A Nuclear Poly(ADP-Ribose)-Dependent Signalosome Confers DNA Damage-Induced I kappa B Kinase Activation

作者：Stilmann Michael; Hinz Michael; Arslan Secla Coel; Zimmer Anja; Schreiber Valerie; Scheidereit Claus^*

来源：Molecular Cell, 2009, 36(3): 365-378.

DOI：10.1016/j.molcel.2009.09.032

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.

• 出版日期2009-11-13