Repository at Hanyang UniversityGRADUATE SCHOOL OF BIOMEDICAL SCIENCE AND ENGINEERING[S](의생명공학전문대학원)BIOMEDICAL SCIENCE(의생명과학과)Theses (Ph.D.)
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| DC Field | Value | Language |
|---|---|---|
| dc.contributor.advisor | SureshRamakrishna | - |
| dc.contributor.author | 아룬판디안찬드라세카란 | - |
| dc.date.accessioned | 2024-03-01T07:33:10Z | - |
| dc.date.available | 2024-03-01T07:33:10Z | - |
| dc.date.issued | 2021.2 | - |
| dc.identifier.uri | http://hanyang.dcollection.net/common/orgView/200000485415 | en_US |
| dc.identifier.uri | https://repository.hanyang.ac.kr/handle/20.500.11754/188241 | - |
| dc.description.abstract | Despiteadvancesincancertherapies,cancerisstillcausingmillionsofdeathsworldwide.Thestandardchemotherapeutictreatmentssuchaslowmolecularweightmoleculesfortreatingvariouscancershavenotbeensuccessful.Further,incrementinthedrugconcentrationisnotpossibleasthedosageisalreadyreachedthemaximumtolerablelevels.Raiseindosagelevelsmaycausedamagestovariousnormaltissuesororgans.Currentdevelopmentsincludetargeted,patient-specificorprecisiontherapiesarealternativeapproachesbuttheoutcomesareverybleak. Deubiquitinatingenzymes(DUBs)areafamilyofproteasesthatremoveubiquitinfromproteinsundergoingdegradation.DUBsplayseveralfunctionalrolesotherthandeubiquitinationsuchasconferringresistancetocancertherapiesandmediatestumorprogression.ConventionalscreeningmethodsforDUBshavelimitations.Aloss-of-functionstudybasedontheknockoutofDUBgenesinmammaliancellscanprovideanexcellentmodelforexploringDUBfunction.Here,IusedCRISPR-Cas9toperformgenome-scaleknockoutoftheentiresetofgenesencodingDUBsandthensystematicallyscreenedforDUBsthatinvolvedinthesmallmoleculeresistancemechanism. Toprovidetheproof-of-conceptthatoverexpressionofDUBsimpedessmallmolecule-basedtherapies,IexploitedourDUBknockoutlibrarytoscreenforprobableDUBcandidate(s)thatinvolveinresistancetoYM155,ananticancercompound.IhaveidentifiedUSP32asapotentialmolecularmarkerforYM155resistancebynegativelyregulatingSLC35F2,acarrierforYM155.IshowedthatUSP32andSLC35F2haveanegativecorrelationfromapanelofcancercelllinestested.CRISPR-mediatedgenerationofUSP32knockoutinMCF7andBT474cellspromotesYM155-drivenDNAdamagebyupregulatingSLC35F2.Importantly,USP32depletionenhancedYM155-mediatedsuppressionofcancerprogressioninvitroandinvivo. IalsoreportedthatourCRISPR-Cas9DUBknockoutlibraryapproachtoidentifyaregulatorforCdc25AtosensitizeATRinhibitors-basedcancertherapies.IfoundUSP3asdeubiquitinaseofCdc25A.DepletionofUSP3reducestheproteinlevelofCdc25AandsensitizesthecancercellstotheATRinhibitors,AZ20andcaffeine. Together,applyingmystrategytootherpotentialsmallmoleculesscheduledforcancertherapymayincreaseitsclinicalefficacy,especiallyduringpostclinicalstages.Ibelievethatthisapproachwillbehelpfultounderstandandovercometheresistanceproblemsexhibitedbyseveralsmallmoleculesandmayrewritetheirtherapeutics. | - |
| dc.publisher | 한양대학교 | - |
| dc.title | CRISPR-baseddevelopmentandscreeningofdeubiquitinasesforthesensitizationofcancercellstosmallmoleculetherapies | - |
| dc.type | Theses | - |
| dc.contributor.googleauthor | ArunPandianChandrasekaran | - |
| dc.contributor.alternativeauthor | 아룬판디안찬드라세카란 | - |
| dc.sector.campus | S | - |
| dc.sector.daehak | 의생명공학전문대학원 | - |
| dc.sector.department | 의생명과학과 | - |
| dc.description.degree | Doctor | - |
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