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

Abstract

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.

Quantification of Nicotine and Cotinine in Plasma, Saliva, and Urine by HPLC Method in Chewing Tobacco Users

“…The treatment of smokeless tobacco extract induced higher concentrations of reactive oxygen species and malondialdehyde in cultured human oral mucosa fibroblasts cells (Li et al, 2018). Peroxynitrite, though not a free radical by chemical nature, is a powerful oxidant that reacts with proteins, DNA, lipids, oxidative injury, committing cells to necrosis or apoptosis (Islam et al, 2015). The levels of peroxynitrites are increased in plasma of chewing tobacco users.…”

Chronic PARP-1 inhibition reduces carotid vessel remodeling and oxidative damage of the dorsal hippocampus in spontaneously hypertensive rats

“…The latter process results in diminished NO bioavailability [8, 51] and also contributes to the over-activation of PARP-1 via oxidants induced damage of the DNA [12, 26, 47, 52]. Excess formation of poly(ADP-ribose) polymers (PAR) alters nuclear NAD + metabolism, originally considered as the main initiator of the caspase-independent form of cell death by cellular metabolic instability and a further boost in ROS production via mitochondrial dysfunction [13, 53, 54].…”

“…In addition to the NAD + preserving effects, it prevents nucleus-to-mitochondria death signaling [47] and also interferes with stress-related biases in intracellular signaling routes [55, 57]. Amongst these, activation of JNK is considered to be a key event in the process of parthanatos via mitochondria damaging properties resulting in AIF release [47, 52, 58–60]. In our study, nuclear translocation of AIF was observed in control hypertensive animals (Fig 2C), indicating PARP-1 over activation initiated cell death events [47].…”

“…Pharmacological inhibition of PARP-1 attenuated this process. Elevated nitrosative stress in this area also contributes to the accumulation of DNA damage by oxidative base modifications [52] assessed by 8-oxG immunohistochemistry (Fig 3F). These processes resulted in excess activation of PARP-1 enzyme in CA1 pyramidal neurons of control hypertensive animals (Fig 3G), leading to PARP-1 dependent cell loss.…”

pH‐Dependent Nitrotyrosine Formation in Ribonuclease A is Enhanced in the Presence of Polyethylene Glycol (PEG)

“…[7] PN has a toxic effect on the biological system by directly reactingw ith the sulfydryl groups at ar ate that is 10 3 times greater than hydrogen peroxide at pH 7.4 and affects cellular metabolism through lipid peroxidation. [8] In addition PN alters the function of mitochondria [9] and promotes DNA damage [10] due to its high reactivity.T he SOD enzyme also reacts with peroxynitrite due to the presence of Cu in its active site which results in the inhibition of enzymatic activity ands imultaneousg eneration of the toxic nitronium ion (NO 2 + ). [7] Changes in the protein structurei np resence of PN are often ar esult of oxidative modification of certain residues like methionine andc ysteine.…”