Ubiquitin-dependentregulationofstemcellbiologyAchimWerner1,#,AndrewG.Manford1,#,andMichaelRape1,2,*1DepartmentofMolecularandCellBiology,UniversityofCaliforniaatBerkeley,Berkeley,CA94720,USA2HowardHughesMedicalInstitute,UniversityofCaliforniaatBerkeley,Berkeley,CA94720,USAAbstractThegrowthofametazoanbodyreliesonaseriesofhighlycoordinatedcell-fatedecisionsbystemcells,whichcanundergoself-renewal,reversiblyenteraquiescentstate,orterminallycommittoacellspecificationprogram.Toguidetheirdecisions,stemcellsmakefrequentuseofubiquitylation,aposttranslationalmodificationthatcanaffecttheactivity,interactionlandscape,orstabilityofstemcellproteins.Inthisreview,wearediscussingnovelfindingsthathaveprovidedinsightintoubiquitin-dependentmechanismsofstemcellcontrolandrevealedhowanessentialandhighlyconservedproteinmodificationcanshapemetazoandevelopment.Keywordsubiquitin;development;E3ligase;stemcell;differentiationTheubiquitinsysteminstemcellsToestablishthestaggeringcomplexityofanadulthumanbodywithitsmorethan200celltypes,adevelopingembryomustcommittoaseriesofcoordinatedandtightlyregulatedcell-fatedecisions.Atthecenterofthisintricatedevelopmentalprogramarestemcellsthateitherdivideandmultiplyorexitthecellcycleandadoptspecificfunctions[1,2].Stemcellscontinuetoplayimportantrolesinadultorganisms,wheretheyhelpmaintainorrepairtissuesthataresubjecttoattritionordamage[3].Preservingthecorrectnumberandfunctionalityofstemcellsisanessentialtaskofhumandevelopment,andproblemsintheunderlyingregulatorycircuitsareresponsibleformanydiseases,rangingfrombirthdefectstocancer.Itisnowknownthatposttranslationalmodificationwithubiquitinisattheheartofmanyessentialsignalingnetworksthatinformthecriticalcell-fatedecisionsmadebystemcellsthroughoutdevelopment.*towhomcorrespondenceshouldbeaddressed:mrape@berkeley.edu.#theseauthorscontributedequallyPublisher'sDisclaimer:ThisisaPDFfileofanuneditedmanuscriptthathasbeenacceptedforpublication.Asaservicetoourcustomersweareprovidingthisearlyversionofthemanuscript.Themanu...
