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

Jean François Haince, Sergei Kozlov, Valina Dawson, Ted M Dawson, Michael J. Hendzel, Martin F. Lavin, Guy G. Poirier

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)16441-16453
Number of pages13
JournalJournal of Biological Chemistry
Volume282
Issue number22
DOIs
StatePublished - Jun 1 2007

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Poly Adenosine Diphosphate Ribose
Ataxia Telangiectasia
DNA Damage
Adenosine Diphosphate
DNA
DNA Breaks
Chromatin Assembly and Disassembly
Post Translational Protein Processing
Cell Cycle Checkpoints
DNA Repair
Protein Kinases
Phosphotransferases
Phosphorylation
Metabolism
Enzymes
Chromatin
Repair
Cells
Modulation
Proteins

ASJC Scopus subject areas

  • Biochemistry

Cite this

Ataxia telangiectasia mutated (ATM) signaling network is modulated by a novel poly(ADP-ribose)-dependent pathway in the early response to DNA-damaging agents. / Haince, Jean François; Kozlov, Sergei; Dawson, Valina; Dawson, Ted M; Hendzel, Michael J.; Lavin, Martin F.; Poirier, Guy G.

In: Journal of Biological Chemistry, Vol. 282, No. 22, 01.06.2007, p. 16441-16453.

Research output: Contribution to journalArticle

Haince, Jean François ; Kozlov, Sergei ; Dawson, Valina ; Dawson, Ted M ; Hendzel, Michael J. ; Lavin, Martin F. ; Poirier, Guy G. / Ataxia telangiectasia mutated (ATM) signaling network is modulated by a novel poly(ADP-ribose)-dependent pathway in the early response to DNA-damaging agents. In: Journal of Biological Chemistry. 2007 ; Vol. 282, No. 22. pp. 16441-16453.
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