Calcium-dependent modulation of poly(ADP-ribose) polymerase-1 alters cellular metabolism and DNA repair

Abstract

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. β-lapachone (β-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. β-lap induces the generation of NQO1-dependent reactive oxygen species (ROS), DNA breaks, and triggers Ca 2+-dependent γ-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 (H 2O2), 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. © 2006 by The American Society for Biochemistry and Molecular Biology, Inc.