Alternative-NHEJ Is a Mechanistically Distinct Pathway of Mammalian Chromosome Break Repair 英文参考文献.docVIP

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Alternative-NHEJ Is a Mechanistically Distinct Pathway of Mammalian Chromosome Break Repair 英文参考文献.doc

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Alternative-NHEJ Is a Mechanistically Distinct Pathway of Mammalian Chromosome Break Repair 英文参考文献

Alternative-NHEJIsaMechanisticallyDistinctPathwayof MammalianChromosomeBreakRepair NicoleBennardo1,2,AnitaCheng1,NickHuang1,JeremyM.Stark1,2* 1Department of Radiation Biology, Beckman Research Institute of the City of Hope, Duarte, California, United States of America, 2City of Hope Graduate School of BiologicalSciences,Duarte,California,UnitedStatesofAmerica Abstract Characterizing the functional overlap and mutagenic potential of different pathways of chromosomal double-strand break (DSB) repair is important to understand how mutations arise during cancer development and treatment. To this end, we have compared the role of individual factors in three different pathways of mammalian DSB repair: alternative- nonhomologousendjoining(alt-NHEJ),single-strandannealing(SSA),andhomologydirectedrepair(HDR/GC).Considering earlystepsofrepair,wefoundthattheDSBend-processingfactorsKUandCtIPaffectallthreepathwayssimilarly,inthat repairissuppressedbyKUandpromotedbyCtIP.Incontrast,bothKUandCtIPappeardispensablefortheabsolutelevelof total-NHEJbetweentwotandemI-SceI–inducedDSBs.Duringlaterstepsofrepair,wefindthatwhiletheannealingand processing factors RAD52 and ERCC1 are important to promote SSA, both HDR/GC and alt-NHEJ are significantly less dependentuponthesefactors.Aswell,whiledisruptionofRAD51causesadecreaseinHDR/GCandanincreaseinSSA, inhibition of this factor did not affect alt-NHEJ. These results suggest that the regulation of DSB end-processing via KU/CtIPisacommonstepduringalt-NHEJ,SSA,andHDR/GC.However,atlaterstepsofrepair,alt-NHEJisamechanistically distinct pathway of DSB repair, and thus may play a unique role in mutagenesis during cancer development and therapy. Citation:BennardoN,ChengA,HuangN,StarkJM(2008)Alternative-NHEJIsaMechanisticallyDistinctPathwayofMammalianChromosomeBreakRepair.PLoS Genet4(6):e1000110.doi:10.1371/journal.pgen.1000110 Editor:JamesE.Haber,BrandeisUniversity,UnitedStatesofAmerica ReceivedOctober31,2007;AcceptedMay28,2008;PublishedJune27,2008 C