–28]. The biochemical mechanism by which translation is affected is at present speculative. However, nucleobase modifications of nucleosides within the mRNA coding region will alter recognition of codonsbytRNA.AnymodificationoftheWatson–Crickhydrogenbond- ing face of a nucleoside will change tRNA’s anticodon base pairing to the codon. Thus, the methyl of an m6A in an mRNA coding region negates canonicalWatson–CricktRNAbasepairing,possiblychangingtheaccuracy andrateofdecodingoraffectingprematuretermination,andeventheeven- tualacceptanceofthemRNAfortranslation.Theerasemechanismcanthen functionalize that codon for tRNA reading. 1.3 RNA Modification and the Accuracy and Efficiency of Translation Accuracy of decoding mRNA at the ribosome’s aminoacyl- or A-site dependsontRNArecognitionofacomplementarymRNAcodon.tRNA asthedecoderofmRNAisalsoposttranscriptionallymodifiedfortheaccu- racy and efficiency of reading mRNA codons [11,29–33]. More than
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