Chromatin Relaxation-Mediated Induction of p19INK4d Increases the Ability of Cells to Repair Damaged DNA.docVIP

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2017-05-07 发布于上海
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Chromatin Relaxation-Mediated Induction of p19INK4d Increases the Ability of Cells to Repair Damaged DNA.doc

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Chromatin Relaxation-Mediated Induction of p19INK4d Increases the Ability of Cells to Repair Damaged DNA

ChromatinRelaxation-MediatedInductionofp19INK4d IncreasestheAbilityofCellstoRepairDamagedDNA Mar?′aF.Ogara.,PabloF.Sirkin.,AbelL.Carcagno,MarielaC.Marazita,SilvinaV.Sonzogni, JulietaM.Ceruti,EduardoT.Ca′nepa* Laboratorio de Biolog?′a Molecular, Departamento de Qu?′mica Biolo′gica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria Pabello′nII,BuenosAires,Argentina Abstract Themaintenanceofgenomicintegrityisofmainimportancetothesurvivalandhealthoforganismswhicharecontinuously exposed to genotoxic stress. Cells respond to DNA damage by activating survival pathways consisting of cell cycle checkpointsandrepairmechanisms.However,thesignalthattriggerstheDNAdamageresponseisnotnecessarilyadirect detectionoftheprimaryDNAlesion.Infact,chromatindefectsmayserveasinitiatingsignalstoactivatethosemechanisms. If the modulation of chromatin structure could initiate a checkpoint response in a direct manner, this supposes the existence of specific chromatin sensors. p19INK4d, a member of the INK4 cell cycle inhibitors, plays a crucial role in regulatinggenomicstabilityandcellviabilitybyenhancingDNArepair.Itsexpressionisinducedincellsinjuredbyoneof several genotoxic treatments like cis-platin, UV light or neocarzinostatin. Nevertheless, when exogenous DNA damaged molecules are introduced into the cell, this induction is not observed. Here, we show that p19INK4d is enhanced after chromatinrelaxationevenintheabsenceofDNAdamage.ThisinductionwasshowntodependuponATM/ATR,Chk1/Chk2 andE2Factivity,asisthecaseofp19INK4dinductionbyendogenousDNAdamage.Interestingly,p19INK4dimprovesDNA repair when the genotoxic damage is caused in a relaxed-chromatin context. These results suggest that changes in chromatinstructure,andnotDNAdamageitself,istheactualtriggerofp19INK4dinduction.Weproposethat,inadditionto its role as a cell cycle inhibitor, p19INK4d could participate in a signaling network directed to detecting and eventually respondingtochromatinanomalies. Cit