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

doi:10.1074/jbc.M603678200

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

Journal article

Open access

Peer reviewed

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

The Journal of biological chemistry, Vol.281(44), pp.33684-33696

11/03/2006

DOI: 10.1074/jbc.M603678200

PMID: 16920718

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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.

Adenosine Triphosphate - metabolism

Calcium - metabolism

Cell Death - drug effects

Chelating Agents - pharmacology

DNA - genetics

DNA Damage - genetics

DNA Repair - genetics

Egtazic Acid - analogs & derivatives

Egtazic Acid - pharmacology

Enzyme Activation - drug effects

Humans

Hydrogen Peroxide - pharmacology

NAD - metabolism

Naphthoquinones - pharmacology

Poly (ADP-Ribose) Polymerase-1

Poly(ADP-ribose) Polymerases - genetics

Poly(ADP-ribose) Polymerases - metabolism

Time Factors

Details

Title: Subtitle: Calcium-dependent modulation of poly(ADP-ribose) polymerase-1 alters cellular metabolism and DNA repair
Creators: Melissa S Bentle - Case Western Reserve University
Kathryn E Reinicke - Case Western Reserve University
Erik A Bey - The University of Texas Southwestern Medical Center
Douglas R Spitz - Holden
David A Boothman - The University of Texas Southwestern Medical Center
Resource Type: Journal article
Publication Details: The Journal of biological chemistry, Vol.281(44), pp.33684-33696
DOI: 10.1074/jbc.M603678200
PMID: 16920718
NLM abbreviation: J Biol Chem
ISSN: 0021-9258
eISSN: 1083-351X
Grant note: 1R01CA10279201 / NCI NIH HHS P30CA43703 / NCI NIH HHS P30CA43703-12 / NCI NIH HHS P30 CA142543 / NCI NIH HHS R01 CA102792 / NCI NIH HHS 1R01CA100045 / NCI NIH HHS
Language: English
Date published: 11/03/2006
Academic Unit: Pathology; Radiation Oncology; Fraternal Order of Eagles Diabetes Research Center
Record Identifier: 9984312989802771

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