The chromatin architectural protein DEK in the DNA damage response

DEK is a DNA-binding, conserved nuclear protein with roles in oncogenesis and inflammation. We have identified DEK as a potential novel mediator of nuclear apoptosis during a proteomic screen of apoptotic nuclei. In cells treated with death-receptor ligands or subjected to DNA damage DEK is heavily post-translationally modified, dissociates from chromatin and is eventually released from the dying cell. Extracellular, modified DEK is recognized by antibodies present in the synovial fluid of patients suffering from juvenile rheumatoid arthritis/juvenile idiopathic arthritis (JRA/JIA). This points at cell death as a potential mechanism by which DEK can be presented to the immune system in addition to exosomal-mediated secretion. One prominent posttranslational modification of DEK after genotoxic stress is poly(ADP-ribosyl)ation. DEK also interacts with PARP1, the enzyme responsible the synthesis and transfer of poly(ADP-ribose)-polymers to acceptor proteins. We are interested in clarifying the functional link between DEK and PARP1 in the response to DNA damage, in particular in the context of DNA replication stress. PARP1 is crucially involved in many aspects of chromatin function and has been shown to be a crucial mediator of genomic stability. Understanding the molecular mechanisms regulating DEK-PARP interaction will shed light on the still poorly understood oncogenic properties of DEK.

Publications

  • Deutzmann A, Ganz M, Schönenberg F, Vervoorts J, Kappes F, Ferrando-May E. The human oncoprotein and chromatin architectural factor DEK counteracts DNA replication stress. Oncogene, in press, doi: 10.1038/onc.2014.346 (2014).
  • Saha AK, Kappes F, Mundade A, Deutzmann A, Rosmarin DM, Legendre M, Chatain N, Al-Obaidi Z, Adams BS, Ploegh HL, Ferrando-May E, Mor-Vaknin N, Markovitz DM. Intercellular trafficking of the nuclear oncoprotein DEK. Proc Natl Acad Sci U S A 110:6847-52 (2013).
  • Mor-Vaknin N, Kappes F, Dick AE, Legendre M, Damoc C, Teitz-Tennenbaum S, Kwok R, Ferrando-May E, Adams BS, Markovitz DM. DEK in the synovium of patients with juvenile idiopathic arthritis: characterization of DEK antibodies and posttranslational modification of the DEK autoantigen. Arthritis Rheum. 63:556-67 (2011)
  • Fahrer J, Popp O, Malanga M, Beneke S, Markovitz DM, Ferrando-May E, Bürkle A, Kappes F. High-affinity interaction of poly(ADP-ribose) and the human DEK oncoprotein depends upon chain length. Biochemistry 49:7119-30 (2010)
  • Kappes F, Fahrer J, Khodadoust MS, Tabbert A, Strasser C, Mor-Vaknin N, Moreno-Villanueva M, Bürkle A, Markovitz DM, Ferrando-May E. DEK is a poly(ADP-ribose) acceptor in apoptosis and mediates resistance to genotoxic stress. Mol Cell Biol. 28:3245-57 (2008)
  • Tabbert A, Kappes F, Knippers R, Kellermann J, Lottspeich F, Ferrando-May E. Hypophosphorylation of the architectural chromatin protein DEK in death-receptor-induced apoptosis revealed by the isotope coded protein label proteomic platform. Proteomics. 6:5758-72 (2006) 

Funding

  • Excellence Initiative by the German State and Federal Governments
  • Research Training Group IRTG1331
  • Collaborative Research Center 969 (SFB 969)
  • German Research Foundation(DFG)