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‡,1,
- Sergei Kozlov§,
- Valina L. Dawson¶,2,
- Ted M. Dawson¶,2,3,
- Michael J. Hendzel∥,
- Martin F. Lavin§ and
- Guy G. Poirier, Holds a Canada Research Chair in Proteomics‡,4
- ‡Health and Environment Unit, Laval University Hospital Research Center, CHUQ, Faculty of Medicine, Laval University, Quebec, Quebec G1V 4G2, Canada, the §Queensland Institute for Medical Research, PO Royal Brisbane Hospital, Brisbane, Queensland 4029, Australia, the ¶Institute for Cell Engineering and the Departments of Neurology and Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, and the ∥Department of Oncology, Faculty of Medicine, University of Alberta and Cross Cancer Institute, Edmonton, Alberta T6G 1Z2, Canada
- ↵4 To whom correspondence should be addressed: CHUL Rm. RC-9700, 2705, Laurier Blvd., Quebec, Quebec G1V 4G2, Canada. Tel.: 418-654-2267; Fax: 418-654-2159; E-mail: guy.poirier{at}crchul.ulaval.ca.
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.
- Received August 31, 2006.
- Revision received April 10, 2007.
- The American Society for Biochemistry and Molecular Biology, Inc.
