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A nuclear poly(ADP-ribose)-dependent signalosome confers DNA damage-induced I{kappa}B kinase activation

Official URL:https://doi.org/10.1016/j.molcel.2009.09.032
PubMed:View item in PubMed
Creators Name:Stilmann, M. and Hinz, M. and Coel Arslan, S. and Zimmer, A. and Schreiber, V. and Scheidereit, C.
Journal Title:Molecular Cell
Journal Abbreviation:Mol Cell
Page Range:365-378
Date:13 November 2009
Keywords:Signaling, Proteins, DNA, Animals, Mice
Abstract:Upon genotoxic stresses, cells activate I{kappa}B kinases (IKKs) and the transcription factor NF-{kappa}B to modulate apoptotic responses. The SUMO-1 ligase PIASy and the kinase ataxia talengiectasia mutated (ATM) have been implicated to SUMOylate and phosphorylate nuclear IKK{gamma} (NEMO) in a consecutive mode of action, which in turn results in activation of cytoplasmic IKK holocomplexes. However, the nuclear signals and scaffold structures that initiate IKK{gamma} recruitment and activation are unknown. Here, we show that poly(ADP-ribose)-polymerase-1 (PARP-1) is the DNA proximal regulator, which senses DNA strand breaks and, through poly(ADP-ribose) (PAR) synthesis, assembles IKK{gamma}, PIASy, and ATM in a dynamic manner. Signalosome formation involves direct protein-protein interactions and binding to ADP-ribose polymers through PAR binding motifs (PARBM). Activated PARP-1 and a PARBM in PIASy are required to trigger IKK{gamma} SUMOylation, which in turn permits IKK and NF-{kappa}B activation, as well as NF-{kappa}B-regulated resistance to apoptosis.
Publisher:Cell Press (U.S.A.)
Item Type:Article

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