DEK Is a Poly(ADP-Ribose) Acceptor in Apoptosis and Mediates Resistance to Genotoxic Stress

Abstract

DEK is a nuclear phosphoprotein implicated in oncogenesis and autoimmunity and a major component of metazoan chromatin. The intracellular cues that control the binding of DEK to DNA and its pleiotropic functions in DNA- and RNA-dependent processes have remained mainly elusive so far. Our recent finding that the phosphorylation status of DEK is altered during death receptor-mediated apoptosis suggested a potential involvement of DEK in stress signaling. In this study, we show that in cells committed to die, a portion of the cellular DEK pool is extensively posttranslationally modified by phosphorylation and poly(ADP-ribosyl)ation. Through interference with DEK expression, we further show that DEK promotes the repair of DNA lesions and protects cells from genotoxic agents that typically trigger poly(ADP-ribose) polymerase activation. The posttranslational modification of DEK during apoptosis is accompanied by the removal of the protein from chromatin and its release into the extracellular space. Released modified DEK is recognized by autoantibodies present in the synovial fluids of patients affected by juvenile rheumatoid arthritis/juvenile idiopathic arthritis. These findings point to a crucial role of poly(ADP-ribosyl)ation in shaping DEK's autoantigenic properties and in its function as a promoter of cell survival.

SUPPLEMENTAL MATERIAL

Supplemental material for this article may be found at http://mcb.asm.org/ .

ACKNOWLEDGMENTS

We gratefully acknowledge Damu Tang and Shigekazu Nagata for dominant negative ICAD (ICAD-dn) expression constructs, Guy G. Poirier for anti-PAR antibodies, Masano Miwa and Takashi Sugimura for 10H cells, and Henning Walczak for lz-TRAIL. We are indebted to Konstantin Matentzoglu for advice in retroviral techniques, to Caterina Giorno for apoptosis assays, and to Daniela Hermann for invaluable technical assistance.

This study was supported by grants from the German Research Foundation (DFG MA/2385 to E.F.M. and FOR 434 to A.B.) and by the Center for Junior Research Fellows of the University of Konstanz. C.S. was supported by a fellowship from the DFG Research Training Group IRTG 1331. F.K. was supported by a William D. Robinson Fellowship from the Arthritis Foundation/Michigan Chapter and is a recipient of an Arthritis Foundation Postdoctoral Fellowship. Work in the laboratory of D.M.M. is supported by grants from the National Institutes of Health and by the Burroughs Wellcome Fund Clinical Scientist Award in Translational Research. M.S.K. was supported in part by NIH training grant T32-GM07863 through the University of Michigan Medical Scientist Training Program and by a graduate research fellowship from the National Science Foundation.