Pathophysiological Role of Peroxynitrite Induced DNA Damage in Human Diseases: A Special Focus on Poly(ADP-ribose) Polymerase (PARP)

Peroxynitrite is formed in biological systems when nitric oxide and superoxide rapidly interact at near equimolar ratio. Peroxynitrite, though not a free radical by chemical nature, is a powerful oxidant which reacts with proteins, DNA and lipids. These reactions trigger a wide array of cellular responses ranging from subtle modulations of cell signaling to overwhelming oxidative injury, committing cells to necrosis or apoptosis. The present review outlines the various peroxynitrite-induced DNA modifications with special mention to the formation of 8-nitroguanine and 8-oxoguanine as well as the induction of DNA single strand breakage. Low concentrations of peroxynitrite cause apoptotic death, whereas higher concentrations cause necrosis with cellular energetics (ATP and NAD(+)) serving as control between the two modes of cell death. DNA damage induced by peroxynitrite triggers the activation of DNA repair systems. A DNA nick sensing enzyme, poly(ADP-ribose) polymerase-1 (PARP-1) becomes activated upon detecting DNA breakage and it cleaves NAD(+) into nicotinamide and ADP-ribose and polymerizes the latter on nuclear acceptor proteins. Over-activation of PARP induced by peroxynitrite consumes NAD(+) and consequently ATP decreases, culminating in cell dysfunction, apoptosis or necrosis. This mechanism has been implicated in the pathogenesis of various diseases like diabetes, cardiovascular diseases and neurodegenerative diseases. In this review, we have discussed the cytotoxic effects (apoptosis and necrosis) of peroxynitrite in the etiology of the mentioned diseases, focusing on the role of PARP in DNA repair in presence of peroxynitrite.