Poly(ADP-ribose)glycohydrolase is an upstream regulator of Ca2+ fluxes in oxidative cell death.
Oxidative DNA damage to cells activates poly(ADP-ribose)polymerase-1 (PARP-1) and the poly(ADP-ribose) formed is rapidly degraded to ADP-ribose by poly(ADP-ribose)glycohydrolase (PARG). Here we show that PARP-1 and PARG control extracellular Ca(2+) fluxes through melastatin-like transient receptor potential 2 channels (TRPM2) in a cell death signaling pathway. TRPM2 activation accounts for essentially the entire Ca(2+) influx into the cytosol, activating caspases and causing the translocation of apoptosis inducing factor (AIF) from the inner mitochondrial membrane to the nucleus followed by cell death. Abrogation of PARP-1 or PARG function disrupts these signals and reduces cell death. ADP-ribose-loading of cells induces Ca(2+) fluxes in the absence of oxidative damage, suggesting that ADP-ribose is the key metabolite of the PARP-1/PARG system regulating TRPM2. We conclude that PARP-1/PARG control a cell death signal pathway that operates between five different cell compartments and communicates via three types of chemical messengers: a nucleotide, a cation, and proteins.
Blenn
C
C
Institute of Pharmacology and Toxicology, University of Zurich-Vetsuisse, Winterthurerstrasse 260, Zurich, Switzerland.
Wyrsch
P
P
Bader
J
J
Bollhalder
M
M
Althaus
Felix R
FR
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects*; D002478:Cells, Cultured; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D005786:Gene Expression Regulation; D006026:Glycoside Hydrolases / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000494:pharmacology; D051379:Mice; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects*
D016877:Oxidants; D006861:Hydrogen Peroxide; D006026:Glycoside Hydrolases; C022407:poly ADP-ribose glycohydrolase; D020169:Caspases; D002118:Calcium