Short Telomeres Initiate Telomere Recombination in Primary and Tumor Cells 英文参考文献.docVIP

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Short Telomeres Initiate Telomere Recombination in Primary and Tumor Cells 英文参考文献.doc

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Short Telomeres Initiate Telomere Recombination in Primary and Tumor Cells 英文参考文献

ShortTelomeresInitiateTelomereRecombinationin PrimaryandTumorCells TammyA.Morrish,CarolW.Greider* DepartmentofMolecularBiologyandGenetics,JohnsHopkinsUniversitySchoolofMedicine,Baltimore,Maryland,UnitedStatesofAmerica Abstract Humantumorsthatlacktelomerasemaintaintelomeresbyalternativelengtheningmechanisms.Tumorscanalsoformin telomerase-deficientmice;however,thegeneticmechanismresponsiblefortumorgrowthwithouttelomeraseisunknown. In yeast, several different recombination pathways maintain telomeres in the absence of telomerase—some result in telomere maintenance with minimal effects on telomere length. To examine non-telomerase mechanisms for telomere maintenance in mammalian cells, we used primary cells and lymphomas from telomerase-deficient mice (mTR2/2 and Emmyc+mTR2/2) and CAST/EiJ mouse embryonic fibroblast cells. These cells were analyzed using pq-ratio analysis, telomerelengthdistributionoutliers,CO-FISH,Q-FISH,andmulticolorFISHtodetectsubtelomericrecombination.Telomere lengthwasmaintainedduringlong-termgrowthinvivoandinvitro.Longtelomeres,characteristicofhumanALTcells,were notobservedineitherlatepassageormTR2/2tumorcells;instead,weobservedonlyminimalchangesintelomerelength. Telomere length variation and subtelomeric recombination were frequent in cells with short telomeres, indicating that lengthmaintenanceisduetotelomericrecombination.WealsodetectedtelomerelengthchangesinprimarymTR2/2cells that had short telomeres. Using mouse mTR+/2 and human hTERT+/2 primary cells with short telomeres, we found frequent length changes indicative of recombination. We conclude that telomere maintenance by non-telomerase mechanisms,includingrecombination,occursinprimarycellsandisinitiatedbyshorttelomeres,eveninthepresenceof telomerase.Mostintriguing,ourdataindicatethatsomenon-telomerasetelomeremaintenancemechanismsoccurwithout asignificantincreaseintelomerelength. Citation:MorrishTA,GreiderCW(2009)ShortTelomeresInitiateTelomereRecombinationinPrimaryandTumorCells.PLoSGenet