UniProtSummary | FUNCTION:VarianthistoneH2AwhichreplacesconventionalH2Ainasubsetofnucleosomes.NucleosomeswrapandcompactDNAintochromatin,limitingDNAaccessibilitytothecellularmachinerieswhichrequireDNAasatemplate.Histonestherebyplayacentralroleintranscriptionregulation,DNArepair,DNAreplicationandchromosomalstability.DNAaccessibilityisregulatedviaacomplexsetofpost-translationalmodificationsofhistones,alsocalledhistonecode,andnucleosomeremodeling.Requiredforcheckpoint-mediatedarrestofcellcycleprogressioninresponsetolowdosesofionizingrADIationandforefficientrepairofDNAdoublestrandbreaks(DSBs)specificallywhenmodifiedbyC-terminalphosphorylation. SUBUNITSTRUCTURE:ThenucleosomeisahistoneoctamercontainingtwomoleculeseachofH2A,H2B,H3andH4assembledinoneH3-H4heterotetramerandtwoH2A-H2Bheterodimers.Theoctamerwrapsapproximately147bpofDNA.InteractswithnumerousproteinsrequiredforDNAdamagesignalingandrepairwhenphosphorylatedonSer-140.TheseincludeMDC1,TP53BP1,BRCA1andtheMRNcomplex,composedofMRE11A,RAD50,andNBN.InteractionwiththeMRNcomplexismediatedatleastinpartbyNBN.AlsointeractswithDHX9/NDHIIwhenphosphorylatedonSer-140.InteractswithARRB2;theinteractionisdetectedinthenucleusuponOR1D2stimulation. SUBCELLULARLOCATION:Nucleus.Chromosome DEVELOPMENTALSTAGE:SynthesizedinG1aswellasinS-phase. DOMAIN:The[ST]-QmotifconstitutesarecognitionsequenceforkinasesfromthePI3/PI4-kinasefamily. PTM:PhosphorylatedonSer-140(toformgamma-H2AFXorH2AX139ph)inresponsetoDNAdoublestrandbreaks(DSBs)generatedbyexogenousgenotoxicagentsandbystalledreplicationforks,andmayalsooccurduringmeioticrecombinationeventsandimmunoglobulinclassswitchinginlymphocytes.PhosphorylationcanextenduptoseveralthousandnucleosomesfromtheactualsiteoftheDSBandmaymarkthesurroundingchromatinforrecruitmentofproteinsrequiredforDNAdamagesignalingandrepair.Widespreadphosphorylationmayalsoservetoamplifythedamagesignaloraidrepairofpersistentlesions.PhosphorylationofSer-140(H2AX139ph)inresponsetoionizingradiationismediatedbybothATMandPRKDCwhiledefectsinDNAreplicationinduceSer-140phosphorylation(H2AX139ph)subsequenttoactivationofATRandPRKDC.DephosphorylationofSer-140byPP2AisrequiredforDNADSBrepair.Inmeiosis,Ser-140phosphorylation(H2AX139ph)mayoccuratsynaptonemalcomplexesduringleptoteneasanATM-dependentresponsetotheformationofprogrammedDSBsbySPO11.Ser-140phosphorylation(H2AX139ph)maysubsequentlyoccursatunsynapsedregionsofbothautosomesandtheXYbivalentduringzygotene,downstreamofATRandBRCA1activation.Ser-140phosphorylation(H2AX139ph)mayalsoberequiredfortranscriptionalrepressionofunsynapsedchromatinandmeioticsexchromosomeinactivation(MSCI),wherebytheXandYchromosomescondenseinpachytenetoformtheheterochromaticXY-body.Duringimmunoglobulinclassswitchrecombinationinlymphocytes,Ser-140phosphorylation(H2AX139ph)mayoccuratsitesofDNA-recombinationsubsequenttoactivationoftheactivation-inducedcytidinedeaminaseAICDA.PhosphorylationatTyr-143(H2AXY142ph)byBAZ1B/WSTFdeterminestherelativerecruitmentofeitherDNArepairorpro-apoptoticfactors.PhosphorylationatTyr-143(H2AXY142ph)favorstherecruitmentofAPBB1/FE65andpro-apoptosisfactorssuchasMAPK8/JNK1,triggeringapoptosis.Incontrast,dephosphorylationofTyr-143byEYAproteins(EYA1,EYA2,EYA3orEYA4)favorstherecruitmentofMDC1-containingDNArepaircomplexestothetailofphosphorylatedSer-140(H2AX139ph). MonoubiquitinationofLys-120(H2AXK119ub)byRING1andRNF2/RING2complexgivesaspecifictagforepigenetictranscriptionalrepression.FollowingDNAdouble-strandbreaks(DSBs),itisubiquitinatedthrough"Lys-63"linkageofubiquitinmoietiesbytheE2ligaseUBE2NandtheE3ligasesRNF8andRNF168,leadingtotherecruitmentofrepairproteinstositesofDNAdamage.Monoubiquitinationandionizingradiation-induced"Lys-63"-linkedubiquitinationaredistinctevents. SEQUENCESIMILARITIES:BelongstothehistoneH2Afamily. |