A nuclear poly(ADP-ribose)-dependent signalosome confers DNA damage-induced IκB kinase activation

Item Type:	Article
Title:	A nuclear poly(ADP-ribose)-dependent signalosome confers DNA damage-induced IκB kinase activation
Creators Name:	Stilmann, M. and Hinz, M. and Coel Arslan, S. and Zimmer, A. and Schreiber, V. and Scheidereit, C.
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.
Keywords:	Signaling, Proteins, DNA, Animals, Mice
Source:	Molecular Cell
ISSN:	1097-2765
Publisher:	Cell Press
Volume:	36
Number:	3
Page Range:	365-378
Date:	13 November 2009
Official Publication:	https://doi.org/10.1016/j.molcel.2009.09.032
PubMed:	View item in PubMed

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