title: The human oncoprotein and chromatin architectural factor DEK counteracts DNA replication stress.
abstract: DNA replication stress is a major source of DNA strand breaks and genomic instability, and a hallmark of precancerous lesions. In these hyperproliferative tissues, activation of the DNA damage response results in apoptosis or senescence preventing or delaying their development to full malignancy. In cells, in which this antitumor barrier is disabled by mutations (for example, in p53), viability and further uncontrolled proliferation depend on factors that help to cope with replication-associated DNA damage. Replication problems preferentially arise in chromatin regions harboring complex DNA structures. DEK is a unique chromatin architectural factor which binds to non-B-form DNA structures, such as cruciform DNA or four-way junctions. It regulates DNA topology and chromatin organization, and is essential for the maintenance of heterochromatin integrity. Since its isolation as part of an oncogenic fusion in a subtype of AML, DEK has been consistently associated with tumor progression and chemoresistance. How DEK promotes cancer, however, is poorly understood. Here we show that DEK facilitates cellular proliferation under conditions of DNA replication stress by promoting replication fork progression. DEK also protects from the transmission of DNA damage to the daughter cell generation. We propose that DEK counteracts replication stress and ensures proliferative advantage by resolving problematic DNA and/or chromatin structures at the replication fork.
authors.affiliation: Bioimaging Center, Department of Biology, University of Konstanz, Konstanz, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Deutzmann
authors.affiliation: Bioimaging Center, Department of Biology, University of Konstanz, Konstanz, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Ganz
authors.affiliation: Bioimaging Center, Department of Biology, University of Konstanz, Konstanz, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Schönenberger
authors.affiliation: Institute of Biochemistry and Molecular Biology, Medical School, RWTH Aachen University, Aachen, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Vervoorts
authors.affiliation: Institute of Biochemistry and Molecular Biology, Medical School, RWTH Aachen University, Aachen, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Kappes
authors.affiliation: Bioimaging Center, Department of Biology, University of Konstanz, Konstanz, Germany.
authors.forename: E
authors.identifier: 0000000255678690
authors.initials: E
authors.lastname: Ferrando-May
mesh_terms: D016590:Aphidicolin / Q000494:pharmacology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002843:Chromatin / Q000235:genetics* / Q000378:metabolism; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics* / Q000378:metabolism; D004249:DNA Damage; D004261:DNA Replication; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D006918:Hydroxyurea / Q000494:pharmacology; D008856:Microscopy, Fluorescence; D015513:Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D000075223:Poly-ADP-Ribose Binding Proteins; D034622:RNA Interference
chemical_list: D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; C084738:DEK protein, human; D004791:Enzyme Inhibitors; D015513:Oncogene Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; D016590:Aphidicolin; D006918:Hydroxyurea