Ataxia telangiectasia mutated (ATM) signaling network is modulated by a novel poly(ADP-ribose)-dependent pathway in the early response to DNA-damaging agents

Poly(ADP- ribosyl)ation is a post-translational modification that is instantly stimulated by DNA strand breaks creating a unique signal for the modulation of protein functions in DNA repair and cell cycle checkpoint pathways. Here we report that lack of poly( ADP- ribose) synthesis leads to a compromised response to DNA damage. Deficiency in poly( ADP- ribosyl) ation metabolism induces profound cellular sensitivity to DNA-damaging agents, particularly in cells deficient for the protein kinase ataxia telangiectasia mutated ( ATM). At the biochemical level, we examined the significance of poly( ADP- ribose) synthesis on the regulation of early DNA damage-induced signaling cascade initiated by ATM. Using potent PARP inhibitors and PARP-1 knock-out cells, we demonstrate a functional interplay between ATM and poly( ADP- ribose) that is important for the phosphorylation of p53, SMC1, and H2AX. For the first time, we demonstrate a functional and physical interaction between the major DSB signaling kinase, ATM and poly( ADP- ribosyl) ation by PARP-1, a key enzyme of chromatin remodeling. This study suggests that poly( ADP- ribose) might serve as a DNA damage sensory molecule that is critical for early DNA damage signaling.