Transcription (biology) - Wikipedia

Transcription is the process of copying a segment of DNA into RNA. The segments of DNA transcribed into RNA molecules that can encode proteins are said to ... Transcription(biology) FromWikipedia,thefreeencyclopedia Jumptonavigation Jumptosearch ProcessofcopyingasegmentofDNAintoRNA Thisarticleisabouttranscriptioninbiology.Forotheruses,seeTranscription. SimplifieddiagramofmRNAsynthesisandprocessing.Enzymesnotshown. TranscriptionistheprocessofcopyingasegmentofDNAintoRNA.ThesegmentsofDNAtranscribedintoRNAmoleculesthatcanencodeproteinsaresaidtoproducemessengerRNA(mRNA).OthersegmentsofDNAarecopiedintoRNAmoleculescallednon-codingRNAs(ncRNAs).Averagedovermultiplecelltypesinagiventissue,thequantityofmRNAismorethan10timesthequantityofncRNA(thoughinparticularsinglecelltypesncRNAsmayexceedmRNAs).[1]ThegeneralpreponderanceofmRNAincellsisvalideventhoughlessthan2%ofthehumangenomecanbetranscribedintomRNA(Humangenome#Codingvs.noncodingDNA),whileatleast80%ofmammaliangenomicDNAcanbeactivelytranscribed(inoneormoretypesofcells),withthemajorityofthis80%consideredtobencRNA.[2] BothDNAandRNAarenucleicacids,whichusebasepairsofnucleotidesasacomplementarylanguage.Duringtranscription,aDNAsequenceisreadbyanRNApolymerase,whichproducesacomplementary,antiparallelRNAstrandcalledaprimarytranscript. Transcriptionproceedsinthefollowinggeneralsteps: RNApolymerase,togetherwithoneormoregeneraltranscriptionfactors,bindstopromoterDNA. RNApolymerasegeneratesatranscriptionbubble,whichseparatesthetwostrandsoftheDNAhelix.ThisisdonebybreakingthehydrogenbondsbetweencomplementaryDNAnucleotides. RNApolymeraseaddsRNAnucleotides(whicharecomplementarytothenucleotidesofoneDNAstrand). RNAsugar-phosphatebackboneformswithassistancefromRNApolymerasetoformanRNAstrand. HydrogenbondsoftheRNA–DNAhelixbreak,freeingthenewlysynthesizedRNAstrand. Ifthecellhasanucleus,theRNAmaybefurtherprocessed.Thismayincludepolyadenylation,capping,andsplicing. TheRNAmayremaininthenucleusorexittothecytoplasmthroughthenuclearporecomplex. IfthestretchofDNAistranscribedintoanRNAmoleculethatencodesaprotein,theRNAistermedmessengerRNA(mRNA);themRNA,inturn,servesasatemplatefortheprotein'ssynthesisthroughtranslation.OtherstretchesofDNAmaybetranscribedintosmallnon-codingRNAssuchasmicroRNA,transferRNA(tRNA),smallnucleolarRNA(snoRNA),smallnuclearRNA(snRNA),orenzymaticRNAmoleculescalledribozymes[3]aswellaslargernon-codingRNAssuchasribosomalRNA(rRNA),andlongnon-codingRNA(lncRNA).Overall,RNAhelpssynthesize,regulate,andprocessproteins;itthereforeplaysafundamentalroleinperformingfunctionswithinacell. Invirology,thetermtranscriptionmayalsobeusedwhenreferringtomRNAsynthesisfromanRNAmolecule(i.e.,equivalenttoRNAreplication).Forinstance,thegenomeofanegative-sensesingle-strandedRNA(ssRNA-)virusmaybeatemplateforapositive-sensesingle-strandedRNA(ssRNA+)[clarificationneeded].Thisisbecausethepositive-sensestrandcontainsthesequenceinformationneededtotranslatetheviralproteinsneededforviralreplication.ThisprocessiscatalyzedbyaviralRNAreplicase.[4][clarificationneeded] Contents 1Background 2Majorsteps 2.1Settingupfortranscription 2.1.1Enhancers,transcriptionfactors,MediatorcomplexandDNAloopsinmammaliantranscription 2.1.2CpGislandmethylationanddemethylation 2.2Initiation 2.3Promoterescape 2.4Elongation 2.5Termination 3RoleofRNApolymeraseinpost-transcriptionalchangesinRNA 4Inhibitors 5Endogenousinhibitors 6Transcriptionfactories 7History 8Measuringanddetecting 9Reversetranscription 10Seealso 11References 12Externallinks Background[edit] ADNAtranscriptionunitencodingforaproteinmaycontainbothacodingsequence,whichwillbetranslatedintotheprotein,andregulatorysequences,whichdirectandregulatethesynthesisofthatprotein.Theregulatorysequencebefore("upstream"from)thecodingsequenceiscalledthefiveprimeuntranslatedregion(5'UTR);thesequenceafter("downstream"from)thecodingsequenceiscalledthethreeprimeuntranslatedregion(3'UTR).[3] AsopposedtoDNAreplication,transcriptionresultsinanRNAcomplementthatincludesthenucleotideuracil(U)inallinstanceswherethymine(T)wouldhaveoccurredinaDNAcomplement. OnlyoneofthetwoDNAstrandsserveasatemplatefortranscription.TheantisensestrandofDNAisreadbyRNApolymerasefromthe3'endtothe5'endduringtranscription(3'→5').ThecomplementaryRNAiscreatedintheoppositedirection,inthe5'→3'direction,matchingthesequenceofthesensestrandwiththeexceptionofswitchinguracilforthymine.ThisdirectionalityisbecauseRNApolymerasecanonlyaddnucleotidestothe3'endofthegrowingmRNAchain.Thisuseofonlythe3'→5'DNAstrandeliminatestheneedfortheOkazakifragmentsthatareseeninDNAreplication.[3]ThisalsoremovestheneedforanRNAprimertoinitiateRNAsynthesis,asisthecaseinDNAreplication. Thenon-template(sense)strandofDNAiscalledthecodingstrand,becauseitssequenceisthesameasthenewlycreatedRNAtranscript(exceptforthesubstitutionofuracilforthymine).ThisisthestrandthatisusedbyconventionwhenpresentingaDNAsequence.[5] Transcriptionhassomeproofreadingmechanisms,buttheyarefewerandlesseffectivethanthecontrolsforcopyingDNA.Asaresult,transcriptionhasalowercopyingfidelitythanDNAreplication.[6] Majorsteps[edit] Furtherinformation:BacterialtranscriptionandEukaryotictranscription Transcriptionisdividedintoinitiation,promoterescape,elongation,andtermination.[7] Settingupfortranscription[edit] ThissectionmayrequirecleanuptomeetWikipedia'squalitystandards.Thespecificproblemis:DuplicationwithRegulatorysequence.Canwejustmakeacanonical"mainarticle"andredirectpeoplethere?Pleasehelpimprovethissectionifyoucan.(September2021)(Learnhowandwhentoremovethistemplatemessage) Enhancers,transcriptionfactors,MediatorcomplexandDNAloopsinmammaliantranscription[edit] Regulationoftranscriptioninmammals.AnactiveenhancerregulatoryregionofDNAisenabledtointeractwiththepromoterDNAregionofitstargetgenebyformationofachromosomeloop.ThiscaninitiatemessengerRNA(mRNA)synthesisbyRNApolymeraseII(RNAPII)boundtothepromoteratthetranscriptionstartsiteofthegene.Theloopisstabilizedbyonearchitecturalproteinanchoredtotheenhancerandoneanchoredtothepromoterandtheseproteinsarejoinedtoformadimer(redzigzags).SpecificregulatorytranscriptionfactorsbindtoDNAsequencemotifsontheenhancer.Generaltranscriptionfactorsbindtothepromoter.Whenatranscriptionfactorisactivatedbyasignal(hereindicatedasphosphorylationshownbyasmallredstaronatranscriptionfactorontheenhancer)theenhancerisactivatedandcannowactivateitstargetpromoter.TheactiveenhanceristranscribedoneachstrandofDNAinoppositedirectionsbyboundRNAPIIs.Mediator(acomplexconsistingofabout26proteinsinaninteractingstructure)communicatesregulatorysignalsfromtheenhancerDNA-boundtranscriptionfactorstothepromoter. Settingupfortranscriptioninmammalsisregulatedbymanycis-regulatoryelements,includingcorepromoterandpromoter-proximalelementsthatarelocatednearthetranscriptionstartsitesofgenes.Corepromoterscombinedwithgeneraltranscriptionfactorsaresufficienttodirecttranscriptioninitiation,butgenerallyhavelowbasalactivity.[8]Otherimportantcis-regulatorymodulesarelocalizedinDNAregionsthataredistantfromthetranscriptionstartsites.Theseincludeenhancers,silencers,insulatorsandtetheringelements.[9]Amongthisconstellationofelements,enhancersandtheirassociatedtranscriptionfactorshavealeadingroleintheinitiationofgenetranscription.[10]AnenhancerlocalizedinaDNAregiondistantfromthepromoterofagenecanhaveaverylargeeffectongenetranscription,withsomegenesundergoingupto100-foldincreasedtranscriptionduetoanactivatedenhancer.[11] Enhancersareregionsofthegenomethataremajorgene-regulatoryelements.Enhancerscontrolcell-type-specificgenetranscriptionprograms,mostoftenbyloopingthroughlongdistancestocomeinphysicalproximitywiththepromotersoftheirtargetgenes.[12]WhiletherearehundredsofthousandsofenhancerDNAregions,[13]foraparticulartypeoftissueonlyspecificenhancersarebroughtintoproximitywiththepromotersthattheyregulate.Inastudyofbraincorticalneurons,24,937loopswerefound,bringingenhancerstotheirtargetpromoters.[11]Multipleenhancers,eachoftenattensorhundredofthousandsofnucleotidesdistantfromtheirtargetgenes,looptotheirtargetgenepromotersandcancoordinatewitheachothertocontroltranscriptionoftheircommontargetgene.[12] Theschematicillustrationinthissectionshowsanenhancerloopingaroundtocomeintoclosephysicalproximitywiththepromoterofatargetgene.Theloopisstabilizedbyadimerofaconnectorprotein(e.g.dimerofCTCForYY1),withonememberofthedimeranchoredtoitsbindingmotifontheenhancerandtheothermemberanchoredtoitsbindingmotifonthepromoter(representedbytheredzigzagsintheillustration).[14]Severalcellfunctionspecifictranscriptionfactors(thereareabout1,600transcriptionfactorsinahumancell[15])generallybindtospecificmotifsonanenhancer[16]andasmallcombinationoftheseenhancer-boundtranscriptionfactors,whenbroughtclosetoapromoterbyaDNAloop,governleveloftranscriptionofthetargetgene.Mediator(acomplexusuallyconsistingofabout26proteinsinaninteractingstructure)communicatesregulatorysignalsfromenhancerDNA-boundtranscriptionfactorsdirectlytotheRNApolymeraseII(polII)enzymeboundtothepromoter.[17] Enhancers,whenactive,aregenerallytranscribedfrombothstrandsofDNAwithRNApolymerasesactingintwodifferentdirections,producingtwoenhancerRNAs(eRNAs)asillustratedintheFigure.[18]Aninactiveenhancermaybeboundbyaninactivetranscriptionfactor.Phosphorylationofthetranscriptionfactormayactivateitandthatactivatedtranscriptionfactormaythenactivatetheenhancertowhichitisbound(seesmallredstarrepresentingphosphorylationoftranscriptionfactorboundtoenhancerintheillustration).[19]AnactivatedenhancerbeginstranscriptionofitsRNAbeforeactivatingtranscriptionofmessengerRNAfromitstargetgene.[20] CpGislandmethylationanddemethylation[edit] Thisshowswherethemethylgroupisaddedwhen5-methylcytosineisformed Transcriptionregulationatabout60%ofpromotersisalsocontrolledbymethylationofcytosineswithinCpGdinucleotides(where5’cytosineisfollowedby3’guanineorCpGsites).5-methylcytosine(5-mC)isamethylatedformoftheDNAbasecytosine(seeFigure).5-mCisanepigeneticmarkerfoundpredominantlywithinCpGsites.About28millionCpGdinucleotidesoccurinthehumangenome.[21]Inmosttissuesofmammals,onaverage,70%to80%ofCpGcytosinesaremethylated(forming5-methylCpGor5-mCpG).[22]Methylatedcytosineswithin5’cytosine-guanine3’sequencesoftenoccuringroups,calledCpGislands.About60%ofpromotersequenceshaveaCpGislandwhileonlyabout6%ofenhancersequenceshaveaCpGisland.[23]CpGislandsconstituteregulatorysequences,sinceifCpGislandsaremethylatedinthepromoterofagenethiscanreduceorsilencegenetranscription.[24] DNAmethylationregulatesgenetranscriptionthroughinteractionwithmethylbindingdomain(MBD)proteins,suchasMeCP2,MBD1andMBD2.TheseMBDproteinsbindmoststronglytohighlymethylatedCpGislands.[25]TheseMBDproteinshavebothamethyl-CpG-bindingdomainaswellasatranscriptionrepressiondomain.[25]TheybindtomethylatedDNAandguideordirectproteincomplexeswithchromatinremodelingand/orhistonemodifyingactivitytomethylatedCpGislands.MBDproteinsgenerallyrepresslocalchromatinsuchasbycatalyzingtheintroductionofrepressivehistonemarks,orcreatinganoverallrepressivechromatinenvironmentthroughnucleosomeremodelingandchromatinreorganization.[25] Asnotedintheprevioussection,transcriptionfactorsareproteinsthatbindtospecificDNAsequencesinordertoregulatetheexpressionofagene.ThebindingsequenceforatranscriptionfactorinDNAisusuallyabout10or11nucleotideslong.Assummarizedin2009,Vaquerizasetal.indicatedthereareapproximately1,400differenttranscriptionfactorsencodedinthehumangenomebygenesthatconstituteabout6%ofallhumanproteinencodinggenes.[26]About94%oftranscriptionfactorbindingsites(TFBSs)thatareassociatedwithsignal-responsivegenesoccurinenhancerswhileonlyabout6%ofsuchTFBSsoccurinpromoters.[16] EGR1proteinisaparticulartranscriptionfactorthatisimportantforregulationofmethylationofCpGislands.AnEGR1transcriptionfactorbindingsiteisfrequentlylocatedinenhancerorpromotersequences.[27]Thereareabout12,000bindingsitesforEGR1inthemammaliangenomeandabouthalfofEGR1bindingsitesarelocatedinpromotersandhalfinenhancers.[27]ThebindingofEGR1toitstargetDNAbindingsiteisinsensitivetocytosinemethylationintheDNA.[27] WhileonlysmallamountsofEGR1transcriptionfactorproteinaredetectableincellsthatareun-stimulated,translationoftheEGR1geneintoproteinatonehourafterstimulationisdrasticallyelevated.[28]ProductionofEGR1transcriptionfactorproteins,invarioustypesofcells,canbestimulatedbygrowthfactors,neurotransmitters,hormones,stressandinjury.[28]Inthebrain,whenneuronsareactivated,EGR1proteinsareup-regulatedandtheybindto(recruit)thepre-existingTET1enzymesthatareproducedinhighamountsinneurons.TETenzymescancatalysedemethylationof5-methylcytosine.WhenEGR1transcriptionfactorsbringTET1enzymestoEGR1bindingsitesinpromoters,theTETenzymescandemethylatethemethylatedCpGislandsatthosepromoters.Upondemethylation,thesepromoterscantheninitiatetranscriptionoftheirtargetgenes.HundredsofgenesinneuronsaredifferentiallyexpressedafterneuronactivationthroughEGR1recruitmentofTET1tomethylatedregulatorysequencesintheirpromoters.[27] Themethylationofpromotersisalsoalteredinresponsetosignals.ThethreemammalianDNAmethyltransferasess(DNMT1,DNMT3A,andDNMT3B)catalyzetheadditionofmethylgroupstocytosinesinDNA.WhileDNMT1isa“maintenance”methyltransferase,DNMT3AandDNMT3Bcancarryoutnewmethylations.TherearealsotwospliceproteinisoformsproducedfromtheDNMT3Agene:DNAmethyltransferaseproteinsDNMT3A1andDNMT3A2.[29] ThespliceisoformDNMT3A2behavesliketheproductofaclassicalimmediate-earlygeneand,forinstance,itisrobustlyandtransientlyproducedafterneuronalactivation.[30]WheretheDNAmethyltransferaseisoformDNMT3A2bindsandaddsmethylgroupstocytosinesappearstobedeterminedbyhistoneposttranslationalmodifications.[31][32][33] Ontheotherhand,neuralactivationcausesdegradationofDNMT3A1accompaniedbyreducedmethylationofatleastoneevaluatedtargetedpromoter.[34] Initiation[edit] TranscriptionbeginswiththebindingofRNApolymerase,togetherwithoneormoregeneraltranscriptionfactors,toaspecificDNAsequencereferredtoasa"promoter"toformanRNApolymerase-promoter"closedcomplex".Inthe"closedcomplex"thepromoterDNAisstillfullydouble-stranded.[7] RNApolymerase,assistedbyoneormoregeneraltranscriptionfactors,thenunwindsapproximately14basepairsofDNAtoformanRNApolymerase-promoter"opencomplex".Inthe"opencomplex"thepromoterDNAispartlyunwoundandsingle-stranded.Theexposed,single-strandedDNAisreferredtoasthe"transcriptionbubble."[7] RNApolymerase,assistedbyoneormoregeneraltranscriptionfactors,thenselectsatranscriptionstartsiteinthetranscriptionbubble,bindstoaninitiatingNTPandanextendingNTP(orashortRNAprimerandanextendingNTP)complementarytothetranscriptionstartsitesequence,andcatalyzesbondformationtoyieldaninitialRNAproduct.[7] Inbacteria,RNApolymeraseholoenzymeconsistsoffivesubunits:2αsubunits,1βsubunit,1β'subunit,and1ωsubunit.Inbacteria,thereisonegeneralRNAtranscriptionfactorknownasasigmafactor.RNApolymerasecoreenzymebindstothebacterialgeneraltranscription(sigma)factortoformRNApolymeraseholoenzymeandthenbindstoapromoter.[7] (RNApolymeraseiscalledaholoenzymewhensigmasubunitisattachedtothecoreenzymewhichisconsistof2αsubunits,1βsubunit,1β'subunitonly).Unlikeeukaryotes,theinitiatingnucleotideofnascentbacterialmRNAisnotcappedwithamodifiedguaninenucleotide.Theinitiatingnucleotideofbacterialtranscriptsbearsa5′triphosphate(5′-PPP),whichcanbeusedforgenome-widemappingoftranscriptioninitiationsites.[35] Inarchaeaandeukaryotes,RNApolymerasecontainssubunitshomologoustoeachofthefiveRNApolymerasesubunitsinbacteriaandalsocontainsadditionalsubunits.Inarchaeaandeukaryotes,thefunctionsofthebacterialgeneraltranscriptionfactorsigmaareperformedbymultiplegeneraltranscriptionfactorsthatworktogether.[7]Inarchaea,therearethreegeneraltranscriptionfactors:TBP,TFB,andTFE.Ineukaryotes,inRNApolymeraseII-dependenttranscription,therearesixgeneraltranscriptionfactors:TFIIA,TFIIB(anorthologofarchaealTFB),TFIID(amultisubunitfactorinwhichthekeysubunit,TBP,isanorthologofarchaealTBP),TFIIE(anorthologofarchaealTFE),TFIIF,andTFIIH.TheTFIIDisthefirstcomponenttobindtoDNAduetobindingofTBP,whileTFIIHisthelastcomponenttoberecruited.Inarchaeaandeukaryotes,theRNApolymerase-promoterclosedcomplexisusuallyreferredtoasthe"preinitiationcomplex."[36] Transcriptioninitiationisregulatedbyadditionalproteins,knownasactivatorsandrepressors,and,insomecases,associatedcoactivatorsorcorepressors,whichmodulateformationandfunctionofthetranscriptioninitiationcomplex.[7] Promoterescape[edit] Afterthefirstbondissynthesized,theRNApolymerasemustescapethepromoter.DuringthistimethereisatendencytoreleasetheRNAtranscriptandproducetruncatedtranscripts.Thisiscalledabortiveinitiation,andiscommonforbotheukaryotesandprokaryotes.[37]AbortiveinitiationcontinuestooccuruntilanRNAproductofathresholdlengthofapproximately10nucleotidesissynthesized,atwhichpointpromoterescapeoccursandatranscriptionelongationcomplexisformed. Mechanistically,promoterescapeoccursthroughDNAscrunching,providingtheenergyneededtobreakinteractionsbetweenRNApolymeraseholoenzymeandthepromoter.[38] Inbacteria,itwashistoricallythoughtthatthesigmafactorisdefinitelyreleasedafterpromoterclearanceoccurs.Thistheoryhadbeenknownastheobligatereleasemodel.However,laterdatashowedthatuponandfollowingpromoterclearance,thesigmafactorisreleasedaccordingtoastochasticmodelknownasthestochasticreleasemodel.[39] Ineukaryotes,atanRNApolymeraseII-dependentpromoter,uponpromoterclearance,TFIIHphosphorylatesserine5onthecarboxyterminaldomainofRNApolymeraseII,leadingtotherecruitmentofcappingenzyme(CE).[40][41]TheexactmechanismofhowCEinducespromoterclearanceineukaryotesisnotyetknown. Elongation[edit] Simplediagramoftranscriptionelongation OnestrandoftheDNA,thetemplatestrand(ornoncodingstrand),isusedasatemplateforRNAsynthesis.Astranscriptionproceeds,RNApolymerasetraversesthetemplatestrandandusesbasepairingcomplementaritywiththeDNAtemplatetocreateanRNAcopy(whichelongatesduringthetraversal).AlthoughRNApolymerasetraversesthetemplatestrandfrom3'→5',thecoding(non-template)strandandnewlyformedRNAcanalsobeusedasreferencepoints,sotranscriptioncanbedescribedasoccurring5'→3'.ThisproducesanRNAmoleculefrom5'→3',anexactcopyofthecodingstrand(exceptthatthyminesarereplacedwithuracils,andthenucleotidesarecomposedofaribose(5-carbon)sugarwhereDNAhasdeoxyribose(onefeweroxygenatom)initssugar-phosphatebackbone).[citationneeded] mRNAtranscriptioncaninvolvemultipleRNApolymerasesonasingleDNAtemplateandmultipleroundsoftranscription(amplificationofparticularmRNA),somanymRNAmoleculescanberapidlyproducedfromasinglecopyofagene.[citationneeded]Thecharacteristicelongationratesinprokaryotesandeukaryotesareabout10-100nts/sec.[42]Ineukaryotes,however,nucleosomesactasmajorbarrierstotranscribingpolymerasesduringtranscriptionelongation.[43][44]Intheseorganisms,thepausinginducedbynucleosomescanberegulatedbytranscriptionelongationfactorssuchasTFIIS.[44] Elongationalsoinvolvesaproofreadingmechanismthatcanreplaceincorrectlyincorporatedbases.Ineukaryotes,thismaycorrespondwithshortpausesduringtranscriptionthatallowappropriateRNAeditingfactorstobind.ThesepausesmaybeintrinsictotheRNApolymeraseorduetochromatinstructure.[citationneeded] Termination[edit] Mainarticle:Terminator(genetics) Bacteriausetwodifferentstrategiesfortranscriptiontermination–Rho-independentterminationandRho-dependenttermination.InRho-independenttranscriptiontermination,RNAtranscriptionstopswhenthenewlysynthesizedRNAmoleculeformsaG-C-richhairpinloopfollowedbyarunofUs.Whenthehairpinforms,themechanicalstressbreakstheweakrU-dAbonds,nowfillingtheDNA–RNAhybrid.Thispullsthepoly-UtranscriptoutoftheactivesiteoftheRNApolymerase,terminatingtranscription.Inthe"Rho-dependent"typeoftermination,aproteinfactorcalled"Rho"destabilizestheinteractionbetweenthetemplateandthemRNA,thusreleasingthenewlysynthesizedmRNAfromtheelongationcomplex.[45] Transcriptionterminationineukaryotesislesswellunderstoodthaninbacteria,butinvolvescleavageofthenewtranscriptfollowedbytemplate-independentadditionofadeninesatitsnew3'end,inaprocesscalledpolyadenylation.[46] RoleofRNApolymeraseinpost-transcriptionalchangesinRNA[edit] ImageshowingRNApolymeraseinteractingwithdifferentfactorsandDNAduringtranscription,especiallyCTD(CTerminalDomain) RNApolymeraseplaysaverycrucialroleinallstepsincludingpost-transcriptionalchangesinRNA. TheImageshowshowCTDiscarryingproteinforfurtherchangesintheRNA AsshownintheimageintherightitisevidentthattheCTD(CTerminalDomain)isatailthatchangesitsshape;thistailwillbeusedasacarrierofsplicing,cappingandpolyadenylation,asshownintheimageontheleft.[47] Inhibitors[edit] Transcriptioninhibitorscanbeusedasantibioticsagainst,forexample,pathogenicbacteria(antibacterials)andfungi(antifungals).Anexampleofsuchanantibacterialisrifampicin,whichinhibitsbacterialtranscriptionofDNAintomRNAbyinhibitingDNA-dependentRNApolymerasebybindingitsbeta-subunit,while8-hydroxyquinolineisanantifungaltranscriptioninhibitor.[48]Theeffectsofhistonemethylationmayalsoworktoinhibittheactionoftranscription.Potent,bioactivenaturalproductsliketriptolidethatinhibitmammaliantranscriptionviainhibitionoftheXPBsubunitofthegeneraltranscriptionfactorTFIIHhasbeenrecentlyreportedasaglucoseconjugatefortargetinghypoxiccancercellswithincreasedglucosetransporterproduction.[49] Endogenousinhibitors[edit] Mainarticle:Regulationoftranscriptionincancer Invertebrates,themajorityofgenepromoterscontainaCpGislandwithnumerousCpGsites.[50]Whenmanyofagene'spromoterCpGsitesaremethylatedthegenebecomesinhibited(silenced).[51]Colorectalcancerstypicallyhave3to6drivermutationsand33to66hitchhikerorpassengermutations.[52]However,transcriptionalinhibition(silencing)maybeofmoreimportancethanmutationincausingprogressiontocancer.Forexample,incolorectalcancersabout600to800genesaretranscriptionallyinhibitedbyCpGislandmethylation(seeregulationoftranscriptionincancer).Transcriptionalrepressionincancercanalsooccurbyotherepigeneticmechanisms,suchasalteredproductionofmicroRNAs.[53]Inbreastcancer,transcriptionalrepressionofBRCA1mayoccurmorefrequentlybyover-producedmicroRNA-182thanbyhypermethylationoftheBRCA1promoter(seeLowexpressionofBRCA1inbreastandovariancancers). Transcriptionfactories[edit] Mainarticle:Transcriptionfactories Activetranscriptionunitsareclusteredinthenucleus,indiscretesitescalledtranscriptionfactoriesoreuchromatin.Suchsitescanbevisualizedbyallowingengagedpolymerasestoextendtheirtranscriptsintaggedprecursors(Br-UTPorBr-U)andimmuno-labelingthetaggednascentRNA.Transcriptionfactoriescanalsobelocalizedusingfluorescenceinsituhybridizationormarkedbyantibodiesdirectedagainstpolymerases.Thereare~10,000factoriesinthenucleoplasmofaHeLacell,amongwhichare~8,000polymeraseIIfactoriesand~2,000polymeraseIIIfactories.EachpolymeraseIIfactorycontains~8polymerases.Asmostactivetranscriptionunitsareassociatedwithonlyonepolymerase,eachfactoryusuallycontains~8differenttranscriptionunits.Theseunitsmightbeassociatedthroughpromotersand/orenhancers,withloopsforminga"cloud"aroundthefactor.[54] History[edit] AmoleculethatallowsthegeneticmaterialtoberealizedasaproteinwasfirsthypothesizedbyFrançoisJacobandJacquesMonod.SeveroOchoawonaNobelPrizeinPhysiologyorMedicinein1959fordevelopingaprocessforsynthesizingRNAinvitrowithpolynucleotidephosphorylase,whichwasusefulforcrackingthegeneticcode.RNAsynthesisbyRNApolymerasewasestablishedinvitrobyseverallaboratoriesby1965;however,theRNAsynthesizedbytheseenzymeshadpropertiesthatsuggestedtheexistenceofanadditionalfactorneededtoterminatetranscriptioncorrectly.[citationneeded] In1972,WalterFiersbecamethefirstpersontoactuallyprovetheexistenceoftheterminatingenzyme. RogerD.Kornbergwonthe2006NobelPrizeinChemistry"forhisstudiesofthemolecularbasisofeukaryotictranscription".[55] Measuringanddetecting[edit] ElectronmicrographoftranscriptionofribosomalRNA.TheformingribosomalRNAstrandsarevisibleasbranchesfromthemainDNAstrand.[citationneeded] Transcriptioncanbemeasuredanddetectedinavarietyofways:[citationneeded] G-LessCassettetranscriptionassay:measurespromoterstrength Run-offtranscriptionassay:identifiestranscriptionstartsites(TSS) Nuclearrun-onassay:measurestherelativeabundanceofnewlyformedtranscripts KAS-seq:measuressingle-strandedDNAgeneratedbyRNApolymerases;canworkwith1,000cells.[56] RNaseprotectionassayandChIP-ChipofRNAP:detectactivetranscriptionsites RT-PCR:measurestheabsoluteabundanceoftotalornuclearRNAlevels,whichmayhoweverdifferfromtranscriptionrates DNAmicroarrays:measurestherelativeabundanceoftheglobaltotalornuclearRNAlevels;however,thesemaydifferfromtranscriptionrates Insituhybridization:detectsthepresenceofatranscript MS2tagging:byincorporatingRNAstemloops,suchasMS2,intoagene,thesebecomeincorporatedintonewlysynthesizedRNA.ThestemloopscanthenbedetectedusingafusionofGFPandtheMS2coatprotein,whichhasahighaffinity,sequence-specificinteractionwiththeMS2stemloops.TherecruitmentofGFPtothesiteoftranscriptionisvisualizedasasinglefluorescentspot.Thisnewapproachhasrevealedthattranscriptionoccursindiscontinuousbursts,orpulses(seeTranscriptionalbursting).Withthenotableexceptionofinsitutechniques,mostothermethodsprovidecellpopulationaverages,andarenotcapableofdetectingthisfundamentalpropertyofgenes.[57] Northernblot:thetraditionalmethod,anduntiltheadventofRNA-Seq,themostquantitative RNA-Seq:appliesnext-generationsequencingtechniquestosequencewholetranscriptomes,whichallowsthemeasurementofrelativeabundanceofRNA,aswellasthedetectionofadditionalvariationssuchasfusiongenes,post-transcriptionaleditsandnovelsplicesites SinglecellRNA-Seq:amplifiesandreadspartialtranscriptomesfromisolatedcells,allowingfordetailedanalysesofRNAintissues,embryos,andcancers Reversetranscription[edit] Schemeofreversetranscription Mainarticle:Reversetranscription Someviruses(suchasHIV,thecauseofAIDS),havetheabilitytotranscribeRNAintoDNA.HIVhasanRNAgenomethatisreversetranscribedintoDNA.TheresultingDNAcanbemergedwiththeDNAgenomeofthehostcell.ThemainenzymeresponsibleforsynthesisofDNAfromanRNAtemplateiscalledreversetranscriptase. InthecaseofHIV,reversetranscriptaseisresponsibleforsynthesizingacomplementaryDNAstrand(cDNA)totheviralRNAgenome.TheenzymeribonucleaseHthendigeststheRNAstrand,andreversetranscriptasesynthesisesacomplementarystrandofDNAtoformadoublehelixDNAstructure("cDNA").ThecDNAisintegratedintothehostcell'sgenomebytheenzymeintegrase,whichcausesthehostcelltogenerateviralproteinsthatreassembleintonewviralparticles.InHIV,subsequenttothis,thehostcellundergoesprogrammedcelldeath,orapoptosisofTcells.[58]However,inotherretroviruses,thehostcellremainsintactasthevirusbudsoutofthecell. Someeukaryoticcellscontainanenzymewithreversetranscriptionactivitycalledtelomerase.Telomeraseisareversetranscriptasethatlengthenstheendsoflinearchromosomes.TelomerasecarriesanRNAtemplatefromwhichitsynthesizesarepeatingsequenceofDNA,or"junk"DNA.ThisrepeatedsequenceofDNAiscalledatelomereandcanbethoughtofasa"cap"forachromosome.Itisimportantbecauseeverytimealinearchromosomeisduplicated,itisshortened.Withthis"junk"DNAor"cap"attheendsofchromosomes,theshorteningeliminatessomeofthenon-essential,repeatedsequenceratherthantheprotein-encodingDNAsequence,thatisfartherawayfromthechromosomeend. Telomeraseisoftenactivatedincancercellstoenablecancercellstoduplicatetheirgenomesindefinitelywithoutlosingimportantprotein-codingDNAsequence.Activationoftelomerasecouldbepartoftheprocessthatallowscancercellstobecomeimmortal.Theimmortalizingfactorofcancerviatelomerelengtheningduetotelomerasehasbeenproventooccurin90%ofallcarcinogenictumorsinvivowiththeremaining10%usinganalternativetelomeremaintenanceroutecalledALTorAlternativeLengtheningofTelomeres.[59] Seealso[edit] Life Cell(biology) Celldivision DBTSS gene generegulation geneexpression Epigenetics Genome Crick'scentraldogma,inwhichtheproductoftranscription,mRNA,istranslatedtoformpolypeptides,andwhereitisassertedthatthereverseprocessesneveroccur Generegulation Longnon-codingRNA MissensemRNA Splicing-processofremovingintronsfromprecursormessengerRNA(pre-mRNA)tomakemessengerRNA(mRNA) Transcriptomics Translation(biology) References[edit] 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Externallinks[edit] WikimediaCommonshasmediarelatedtoTranscription(genetics). InteractiveJavasimulationoftranscriptioninitiation.Archived2011-07-22attheWaybackMachineFromCenterforModelsofLifeattheNielsBohrInstitute. InteractiveJavasimulationoftranscriptioninterference--agameofpromoterdominanceinbacterialvirus.Archived2011-08-26attheWaybackMachineFromCenterforModelsofLifeattheNielsBohrInstitute. VirtualCellAnimationCollection,IntroducingTranscription vteGeneexpressionIntroductiontogenetics Geneticcode Centraldogma DNA →RNA →Protein Specialtransfers RNA→RNA RNA→DNA Protein→Protein TranscriptionTypes Bacterial Archaeal Eukaryotic Keyelements Transcriptionfactor RNApolymerase Promoter Post-transcription PrecursormRNA(pre-mRNA /hnRNA) 5'capping Splicing Polyadenylation Histoneacetylationanddeacetylation TranslationTypes Bacterial Archaeal Eukaryotic Keyelements Ribosome TransferRNA(tRNA) Ribosome-nascentchaincomplex(RNC) Post-translationalmodification Regulation Epigenetic imprinting Transcriptional Generegulatorynetwork cis-regulatoryelement lacoperon Post-transcriptional sequestration(P-bodies) alternativesplicing microRNA Translational Post-translational reversible irreversible Influentialpeople FrançoisJacob JacquesMonod vteTranscription(Bacterial,Eukaryotic)Transcriptionalregulationprokaryotic Operon lacoperon trpoperon gaboperon araoperon galoperon Repressor lacrepressor trprepressor eukaryoticHistone-modifyingenzymes(histone/nucleosome): Histonemethylation/Histonemethyltransferase EZH2 Histonedemethylase Histoneacetylationanddeacetylation HistonedeacetylaseHDAC1 Histoneacetyltransferase DNAmethylation: DNAmethyltransferase Chromatinremodeling: CHD7 both Transcriptioncoregulator Coactivator Corepressor Inducer Promotion Promoter Pribnowbox TATAbox BRE CAATbox Responseelement Enhancer E-box Responseelement Insulator Silencer Internalcontrolregion Initiation Bacterial Eukaryotic ArchaealtranscriptionfactorB Elongation bacterialRNApolymerase:rpoB eukaryoticRNApolymerase:RNApolymeraseII Termination(bacterial,eukaryotic) Terminator Intrinsictermination Rhofactor vteSelf-replicatingorganicstructuresCellularlife Bacteria Archaea Eukaryota Animalia Fungi Plantae Protista Incertaesedis Parakaryonmyojinensis Biologicaldarkmatter Virus dsDNAvirus Giantvirus ssDNAvirus dsRNAvirus (+)ssRNAvirus (−)ssRNAvirus ssRNA-RTvirus dsDNA-RTvirus SubviralagentsViroid 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