RAG2 - Wikipedia

In 1992, a RAG2 knockout mice strain was generated. Since then, it became a widely used mouse model in immunological research. This mice strain has an ... RAG2 FromWikipedia,thefreeencyclopedia Jumptonavigation Jumptosearch RAG2IdentifiersAliasesRAG2,RAG-2,recombinationactivatinggene2,recombinationactivating2ExternalIDsOMIM:179616MGI:97849HomoloGene:7507GeneCards:RAG2Genelocation(Human)Chr.Chromosome11(human)[1]Band11p12Start36,575,574bp[1]End36,598,279bp[1]Genelocation(Mouse)Chr.Chromosome2(mouse)[2]Band2E2|253.87cMStart101,455,063bp[2]End101,462,874bp[2]RNAexpressionpatternBgeeTopexpressedin bonemarrow thymus thyroidgland pancreas lung Achillestendon stomachMorereferenceexpressiondataBioGPSn/aGeneontologyMolecularfunction DNAbinding GO:1904264,GO:1904822,GO:0090622,GO:0090302ubiquitinproteinligaseactivity zincionbinding chromatinbinding phosphatidylinositol-3,5-bisphosphatebinding metalionbinding phosphatidylinositol-3,4-bisphosphatebinding methylatedhistonebinding phosphatidylinositolbinding phosphatidylinositol-4,5-bisphosphatebinding phosphatidylinositol-3,4,5-trisphosphatebinding sequence-specificDNAbinding Cellularcomponent nucleoplasm nucleus DNArecombinasecomplex Biologicalprocess DNArecombination Bcellhomeostaticproliferation Tcelldifferentiationinthymus positiveregulationoforgangrowth Tcelldifferentiation Bcelllineagecommitment proteinubiquitination V(D)Jrecombination pre-Bcellallelicexclusion Bcelldifferentiation Tcelllineagecommitment defenseresponsetobacterium chromatinorganization Sources:Amigo/QuickGOOrthologsSpeciesHumanMouseEntrez589719374EnsemblENSG00000175097ENSMUSG00000032864UniProtP55895P21784RefSeq(mRNA)NM_000536NM_001243785NM_001243786NM_009020RefSeq(protein)NP_000527NP_001230714NP_001230715NP_033046Location(UCSC)Chr11:36.58–36.6MbChr2:101.46–101.46MbPubMedsearch[3][4]WikidataView/EditHumanView/EditMouse Recombinationactivatinggene2protein(alsoknownasRAG-2)isalymphocyte-specificproteinencodedbyRAG2geneonhumanchromosome11.TogetherwithRAG1protein,RAG2formsaV(D)Jrecombinase,aproteincomplexrequiredfortheprocessofV(D)JrecombinationduringwhichthevariableregionsofimmunoglobulinandTcellreceptorgenesareassembledindevelopingBandTlymphocytes.Therefore,RAG2isessentialforgenerationofmatureBandTlymphocytes. Contents 1Structure 2Function 3Clinicalsignificance 4RAG2knockoutmice 5References Structure[edit] RAG2isa527-aminoacidlongprotein.ItsN-terminalpartisthoughttoformasix-bladedpropellerintheactivecore.[5]RAG2isconservedamongallspeciesthatcarryoutV(D)JrecombinationanditsexpressionpatterncorrelatespreciselywithV(D)Jrecombinaseactivity.[6]RAG2isexpressedinimmaturelymphoidcells.WhileamountofRAG1isconstantduringthecellcycle,RAG2accumulatesmainlyinG0andG1phaseofcellcycleanditundergoesrapiddegradationwhenthecellentersSphase.[7][8]ThisservesasanimportantregulatorymechanismofV(D)Jrecombinationandapreventionofgenomicinstability. Function[edit] RAG2isoneofthetwocorecomponentsoftheRAGcomplex.RAGcomplexisamultiproteincomplexthatmediatestheDNAcleavagephaseduringV(D)Jrecombination.Thiscomplexcanmakedouble-strandbreaksbycleavingDNAatconservedrecombinationsignalsequences(RSS). TheothercorecomponentofthiscomplexisRAG1.ThisproteinisthoughttopossessmostofthecatalyticactivityoftheRAGcomplex.TheRAG1proteinisthecomponentthatactuallybindstoDNAandcleavesit.[9][10]UnlikeRAG1,RAG2proteindoesnotappeartopossessanyendonucleaseactivityortoevenbindtoDNAstrand.RAG2playsaroleofanaccessoryfactor.ItsprimaryfunctionseemstobetointeractwithRAG1proteinandactivateitsendonucleasefunctions.RAG2alsoenhancesRSSrecognitionandtherebydecreasesnonspecificDNAbindingbyRAGcomplex.[11][12]TheN-terminaloftherecombinationactivatinggene2componentisthoughttoformasix-bladedpropellerintheactivecorethatservesasabindingscaffoldforthetightassociationofthecomplexwithDNA.AC-terminalplanthomeodomainfinger-likemotifinthisproteinisnecessaryforinteractionswithchromatincomponents,specificallywithhistoneH3thatistrimethylatedatlysine4. AsrecombinationdoesnotoccurintheabsenceofRAG2,itsinteractionswithRAG1arethoughttobecrucialforcatalyticfunctionofRAG1protein.[13]Therefore,presenceofbothRAG1andRAG2isessentialforgenerationofmatureBandTlymphocytes. Clinicalsignificance[edit] Asmentioned,RAG2iscrucialformaturationofBandTcells.Therefore,mutationsofRAG2genecanresultinsevereimmunedisorderssuchasSCID(SevereCombinedImmunodeficiency)orOmennsyndrome.[14]OmennSyndromiscausedbyahypomorphicmutationofRAG2gene,whichleadstoreducedbutstillpresentfunctionoftheRAGcomplex.[15]AlthoughpatientsdonothaveanycirculatingBcells,asmallnumberofoligoclonalTcellsisdeveloped.OverfiftypercentofRAG1isconservedinhumans.Therefore,functionallyvalidatingnovelgeneticfindingsiscrucialforcharacterisinghumanRAGdeficiency.71RAG1and39RAG2variantshavebeenfunctionallyassayed.Variantsthataremostlikelytooccurandpresentasdisease-causinghavebeenpredicted.[16]Combinedwithpathogenicityprediction,thisapplicationguidesresearchtotesttheeffectoftopcandidatevariantsinpreparationfornoveldiseasecases. RAG2knockoutmice[edit] In1992,aRAG2knockoutmicestrainwasgenerated.Sincethen,itbecameawidelyusedmousemodelinimmunologicalresearch.ThismicestrainhasaninactivatedRAG2gene,thereforehomozygousmiceareunabletoinitiateV(D)JrearrangementandconsequentlyfailtogeneratematureTandBlymphocytes.[13]AssuchRAG2knockoutmicerepresentaveryvaluableresearchtoolusedintransplantationexperiments,vaccinedevelopmentandhematopoiesisresearch.Also,theRAG2mutationcanbecombinedwithothermutationsinordertodevelopfurthermodelsusefulforbasicimmunologyresearch.Furthermore,methylcholantrenecanbeusedtodeveloptumorsinRAG2knockoutmice.[17] References[edit] ^abcGRCh38:Ensemblrelease89:ENSG00000175097-Ensembl,May2017 ^abcGRCm38:Ensemblrelease89:ENSMUSG00000032864-Ensembl,May2017 ^"HumanPubMedReference:".NationalCenterforBiotechnologyInformation,U.S.NationalLibraryofMedicine. ^"MousePubMedReference:".NationalCenterforBiotechnologyInformation,U.S.NationalLibraryofMedicine. ^ZhangYH,ShettyK,SurleacMD,PetrescuAJ,SchatzDG(May2015)."MappingandQuantitationoftheInteractionbetweentheRecombinationActivatingGeneProteinsRAG1andRAG2".TheJournalofBiologicalChemistry.290(19):11802–17.doi:10.1074/jbc.M115.638627.PMC 4424321.PMID 25745109. ^OettingerMA,SchatzDG,GorkaC,BaltimoreD(June1990)."RAG-1andRAG-2,adjacentgenesthatsynergisticallyactivateV(D)Jrecombination".Science.248(4962):1517–23.doi:10.1126/science.2360047.PMID 2360047. ^LinWC,DesiderioS(March1994)."CellcycleregulationofV(D)Jrecombination-activatingproteinRAG-2".ProceedingsoftheNationalAcademyofSciencesoftheUnitedStatesofAmerica.91(7):2733–7.doi:10.1073/pnas.91.7.2733.PMC 43444.PMID 8146183. ^Lee,Jinhak;Desiderio,Stephen(December1999)."CyclinA/CDK2RegulatesV(D)JRecombinationbyCoordinatingRAG-2AccumulationandDNARepair".Immunity.11(6):771–781.doi:10.1016/s1074-7613(00)80151-x.ISSN 1074-7613.PMID 10626899. ^Landree,M.A.;Wibbenmeyer,J.A.;Roth,D.B.(1999-12-01)."MutationalanalysisofRAG1andRAG2identifiesthreecatalyticaminoacidsinRAG1criticalforbothcleavagestepsofV(D)Jrecombination".Genes&Development.13(23):3059–3069.doi:10.1101/gad.13.23.3059.ISSN 0890-9369.PMC 317185.PMID 10601032. ^KimDR,DaiY,MundyCL,YangW,OettingerMA(December1999)."MutationsofacidicresiduesinRAG1definetheactivesiteoftheV(D)Jrecombinase".Genes&Development.13(23):3070–80.doi:10.1101/gad.13.23.3070.PMC 317176.PMID 10601033. ^Stephen,Swanson,PatrickC.Desiderio.RAG-2PromotesHeptamerOccupancybyRAG-1intheAssemblyofaV(D)JInitiationComplex†.AmericanSocietyforMicrobiology.OCLC 679256409. ^ZhaoS,GwynLM,DeP,RodgersKK(April2009)."Anon-sequence-specificDNAbindingmodeofRAG1isinhibitedbyRAG2".JournalofMolecularBiology.387(3):744–58.doi:10.1016/j.jmb.2009.02.020.PMC 2659343.PMID 19232525. ^abShinkaiY,RathbunG,LamKP,OltzEM,StewartV,MendelsohnM,CharronJ,DattaM,YoungF,StallAM(March1992)."RAG-2-deficientmicelackmaturelymphocytesowingtoinabilitytoinitiateV(D)Jrearrangement".Cell.68(5):855–67.doi:10.1016/0092-8674(92)90029-c.PMID 1547487.S2CID 824033. ^"EntrezGene:Recombinationactivatinggene2". ^CorneoB,MoshousD,GüngörT,WulffraatN,PhilippetP,LeDeistFL,FischerA,deVillartayJP(May2001)."IdenticalmutationsinRAG1orRAG2genesleadingtodefectiveV(D)JrecombinaseactivitycancauseeitherT-B-severecombinedimmunedeficiencyorOmennsyndrome".Blood.97(9):2772–6.doi:10.1182/blood.V97.9.2772.PMID 11313270. ^LawlessD,LangoAllenH,ThaventhiranJ,HodelF,AnwarR,FellayJ,et al.(August2019)."PredictingtheOccurrenceofVariantsinRAG1andRAG2".JournalofClinicalImmunology.39(7):688–701.doi:10.1007/s10875-019-00670-z.PMC 6754361.PMID 31388879. ^Shankaran,V.;Ikeda,H.;Bruce,A.T.;White,J.M.;Swanson,P.E.;Old,L.J.;Schreiber,R.D.(2001-04-26)."IFNgammaandlymphocytespreventprimarytumourdevelopmentandshapetumourimmunogenicity".Nature.410(6832):1107–1111.doi:10.1038/35074122.ISSN 0028-0836.PMID 11323675.S2CID 205016599. 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