title: The human DEK oncogene regulates DNA damage response signaling and repair.
abstract: The human DEK gene is frequently overexpressed and sometimes amplified in human cancer. Consistent with oncogenic functions, Dek knockout mice are partially resistant to chemically induced papilloma formation. Additionally, DEK knockdown in vitro sensitizes cancer cells to DNA damaging agents and induces cell death via p53-dependent and -independent mechanisms. Here we report that DEK is important for DNA double-strand break repair. DEK depletion in human cancer cell lines and xenografts was sufficient to induce a DNA damage response as assessed by detection of γH2AX and FANCD2. Phosphorylation of H2AX was accompanied by contrasting activation and suppression, respectively, of the ATM and DNA-PK pathways. Similar DNA damage responses were observed in primary Dek knockout mouse embryonic fibroblasts (MEFs), along with increased levels of DNA damage and exaggerated induction of senescence in response to genotoxic stress. Importantly, Dek knockout MEFs exhibited distinct defects in non-homologous end joining (NHEJ) when compared to their wild-type counterparts. Taken together, the data demonstrate new molecular links between DEK and DNA damage response signaling pathways, and suggest that DEK contributes to DNA repair.
authors.affiliation: Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Gina M
authors.initials: GM
authors.lastname: Kavanaugh
authors.forename: Trisha M
authors.initials: TM
authors.lastname: Wise-Draper
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Morreale
authors.forename: Monique A
authors.initials: MA
authors.lastname: Morrison
authors.forename: Boris
authors.initials: B
authors.lastname: Gole
authors.forename: Sandy
authors.initials: S
authors.lastname: Schwemberger
authors.forename: Elisia D
authors.initials: ED
authors.lastname: Tichy
authors.forename: Lu
authors.initials: L
authors.lastname: Lu
authors.forename: George F
authors.initials: GF
authors.lastname: Babcock
authors.forename: James M
authors.initials: JM
authors.lastname: Wells
authors.forename: Rachid
authors.initials: R
authors.lastname: Drissi
authors.forename: John J
authors.initials: JJ
authors.lastname: Bissler
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Stambrook
authors.forename: Paul R
authors.initials: PR
authors.lastname: Andreassen
authors.forename: Lisa
authors.initials: L
authors.lastname: Wiesmüller
authors.forename: Susanne I
authors.initials: SI
authors.lastname: Wells
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002868:Chromosomal Proteins, Non-Histone / Q000037:antagonists & inhibitors / Q000502:physiology*; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D051747:DNA-Activated Protein Kinase / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D015513:Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D000075223:Poly-ADP-Ribose Binding Proteins; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; C519564:DEK protein, mouse; D004268:DNA-Binding Proteins; C084738:DEK protein, human; D015513:Oncogene Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D051747:DNA-Activated Protein Kinase; D017346:Protein Serine-Threonine Kinases