ATM Deficiency Results in Accumulation of DNA-Topoisomerase I Covalent Intermediates in Neural Cells.docVIP

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ATM Deficiency Results in Accumulation of DNA-Topoisomerase I Covalent Intermediates in Neural Cells.doc

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ATM Deficiency Results in Accumulation of DNA-Topoisomerase I Covalent Intermediates in Neural Cells

ATMDeficiencyResultsinAccumulationofDNA- TopoisomeraseICovalentIntermediatesinNeuralCells MeryemAlagoz1.,Shih-ChiehChiang1.,AbhishekSharma1,SherifF.El-Khamisy1,2,3* 1GenomeDamageandStabilityCentre,SchoolofLifeSciences,UniversityofSussex,Brighton,UnitedKingdom,2DepartmentofBiochemistry,FacultyofPharmacy,Ain ShamsUniversity,Cairo,Egypt,3GenomeCentre,HelmyInstituteforMedicalSciences,ZewailCity,Giza,Egypt Abstract Accumulationofpeptide-linkedDNAbreakscontributestoneurodegerationinhumans.Thisistypifiedbydefectsintyrosyl DNA phosphodiesterase 1 (TDP1) and human hereditary ataxia. TDP1 primarily operates at single-strand breaks (SSBs) createdbyoxidativestressorbycollisionoftranscriptionmachinerywithtopoisomeraseIintermediates(Top1-CCs).Cellular andcell-freestudieshaveshownthatTop1atstalledTop1-CCsisfirstdegradedtoasmallpeptideresultinginTop1-SSBs, whicharetheprimarysubstratesforTDP1.HereweestablishedanassaytodirectlycompareTop1-SSBsandTop1-CCs.We subsequently employed this assay to reveal an increased steady state level of Top1-CCs in neural cells lacking Atm; the proteinmutatedinataxiatelangiectasia.OurdatasuggestthattheaccumulationofendogenousTop1-CCsinAtm-/-neural cells isprimarily duetoelevatedlevelsofreactive oxygenspecies.Biochemicalpurification ofTop1-CCsfromneural cell extractandtheuseofTop1poisonsfurtherconfirmedaroleforAtmduringtheformation/resolutionofTop1-CCs.Finally, wereportthatglobaltranscriptionisreducedinAtm-/-neuralcellsandfailstorecovertonormallevelsfollowingTop1- mediated DNA damage. Together, these data identify a distinct role for ATM during the formation/resolution of neural Top1-CCsandsuggestthattheiraccumulationcontributestotheneuropathologyofataxiatelangiectasia. Citation: Alagoz M, Chiang S-C, Sharma A, El-Khamisy SF (2013) ATM Deficiency Results inAccumulation of DNA-Topoisomerase I Covalent Intermediates in NeuralCells.PLoSONE8(4):e58239.doi:10.1371/journal.pone.0058239 Editor:MichalHetman,UniversityofLouisville,UnitedStatesofAmerica Rec