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PARP-1 and the Shape of Cell Death

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Poly(ADP-Ribosyl)ation

Part of the book series: Molecular Biology Intelligence Unit ((MBIU))

Abstract

The following review discusses the mechanisms through which cell death may be regulated by poly(ADP-ribose) polymerase-1(PARP-1), a nuclear enzyme that catalyzes the synthesis of long, branching (ADP-ribose)n polymers from NAD+. Cell death may be caused by nongenotoxic or genotoxic stimuli. Whereas the former mainly occurs in the form of apoptosis, genotoxic exposure can cause both apoptotic and necrotic cell death, depending on the intensity of DNA damage. Although PARP-1 has been shown to play a role in some models of apoptosis triggered by nongenotoxic stimuli, most studies have found PARP-1 to be dispensable for this form of cell death. However, in many models of necrosis caused by genotoxic damage, PARP-1 appears to be a key player causing necrotic cell death by depleting NAD+ (the substrate of PARP) and ATP (used in futile attempt to resynthesize NAD+). The author and his colleagues were among the first to show that upon reaching a genotoxic threshold, PARP-1 ovaractivation switches the “default” apoptotic death to necrosis, likely via cellular energetic depletion. PARP activation has also been shown by us, and later by others, to trigger mitochondrial alterations such as mitochondrial membrane depolarization and secondary superoxide production during necrosis or AIF-mediated, caspase-independent apoptosis. It appears that a finely tuned network involving multilevel mitochondrial-nuclear cross talk between PARP-1, p53, the mitochondrial electron transport chain, energy carriers, as well as nuclear and mitochondrial death mediators regulates genotoxic stress-induced cell death.

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  1. Department of Medical Chemistry Medical and Health Science Center, University of Debrecen, Debrecen, Hungary

    László Virág

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© 2006 Landes Bioscience and Springer Science+Business Media

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Virág, L. (2006). PARP-1 and the Shape of Cell Death. In: Poly(ADP-Ribosyl)ation. Molecular Biology Intelligence Unit. Springer, Boston, MA. https://doi.org/10.1007/0-387-36005-0_13

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