14december2017|VOL552|NATUre|273LeTTerdoi:10.1038/nature25003KAT2Acoupledwiththeα-KGDHcomplexactsasahistoneH3succinyltransferaseYugangWang1*,Yusongr.Guo2*,KeLiu3,ZhengYin4,ruiLiu1,YanXia1,LinTan5,PeiyingYang5,Jong-HoLee1,Xin-jianLi1,davidHawke6,YanhuaZheng1,XuQian7,JianxinLyu7,8,JieHe9,dongmingXing10,11,12§,YizhiJaneTao2§&ZhiminLu1,13,14§Histonemodifications,suchasthefrequentlyoccurringlysinesuccinylation1,2,arecentraltotheregulationofchromatin-basedprocesses.However,themechanismandfunctionalconsequencesofhistonesuccinylationareunknown.Hereweshowthattheα-ketoglutaratedehydrogenase(α-KGDH)complexislocalizedinthenucleusinhumancelllinesandbindstolysineacetyltransferase2A(KAT2A,alsoknownasGCN5)inthepromoterregionsofgenes.Weshowthatsuccinyl-coenzymeA(succinyl-CoA)bindstoKAT2A.ThecrystalstructureofthecatalyticdomainofKAT2Aincomplexwithsuccinyl-CoAat2.3Åresolutionshowsthatsuccinyl-CoAbindstoadeepcleftofKAT2Awiththesuccinylmoietypointingtowardstheendofaflexibleloop3,whichadoptsdifferentstructuralconformationsinsuccinyl-CoA-boundandacetyl-CoA-boundforms.Site-directedmutagenesisindicatesthattyrosine645inthisloophasanimportantroleintheselectivebindingofsuccinyl-CoAoveracetyl-CoA.KAT2AactsasasuccinyltransferaseandsuccinylateshistoneH3onlysine79,withamaximumfrequencyaroundthetranscriptionstartsitesofgenes.Preventingtheα-KGDHcomplexfromenteringthenucleus,orexpressionofKAT2A(Tyr645Ala),reducesgeneexpressionandinhibitstumourcellproliferationandtumourgrowth.Thesefindingsrevealanimportantmechanismofhistonemodificationanddemonstratethatlocalgenerationofsuccinyl-CoAbythenuclearα-KGDHcomplexcoupledwiththesuccinyltransferaseactivityofKAT2Aisinstrumentalinhistonesuccinylation,tumourcellproliferation,andtumourdevelopment.MetabolicenzymessuchaspyruvatekinaseM2,fumarase,andpyruvatedehydrogenasecomplextranslocateintothenucleusandhaveinstrumentalrolesintheepigeneticregulationofgeneexpres-sionandDNArepair3–5.KAT2A,amemberoftheGCN5-relatedN-acetyltransferase(GNAT)superfamily,wasiden...
