Progressive Telomere Dysfunction Causes Cytokinesis Failure and Leads to the Accumulation of Polyploid Cells 英文参考文献.docVIP

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Progressive Telomere Dysfunction Causes Cytokinesis Failure and Leads to the Accumulation of Polyploid Cells 英文参考文献.doc

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Progressive Telomere Dysfunction Causes Cytokinesis Failure and Leads to the Accumulation of Polyploid Cells 英文参考文献

ProgressiveTelomereDysfunctionCausesCytokinesis FailureandLeadstotheAccumulationofPolyploidCells JuditPampalona¤a,CristinaFr?′as¤b,AnnaGenesca`,LauraTusell* DepartmentofCellBiology,Physiology,andImmunology,BioscienceSchool,UniversitatAuto`nomadeBarcelona,Bellaterra,Spain Abstract Most cancer cells accumulate genomic abnormalities at a remarkably rapid rate, as they are unable to maintain their chromosomestructureandnumber.Excessivelyshorttelomeres,aknownsourceofchromosomeinstability,areobservedin earlyhuman-cancerlesions.Besidestelomeredysfunction,ithasbeensuggestedthatatransientphaseofpolyploidization, in most cases tetraploidization, has a causative role in cancer. Proliferation of tetraploids can gradually generate subtetraploid lineages of unstable cells that might fire the carcinogenic process by promoting further aneuploidy and genomicinstability.Giventhesignificanceoftelomeredysfunctionandtetraploidyintheearlystagesofcarcinogenesis,we investigatedwhetherthereisaconnectionbetweenthesetwoimportantpromotersofchromosomalinstability.Wereport that human mammary epithelial cells exhibiting progressive telomere dysfunction, in a pRb deficient and wild-type p53 background,failtocompletethecytoplasmaticcelldivisionduetothepersistenceofchromatinbridgesinthemidzone. Flowcytometrytogetherwithfluorescence insituhybridizationdemonstratedanaccumulationofbinucleatedpolyploid cellsuponserialpassagingcells.RestorationoftelomerefunctionthroughhTERTtransduction,whichlessenstheformation ofanaphasebridgesbyrecappingthechromosomeends,rescuedthepolyploidphenotype.Live-cellimagingrevealedthat thesepolyploidcellsemergedafterabortivecytokinesisduetothepersistenceofanaphasebridgeswithlargeintervening chromatininthecleavageplane.Inagreementwithaprimaryroleofanaphasebridgeintermediatesinthepolyploidization process, treatment of HMEC-hTERT cells with bleomycin, which produces chromatin bridges through illegimitate repair, resultedintetraploidbinucleatedcells.Takentogether,wedemonstratet