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

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.