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, David A. Boothman

Research output: Contribution to journalArticle

92 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)33684-33696
Number of pages13
JournalJournal of Biological Chemistry
Volume281
Issue number44
DOIs
StatePublished - Nov 3 2006

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'Calcium-dependent modulation of poly(ADP-ribose) polymerase-1 alters cellular metabolism and DNA repair'. Together they form a unique fingerprint.

  • Cite this