Mitochondrial reactive oxygen species are scavenged by Cockayne syndrome B protein in human fibroblasts without nuclear DNA damage
| Autor: | Ka Wing Fong, Kai Ming Chou, Ingrid Revet, Raymond A. Swanson, Angela M. Brennan-Minnella, Vladimir Bezrookove, Yih Wen Chen, James E. Cleaver, Junjie Chen |
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| Rok vydání: | 2014 |
| Předmět: |
Mitochondrial ROS
Ultraviolet Rays DNA damage DNA repair Intellectual and Developmental Disabilities (IDD) hydrogen peroxide Neurodegenerative Biology Mitochondrion medicine.disease_cause Cockayne syndrome Cell Line oxidative DNA damage Histones Rare Diseases comet assay Rotenone Ethidium Genetics medicine 2.1 Biological and endogenous factors Humans Aetiology Poly-ADP-Ribose Binding Proteins Cell Nucleus Multidisciplinary gamma H2Ax DNA Helicases Hydrogen Peroxide Base excision repair Biological Sciences Fibroblasts medicine.disease Molecular biology Brain Disorders Mitochondria DNA Repair Enzymes bromate γH2Ax Reactive Oxygen Species Carrier Proteins Oxidation-Reduction Oxidative stress DNA Damage Nucleotide excision repair |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America, vol 111, iss 37 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.1414135111 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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