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| Item Type: | Article |
|---|---|
| Title: | A nuclear poly(ADP-ribose)-dependent signalosome confers DNA damage-induced IκB kinase activation |
| Creators Name: | Stilmann, M., Hinz, M., Coel Arslan, S., Zimmer, A., 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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