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. beta-lapachone (beta-lap) is the first chemotherapeutic agent to elicit a Ca(2+)-mediated cell death by PARP-1 hyperactivation at clinically relevant doses in cancer cells expressing elevated NAD(P)H:quinone oxidoreductase 1 (NQO1) levels. Beta-lap induces the generation of NQO1-dependent reactive oxygen species (ROS), DNA breaks, and triggers Ca(2+)-dependent gamma-H2AX formation and PARP-1 hyperactivation. Subsequent NAD(+) and ATP losses suppress DNA repair and cause cell death. Reduction of PARP-1 activity or Ca(2+) chelation protects cells. Interestingly, Ca(2+) chelation abrogates hydrogen peroxide (H(2)O(2)), but not N-Methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced PARP-1 hyperactivation and cell death. Thus, Ca(2+) appears to be an important co-factor in PARP-1 hyperactivation after ROS-induced DNA damage, which alters cellular metabolism and DNA repair.

• Authors: Melissa S Bentle, Kathryn E Reinicke, Erik A Bey, Douglas R Spitz, David A Boothman
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 281 Issue 44 Pg. 33684-96 (Nov 03 2006) ISSN: 0021-9258 [Print] United States
• PMID: 16920718 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Chelating Agents
• Naphthoquinones
• NAD
• 1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester
• Egtazic Acid
• beta-lapachone
• Adenosine Triphosphate
• DNA
• Hydrogen Peroxide
• PARP1 protein, human
• Poly (ADP-Ribose) Polymerase-1
• Poly(ADP-ribose) Polymerases
• Calcium

Topics

• Adenosine Triphosphate (metabolism)
• Calcium (metabolism)
• Cell Death (drug effects)
• Chelating Agents (pharmacology)
• DNA (genetics)
• DNA Damage (genetics)
• DNA Repair (genetics)
• Egtazic Acid (analogs & derivatives, pharmacology)
• Enzyme Activation (drug effects)
• Humans
• Hydrogen Peroxide (pharmacology)
• NAD (metabolism)
• Naphthoquinones (pharmacology)
• Poly (ADP-Ribose) Polymerase-1
• Poly(ADP-ribose) Polymerases (genetics, metabolism)
• Time Factors