Expanded CAGCTG Repeat DNA Induces a Checkpoint Response That Impacts Cell Proliferation in Saccharomyces cerevisiae 英文参考文献.docVIP

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Expanded CAGCTG Repeat DNA Induces a Checkpoint Response That Impacts Cell Proliferation in Saccharomyces cerevisiae 英文参考文献.doc

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Expanded CAGCTG Repeat DNA Induces a Checkpoint Response That Impacts Cell Proliferation in Saccharomyces cerevisiae 英文参考文献

ExpandedCAG/CTGRepeatDNAInducesaCheckpoint ResponseThatImpactsCellProliferationin Saccharomycescerevisiae RangapriyaSundararajan,CatherineH.Freudenreich* DepartmentofBiology,TuftsUniversity,Medford,Massachusetts,UnitedStatesofAmerica Abstract Repetitive DNA elements are mutational hotspots in the genome, and their instability is linked to various neurological disorders andcancers. Although it is knownthat expandedtrinucleotide repeats caninterfere with DNA replication and repair,thecellularresponsetotheseeventshasnotbeencharacterized.Here,wedemonstratethatanexpandedCAG/CTG repeatelicitsaDNAdamagecheckpointresponseinbuddingyeast.Usingmicrocolonyandsinglecellpedigreeanalysis,we foundthatcellscarryinganexpandedCAGrepeatfrequentlyexperienceprotractedcelldivisioncycles,persistentarrests, and morphological abnormalities. These phenotypes were further exacerbated by mutations in DSB repair pathways, includinghomologousrecombinationandendjoining,implicatingaDNAdamageresponse.Cellcycleanalysisconfirmed repeat-dependentSphasedelaysandG2/Marrests.Furthermore,wedemonstratethattheabovephenotypesaredueto the activation of the DNA damage checkpoint, since expanded CAG repeats induced the phosphorylation of the Rad53 checkpointkinaseinarad52Drecombinationdeficientmutant.Interestingly,cellsmutatedfortheMRXcomplex(Mre11- Rad50-Xrs2),acentralcomponentofDSBrepairwhichisrequiredtorepairbreaksatCAGrepeats,failedtoelicitrepeat- specificarrests,morphologicaldefects,orRad53phosphorylation.WethereforeconcludethatdamageatexpandedCAG/ CTGrepeatsislikelysensedbytheMRXcomplex,leadingtoacheckpointresponse.Finally,weshowthatrepeatexpansions preferentiallyoccurincellsexperiencinggrowthdelays.ActivationofDNAdamagecheckpointsinrepeat-containingcells couldcontributetothetissuedegenerationobservedintrinucleotiderepeatexpansiondiseases. Citation: Sundararajan R, Freudenreich CH (2011) Expanded CAG/CTG Repeat DNA Induces a Checkpoint Response That Impacts Cell Proliferation in Saccharomycescerevisiae.P