UHRF1 is a genome caretaker that facilitates the DNA damage response to γ-irradiation 英文参考文献.docVIP

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UHRF1 is a genome caretaker that facilitates the DNA damage response to γ-irradiation 英文参考文献.doc

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UHRF1 is a genome caretaker that facilitates the DNA damage response to γ-irradiation 英文参考文献

Mistryetal.GenomeIntegrity2010,1:7 /content/1/1/7 GENOME INTEGRITY RESEARCH OpenAccess UHRF1isagenomecaretakerthatfacilitatesthe DNAdamageresponsetog-irradiation HelenaMistry1?,LauraTamblyn1?,HusseinButt1,DanielSisgoreo1,AileenGracias1,MeghanLarin1, KalpanaGopalakrishnan2,ManoorPrakashHande2,JohnPeterMcPherson1* Abstract Background:DNAdouble-strandbreaks(DSBs)causedbyionizingradiationorbythestallingofDNAreplication forksareamongthemostdeleteriousformsofDNAdamage.TheabilityofcellstorecognizeandrepairDSBs requirespost-translationalmodificationstohistonesandotherproteinsthatfacilitateaccesstolesionsin compactedchromatin,howeverourunderstandingoftheseprocessesremainsincomplete.UHRF1isanE3 ubiquitinligasethathaspreviouslybeenlinkedtoeventsthatregulatechromatinremodelingandepigenetic maintenance.PreviousstudieshavedemonstratedthatlossofUHRF1increasesthesensitivityofcellstoDNA damagehowevertheroleofUHRF1inthisresponseisunclear. Results:WedemonstratethatUHRF1playsacriticalroleforfacilitatingtheresponsetoDSBdamagecausedbyg- irradiation.UHRF1-depletedcellsexhibitincreasedsensitivitytog-irradiation,suggestingacompromisedcellular responsetoDSBs.UHRF1-depletedcellsshowimpairedcellcyclearrestandanimpairedaccumulationofhistone H2AXphosphorylation(gH2AX)inresponsetog-irradiationcomparedtocontrolcells.Wealsodemonstratethat UHRF1isrequiredforgenomeintegrity,inthatUHRF1-depletedcellsdisplayedanincreasedfrequencyof chromosomalaberrationscomparedtocontrolcells. Conclusions:OurfindingsindicateacriticalroleforUHRF1inmaintenanceofchromosomeintegrityandan optimalresponsetoDSBdamage. Background onto newly replicated DNA by recruiting the DNA UHRF1 (also known as Np95 and ICBP90) was origin- methyltransferaseDnmt1toreplicationsites[10-14].In allyidentifiedasaproteinwhosesubcellularexpression additiontoitsfunctioninduplicatingDNAmethylation pattern coincided with sites of DNA replication [1-3]. patterns, UHRF1binds tohistone H3tri-methylated at Further studies supported a role for thi