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, J. F., Kozlov, S., Dawson, V. L., Dawson, T. M., Hendzel, M. J., Lavin, M. F. and Poirier, G. G. (2007) Ataxia telangiectasia mutated (ATM) signaling network is modulated by a novel poly (ADP-ribose) dependent pathway in the early response to DNA-damaging agents. Journal of Biological Chemistry, 282 22: 16441-16453. doi:10.1074/jbc.M608406200

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Author Haince, J. F.
Kozlov, S.
Dawson, V. L.
Dawson, T. M.
Hendzel, M. J.
Lavin, M. F.
Poirier, G. G.
Title Ataxia telangiectasia mutated (ATM) signaling network is modulated by a novel poly (ADP-ribose) dependent pathway in the early response to DNA-damaging agents
Journal name Journal of Biological Chemistry   Check publisher's open access policy
ISSN 0021-9258
Publication date 2007-01-01
Sub-type Article (original research)
DOI 10.1074/jbc.M608406200
Open Access Status File (Publisher version)
Volume 282
Issue 22
Start page 16441
End page 16453
Total pages 13
Editor H. Tabor
Place of publication Bethesda, M.D, U.S.A.
Publisher American Society for Biochemistry and Molecular Biology
Collection year 2008
Language eng
Subject C1
320307 Medical Biochemistry - Other
730100 Clinical (Organs, Diseases and Abnormal Conditions)
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.
Q-Index Code C1
Q-Index Status Confirmed Code

Document type: Journal Article
Sub-type: Article (original research)
Collections: Excellence in Research Australia (ERA) - Collection
2008 Higher Education Research Data Collection
School of Medicine Publications
 
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Created: Tue, 22 Apr 2008, 20:22:42 EST by Sarah Elliott on behalf of Surgery - Royal Brisbane and Women's Hospital