ContentslistsavailableatScienceDirectSeminarsinCancerBiologyjournalhomepage:www.elsevier.com/locate/semcancerReplicationstressresponseincancerstemcellsasatargetforchemotherapyGwenolaManica,⁎,AntonellaSistigua,b,FrancescaCorradic,MartinaMusellaa,d,RuggeroDeMariab,1,⁎⁎,IlioVitalea,c,1,⁎⁎⁎aDepartmentofResearch,AdvancedDiagnosticsandTechnologicalInnovation,IRCCS-ReginaElenaNationalCancerInstitute,Rome,ItalybInstituteofGeneralPathology,CatholicUniversityandGemelliPolyclinic,Rome,ItalycDepartmentofBiology,UniversityofRome“TorVergata”,Rome,ItalydDepartmentofMolecularMedicine,University"LaSapienza",Rome,ItalyARTICLEINFOOfficialgenesymbolsandnames:SupplementaryTable1Keywords:AneuploidyChromosomalinstabilityForkreversalReplicationcatastropheTumor-initiatingcellsABSTRACTCancerstemcells(CSCs)aresubpopulationsofmultipotentstemcells(SCs)responsiblefortheinitiation,long-termclonalmaintenance,growthandspreadingofmosthumanneoplasms.Reportedly,CSCsshareaveryrobustDNAdamageresponse(DDR)withembryonicandadultSCs,whichallowsthemtosurviveendogenousandexogenousgenotoxins.ArangeofexperimentalevidenceindicatesthatCSCshavehighbutheterogeneouslevelsofreplicationstress(RS),arisingfrom,andbeingboostedby,endogenouscauses,suchasspecificgeneticbackgrounds(e.g.,p53deficiency)and/oraberrantkaryotypes(e.g.,supernumerarychromosomes).Amulti-prongedRSresponse(RSR)isputinplacebyCSCstolimitandensuretolerabilitytoRS.Thecharacteristicsofsuchdedicatedcascadehavetwooppositeconsequences,bothrelevantforcancertherapy.Ontheonehand,RSRefficiencyoftenincreasestherelianceofCSCsonspecificDDRcomponents.Ontheotherhand,thefunctionalredundancyofpathwaysoftheRSRcanparadoxicallypromotetheacquisitionofresistancetoRS-and/orDNAdamage-inducingagents.Here,weprovideanoverviewofthemolecularmechanismsoftheRSRincancercellsandCSCs,focusingontheroleofCHK1andsomeemergingplayers,suchasPARP1andcomponentsofthehomologousrecombinationrepair,whosetargetingcanrepresentalong-termeffectiveanti-CSCstrategy.1.IntroductionThetumorsystem...
