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Role of Histone Metabolism and Chromatin Structure in DNA Repair

dc.contributor.advisorJohnsen, Steven A. Prof. Dr.
dc.contributor.authorKari, Vijaya Lakshmi
dc.titleRole of Histone Metabolism and Chromatin Structure in DNA Repairde
dc.contributor.refereeReichardt, Holger Prof. Dr.
dc.description.abstractengDuring the cell cycle progression, synthesis of new histones is important to pack newly synthesized DNA and to maintain proper chromatin structure. Unlike normal mRNAs, mRNAs from replication-dependent histone genes that are expressed in the S phase of the cell cycle are not polyadenylated at the 3‘end. They contain a conserved stem-loop sequence which forms a stem-loop structure which is required for the proper processing of the 3’end, translation and degradation of histone mRNAs. However, a number of studies show that replication-dependent histone genes can produce mRNAs which have a polyA tail at the 3’end under certain conditions the physiological function of polyadenylated histone mRNAs is not clear. In the present study, we analyzed the expression of polyadenylated histone mRNAs from the replication-dependent histone H2B genes. Furthermore, the expression of polyadenylated mRNAs from HIST1H2BD and HIST1H2AC genes are up-regulated during differentiation and up on induction of DNA damage. We showed that polyadenylated HIST1H2BD and HIST1H2AC mRNAs are transported to the cytoplasm and can form polysomes suggesting that theses transcripts can be translated into proteins. In addition to new synthesis of histone proteins, post-translational histone modifications, ATP-dependent chromatin remodelers and histone chaperones play important roles in maintaining genome structure and controlling DNA associated processes such as replication, transcription and DNA repair. Here we showed that one of the post-translational histone modifications, the H2B monoubiquitination (H2Bub1) which was shown to be associated with actively transcribed genes, is important for DNA double strand break (DSB) repair. H2Bub1 is carried out by an E3 ubiquitin ligase complex RNF20/40 and knockdown of RNF40 leads to the loss of checkpoint activation. In addition, RNF40 also regulates the recruitment of the histone chaperone complex FACT to chromatin and is required for the chromatin dynamics at the DSB site. Further, we showed that CHD1 an ATP-dependent DNA helicase is recruited to the site of DSB and regulates the binding of CtIP to chromatin. Depletion of CHD1 causes a decrease in homologous recombination-mediated repair efficiency and an increase in the cellular sensitivity to Mitomycin C treatment. In summary, the data imply that E3 ubiquitin ligase RNF40 and chromatin remodeler CHD1 mediate DNA DSB repair through chromatin remodeling at the site of DNA
dc.contributor.coRefereeKehlenbach, Ralph Prof. Dr.
dc.subject.engDNA damagede
dc.subject.enghistone mRNA processingde
dc.affiliation.instituteGöttinger Graduiertenschule für Neurowissenschaften, Biophysik und molekulare Biowissenschaften (GGNB)de
dc.subject.gokfullBiologie (PPN619462639)de

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