Parp1 Localizes within the Dnmt1 Promoter and Protects Its Unmethylated State by Its Enzymatic Activity 英文参考文献.docVIP

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Parp1 Localizes within the Dnmt1 Promoter and Protects Its Unmethylated State by Its Enzymatic Activity 英文参考文献.doc

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Parp1 Localizes within the Dnmt1 Promoter and Protects Its Unmethylated State by Its Enzymatic Activity 英文参考文献

Parp1LocalizeswithintheDnmt1PromoterandProtects ItsUnmethylatedStatebyItsEnzymaticActivity MicheleZampieri1,3,ClaudioPassananti4,RobertaCalabrese1,MariagraziaPerilli4,NicolettaCorbi4, FabianaDeCave1,TizianaGuastafierro1,3,MariaGiuliaBacalini1,AnnaReale1,3 ,Gianfranco Amicosante5,LiliaCalabrese2,JordankaZlatanova6,PaolaCaiafa1,3* 1Department of Cellular Biotechnologies and Hematology, Second Faculty of Medicine, University ‘‘La Sapienza’’,Rome, Italy, 2Department of Biochemical Sciences, University ‘‘La Sapienza’’, Rome, Italy, 3Pasteur Institute-Fondazione Cenci Bolognetti, Rome, Italy, 4Institute of Molecular Biology and Pathology CNR, Rome, Italy, 5Department of Biomedical Sciences and Technologies, University of L’Aquila, L’Aquila, Italy, 6Department of Molecular Biology, University of Wyoming, Laramie, Wyoming,UnitedStatesofAmerica Abstract Background: Aberrant hypermethylation of CpG islands in housekeeping gene promoters and widespread genome hypomethylation are typical events occurring in cancer cells. The molecular mechanisms behind these cancer-related changesinDNAmethylationpatternsarenotwellunderstood.Twoquestionsareparticularlyimportant:(i)howareCpG islandsprotectedfrommethylationinnormalcells,andhowisthisprotectioncompromisedincancercells,and(ii)how doesthegenome-widedemethylationincancercellsoccur.ThelatterquestionisespeciallyintriguingsincesofarnoDNA demethylaseenzymehasbeenfound. Methodology/PrincipalFindings:OurdatashowthattheabsenceofADP-ribosepolymers(PARs),causedbyectopicover- expressionofpoly(ADP-ribose)glycohydrolase(PARG)inL929mousefibroblastcellsleadstoaberrantmethylationofthe CpGislandinthepromoteroftheDnmt1gene,whichinturnshutsdownitstranscription.Thetranscriptionalsilencingof Dnmt1mayberesponsibleforthewidespreadpassivehypomethylationofgenomicDNAwhichwedetectontheexample ofpericentromericrepeatsequences.ChromatinimmunoprecipitationresultsshowthatinnormalcellstheDnmt1promoter isoccupiedbypoly(ADP-ribosyl)atedParp1,suggestingthatPARylatedP