Browsing by Subject "Oxidative DNA damage"

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    Mitochondrial reactive oxygen species are scavenged by Cockayne syndrome B protein in human fibroblasts without nuclear DNA damage
    (PNAS, 2014-09-16) Cleaver, James E.; Brennan-Minnella, Angela M.; Swanson, Raymond A.; Fong, Ka-wing; Chen, Junjie; Chou, Kai-ming; Chen, Yih-wen; Revet, Ingrid; Bezrookove, Vladimir; Department of Pharmacology and Toxicology, IU School of Medicine
    Cockayne syndrome (CS) is a human DNA repair-deficient disease that involves transcription coupled repair (TCR), in which three gene products, Cockayne syndrome A (CSA), Cockayne syndrome B (CSB), and ultraviolet stimulated scaffold protein A (UVSSA) cooperate in relieving RNA polymerase II arrest at damaged sites to permit repair of the template strand. Mutation of any of these three genes results in cells with increased sensitivity to UV light and defective TCR. Mutations in CSA or CSB are associated with severe neurological disease but mutations in UVSSA are for the most part only associated with increased photosensitivity. This difference raises questions about the relevance of TCR to neurological disease in CS. We find that CSB-mutated cells, but not UVSSA-deficient cells, have increased levels of intramitochondrial reactive oxygen species (ROS), especially when mitochondrial complex I is inhibited by rotenone. Increased ROS would result in oxidative damage to mitochondrial proteins, lipids, and DNA. CSB appears to behave as an electron scavenger in the mitochondria whose absence leads to increased oxidative stress. Mitochondrial ROS, however, did not cause detectable nuclear DNA damage even when base excision repair was blocked by an inhibitor of polyADP ribose polymerase. Neurodegeneration in Cockayne syndrome may therefore be associated with ROS-induced damage in the mitochondria, independent of nuclear TCR. An implication of our present results is that mitochondrial dysfunction involving ROS has a major impact on CS-B pathology, whereas nuclear TCR may have a minimal role.
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    Oxidative DNA Damage: A Role in Altering Neuronal Function
    (Scientific Archives, 2022) Behrouzi, Adib; Kelley, Mark R.; Fehrenbacher, Jill C.; Pharmacology and Toxicology, School of Medicine
    A role for oxidative stress in the etiology of myriad neuropathologies is well accepted. However, the specific effects of oxidative DNA damage in the onset or promotion of neuronal dysfunction have been less studied. In our recent publication by Behrouzi et al. (Oxidative DNA Damage and Cisplatin Neurotoxicity Is Exacerbated by Inhibition of OGG1 Glycosylase Activity and APE1 Endonuclease Activity in Sensory Neurons), inhibition of enzymes that play a role in repairing oxidative DNA damage exacerbated neurotoxic effects of the chemotherapeutic agent, cisplatin. In this Commentary, we aim to expand on the contribution of oxidative DNA damage to other neuropathologies within the peripheral and central nervous systems, including irritable bowel disease, aging and Alzheimer's disease, amyotrophic lateral sclerosis, and other neurodegenerative diseases. Consistently, clinical neuropathology and disease progression correlates with increases in oxidative DNA damage within clinical biopsies. Progress in animal models of these diseases has elucidated a causative role for oxidative DNA damage in disease progression, as dampening the DNA repair response exacerbates disease, whereas promoting DNA repair mitigates disease. Overall, this Commentary highlights the importance of expanding our studies on oxidative DNA damage in the nervous system, as enhancing oxidative DNA repair might prove to be a potential therapeutic target for the mitigation of neurodegeneration.