Alkylation Base Damage Is Converted into Repairable Double-Strand Breaks and Complex Intermediates in G2 Cells Lacking AP Endonuclease 英文参考文献.docVIP

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Alkylation Base Damage Is Converted into Repairable Double-Strand Breaks and Complex Intermediates in G2 Cells Lacking AP Endonuclease 英文参考文献.doc

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Alkylation Base Damage Is Converted into Repairable Double-Strand Breaks and Complex Intermediates in G2 Cells Lacking AP Endonuclease 英文参考文献

AlkylationBaseDamageIsConvertedintoRepairable Double-StrandBreaksandComplexIntermediatesinG2 CellsLackingAPEndonuclease WenjianMa,JimW.Westmoreland,DmitryA.Gordenin,MikeA.Resnick* Chromosome Stability Group, Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health, Research TrianglePark,NorthCarolina,UnitedStatesofAmerica Abstract DNAdouble-strandbreaks(DSBs)arepotentsourcesofgenomeinstability.Whilethereisconsiderablegeneticandmolecular informationaboutthedispositionofdirectDSBsandbreaksthatariseduringreplication,relativelylittleisknownaboutDSBs derivedduringprocessingofsingle-strandlesions,especiallyforthecaseofsingle-strandbreaks(SSBs)with39-blockedtermini generatedinvivo.Usingourrecentlydevelopedassayfordetectingend-processingatrandomDSBsinbuddingyeast,we showthatsingle-strandlesionsproducedbythealkylatingagentmethylmethanesulfonate(MMS)cangenerateDSBsinG2- arrestedcells,i.e.,S-phaseindependent.ThesederivedDSBswereobservedinapn1/2endonucleasemutantsandresulted fromabortedbaseexcisionrepairleadingto39blockedsingle-strandbreaksfollowingthecreationofabasic(AP)sites.DSB formationwasreducedbyadditionalmutationsthataffectprocessingofAPsitesincludingntg1,ntg2,and,unexpectedly, ogg1,orbyalackofAPsitesduetodeletionoftheMAG1glycosylasegene.SimilartodirectDSBs,thederivedDSBswere subjecttoMRX(Mre11,Rad50,Xrs2)-determinedresectionandreliedupontherecombinationalrepairgenesRAD51,RAD52 ,as wellasontheMCD1cohesingene,forrepair.Inaddition,weidentifiedanovelDNAintermediate,detectedasslow-moving chromosomalDNA(SMD)inpulsedfieldelectrophoresisgelsshortlyafterMMSexposureinapn1/2cells.TheSMDrequires nickedAPsites,butisindependentofresection/recombinationprocesses,suggestingthatitisanovelstructuregenerated during processing of 39-blocked SSBs. Collectively, this study provides new insights into the potential consequences of alkylationbasedamageinvivo,includingcreationofnovelstructuresaswellasgenerationandrepairofDSBsi