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J. Biol. Chem., Vol. 281, Issue 44, 33684-33696, November 3, 2006

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Calcium-dependent Modulation of Poly(ADP-ribose) Polymerase-1 Alters Cellular Metabolism and DNA Repair^*

Melissa S. Bentle, Kathryn E. Reinicke, Erik A. Bey^¶, Douglas R. Spitz^||, and David A. Boothman^¶1

From the Departments of Pharmacology and Biochemistry, Case Western Reserve University, Cleveland, Ohio 44106, the ^¶Department of Pharmacology, Laboratory of Molecular Stress Responses, and the Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390, and the ^||Department of Radiation Oncology, Free Radical and Radiation Biology Program, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa 52242

After genotoxic stress poly(ADP-ribose) polymerase-1 (PARP-1) can be hyperactivated, causing (ADP-ribosyl)ation of nuclear proteins (including itself), resulting in NAD⁺ and ATP depletion and cell death. Mechanisms of PARP-1-mediated cell death and downstream proteolysis remain enigmatic. -lapachone (-lap) is the first chemotherapeutic agent to elicit a Ca²⁺-mediated cell death by PARP-1 hyperactivation at clinically relevent doses in cancer cells expressing elevated NAD(P)H:quinone oxidoreductase 1 (NQO1) levels. -lap induces the generation of NQO1-dependent reactive oxygen species (ROS), DNA breaks, and triggers Ca²⁺-dependent -H2AX formation and PARP-1 hyperactivation. Subsequent NAD⁺ and ATP losses suppress DNA repair and cause cell death. Reduction of PARP-1 activity or Ca²⁺ chelation protects cells. Interestingly, Ca²⁺ chelation abrogates hydrogen peroxide (H₂O₂), but not N-Methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced PARP-1 hyperactivation and cell death. Thus, Ca²⁺ appears to be an important co-factor in PARP-1 hyperactivation after ROS-induced DNA damage, which alters cellular metabolism and DNA repair.

Received for publication, April 17, 2006 , and in revised form, August 17, 2006.

^* This work was supported in part by National Institutes of Health/NCI Grant 1R01CA10279201 (to D. A. B.), 1R01CA100045 (to D. R. S.), CWRU Core Grants P30CA43703 and P30CA43703-12, as well as Department of Defense Breast Cancer Program Predoctoral Fellowships, W81XWH-04-1-0301 and W81XWH-05-1-0248 (to M. S. B. and K. E. R.), respectively. This is manuscript CSCN 001 from the Cell Stress and Cancer Nanomedicine program in the Simmons Comprehensive Cancer Center at the University of Texas Southwestern Medical Center at Dallas. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental experimental procedures, Figs. S1-S5, and Table S1.

¹ To whom correspondence should be addressed: Dept. of Pharmacology, Laboratory of Molecular Stress Responses, and the Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390. Tel.: 214-648-9255; Fax: 214-648-0264; E-mail: David.Boothman{at}UTSouthwestern.edu.

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