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Poly(ADP-ribose)glycohydrolase is an upstream regulator of Ca 2+ fluxes in oxidative cell death

Poly(ADP-ribose)glycohydrolase is an upstream regulator of Ca 2+ fluxes in oxidative cell death,10.1007/s00018-010-0533-1,Experientia,C. Blenn,P. Wyrs

Poly(ADP-ribose)glycohydrolase is an upstream regulator of Ca 2+ fluxes in oxidative cell death  
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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 Ca2+ fluxes through melastatin-like transient receptor potential 2 channels (TRPM2) in a cell death signaling pathway. TRPM2 activation accounts for essentially the entire Ca2+ 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 Ca2+ 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.
Journal: Experientia , vol. 68, no. 8, pp. 1455-1466, 2011
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