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.
Mesh Terms:
Animals, Cell Cycle Proteins, Cell Line, Transformed, Cell Line, Tumor, Chromatin Assembly and Disassembly, Chromosomal Proteins, Non-Histone, DNA Damage, DNA-Binding Proteins, Histones, Humans, Mice, Mice, Knockout, Poly Adenosine Diphosphate Ribose, Poly(ADP-ribose) Polymerases, Protein Processing, Post-Translational, Protein-Serine-Threonine Kinases, Signal Transduction, Tumor Suppressor Protein p53, Tumor Suppressor Proteins
J. Biol. Chem.
Date: Jun. 01, 2007
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