The role of the oncoprotein DEK in DNA replication stress and damage repair

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DEUTZMANN, Anja, 2013. The role of the oncoprotein DEK in DNA replication stress and damage repair [Dissertation]. Konstanz: University of Konstanz

@phdthesis{Deutzmann2013oncop-25970, title={The role of the oncoprotein DEK in DNA replication stress and damage repair}, year={2013}, author={Deutzmann, Anja}, address={Konstanz}, school={Universität Konstanz} }

deposit-license The role of the oncoprotein DEK in DNA replication stress and damage repair Deutzmann, Anja 2014-01-22T11:05:55Z Deutzmann, Anja 2013 The DEK oncoprotein is a chromatin architectural factor that has essential functions in the maintenance of heterochromatin integrity. It is an abundant and unique chromatin constituent showing no sequence homology to any other known protein, and is highly conserved among multicellular eukaryotes. DEK binds to DNA, RNA, and interacts with various chromatin components including histones. The affinity of DEK to its binding partners is determined by posttranslational modifications, predominantly by phosphorylation as well as poly(ADP-ribosyl)ation. When interacting with DNA, DEK preferentially binds to cruciform DNA structures which arise during perturbed DNA replication and the repair of DNA strand breaks.<br /><br /><br />Several lines of evidence, among others the frequent overexpression in highly malignant tumors and the positive correlation between DEK expression levels and chemoresistance, have led to the definition of DEK as a bona fide oncogene. On the other hand, investigation of a potential role of this protein in DNA repair revealed that DNA strand breaks are repaired less efficiently when DEK expression is downregulated leading to hypersensitivity towards genotoxic insults. DEK’s function as a positive regulator of DNA repair has been difficult to reconcile with a genuine tumor promoting activity, since cancer development is most often characterized by defects in DNA repair and genomic instability. This thesis aimed at elucidating this apparent conundrum by a detailed investigation of the impact of DEK on DNA damage susceptibility. The study focused on DNA replication stress as a characteristic source of DNA damage in hyperproliferating tumors.<br /><br /><br />The data obtained show that DEK renders cells less sensitive to DNA replication stress counteracting accumulation of replication stress-induced DNA damage. DEK facilitates replication fork progression, in particular under conditions of mild but prolonged replication stress, as occurring at the early stages of transformation. For this function, DEK was shown to depend on PARP1/2 activity. DEK’s proliferation promoting activity was also confirmed in the human cancer model of c-myc-induced replication stress. Furthermore, DEK was demonstrated to reduce damage transmission through mitosis to the next cell generation. Evidence for a role of DEK in the regulation of mitosis progression and chromosome congression was also gained. Finally, DEK localization was shown to be drastically and persistently affected by DNA replication stress, an effect that might be mediated by SUMO1-modification.<br /><br /><br />In sum, the study presented here proposes a model for DEK´s tumorigenic activity in which this protein contributes to circumvent the cell´s intrinsic barrier against cancerogenesis imposed by the DNA damage response thereby enabling proliferation under stress and eventually tumor growth and malignancy. This study discloses a novel mode of action of this protein frequently deregulated in aggressive tumors that bears the potential for new therapeutic approaches. eng

Dateiabrufe seit 01.10.2014 (Informationen über die Zugriffsstatistik)

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