Segmental Duplications Arise from Pol32-Dependent Repair of Broken Forks through Two Alternative Replication-Based Mechanisms 英文参考文献.docVIP

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Segmental Duplications Arise from Pol32-Dependent Repair of Broken Forks through Two Alternative Replication-Based Mechanisms 英文参考文献.doc

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Segmental Duplications Arise from Pol32-Dependent Repair of Broken Forks through Two Alternative Replication-Based Mechanisms 英文参考文献

SegmentalDuplicationsArisefromPol32-Dependent RepairofBrokenForksthroughTwoAlternative Replication-BasedMechanisms CeliaPayen.,RomainKoszul.¤,BernardDujon,GillesFischer* InstitutPasteur,Unite′ deGe′ne′tiqueMole′culaire desLevures,CNRS,URA2171,Universite′ PierreetMarieCurie-Paris6,UFR927,Paris,France Abstract The propensity of segmental duplications (SDs) to promote genomic instability is of increasing interest since their involvementinnumeroushumangenomicdiseasesandcancerswasrevealed.However,themechanism(s)responsiblefor theirappearanceremainmostlyspeculative.Here,weshowthatinbuddingyeast,replicationaccidents,whicharemost likelytransformedintobrokenforks,playacausalroleintheformationofSDs.ThePol32subunitofthemajorreplicative polymerasePoldisrequiredforallSDformation,demonstratingthatSDsresultfromuntimelyDNAsynthesisratherthan from unequal crossing-over. Although Pol32 is known to be required for classical (Rad52-dependant) break-induced replication,onlyhalfoftheSDscanbeattributedtothismechanism.TheremainingSDsaregeneratedthroughaRad52- independent mechanism of template switching between microsatellites or microhomologous sequences. This new mechanism, namedmicrohomology/microsatellite-induced replication (MMIR), differs from all known DNA double-strand breakrepairpathways,asMMIR-mediatedduplicationsstilloccurinthecombinedabsenceofhomologousrecombination, microhomology-mediated, and nonhomologous end joining machineries. The interplay between these two replication- basedpathwaysexplainsimportantfeaturesofhighereukaryoticgenomes,suchasthestrong,butnotstrict,association betweenSDsandtransposableelements,aswellasthefrequentformationofoncogenicfusiongenesgeneratingprotein innovationsatSDjunctions. Citation: Payen C, Koszul R, Dujon B, Fischer G (2008) Segmental Duplications Arise from Pol32-Dependent Repair ofBroken Forks throughTwo Alternative Replication-BasedMechanisms.PLoSGenet4(9):e1000175.doi:10.1371/journal.pgen.1000175 Editor:JamesE.Haber,BrandeisUniversity