DNA Damage in Nijmegen Breakage Syndrome Cells Leads to PARP Hyperactivation and Increased Oxidative Stress 英文参考文献.docVIP

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DNA Damage in Nijmegen Breakage Syndrome Cells Leads to PARP Hyperactivation and Increased Oxidative Stress 英文参考文献.doc

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DNA Damage in Nijmegen Breakage Syndrome Cells Leads to PARP Hyperactivation and Increased Oxidative Stress 英文参考文献

DNADamageinNijmegenBreakageSyndromeCells LeadstoPARPHyperactivationandIncreasedOxidative Stress HaraldKrenzlin1,IljaDemuth1,2,BastianSalewsky1,PetraWessendorf1,KathrinWeidele3 ,Alexander Bu¨rkle3,MartinDigweed1* 1Institute ofMedical andHuman Genetics,Charite′ –Universita¨tsmedizin Berlin,Berlin, Germany, 2TheBerlin AgingStudy II, ResearchGroupon Geriatrics, Charite′ – Universita¨tsmedizin Berlin,Berlin,Germany,3MolecularToxicology,DepartmentofBiology,UniversityofKonstanz,Konstanz,Germany Abstract Nijmegen Breakage Syndrome (NBS), an autosomal recessive genetic instability syndrome, is caused by hypomorphic mutation of the NBN gene, which codes for the protein nibrin. Nibrin is an integral member of the MRE11/RAD50/NBN (MRN)complexessentialforprocessingDNAdouble-strandbreaks.CardinalfeaturesofNBSareimmunodeficiencyandan extremely high incidence of hematological malignancies. Recent studies in conditional null mutant mice have indicated disturbances in redox homeostasis due to impaired DSB processing. Clearly this could contribute to DNA damage, chromosomalinstability,andcanceroccurrence.Hereweshow,inthecompleteabsenceofnibrininnullmutantmouse cells,highlevelsofreactiveoxygenspeciesseveralhoursafterexposuretoamutagen.WeshowfurtherthatNBSpatient cells,whichunlikemousenullmutantcellshaveatruncatednibrinprotein,alsohavehighlevelsofreactiveoxygenafter + DNAdamageandthatthisincreasedoxidativestressiscausedbydepletionofNAD duetohyperactivationofthestrand- breaksensor,Poly(ADP-ribose)polymerase.BothhyperactivationofPoly(ADP-ribose)polymeraseandincreasedROSlevels were reversed by use of a specific Poly(ADP-ribose) polymerase inhibitor. The extremely high incidence of malignancy among NBS patients is the result of the combination of a primary DSB repair deficiency with secondary oxidative DNA damage. Citation: Krenzlin H, Demuth I, Salewsky B, Wessendorf P, Weidele K, et al. (2012) DNA Damage in Nijmegen Breakage Syndrome Cells Leads to PARP HyperactivationandIncreas