Biological Significance of the Defense Mechanisms against Oxidative Damage in Nucleic Acids Caused by Reactive Oxygen Species: From Mitochondria to Nuclei
| Autor: | Yohei Tominaga, Daisuke Tsuchimoto, Seiki Hirano, Akimasa Ichinoe, Yusaku Nakabeppu, Kunihiko Sakumi, Yasuhito Ide, Masato Furuichi, Daisuke Yoshimura, Mizuki Ohno |
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| Rok vydání: | 2004 |
| Předmět: |
DNA Repair
DNA repair DNA damage Biology General Biochemistry Genetics and Molecular Biology Cell Line DNA Glycosylases AP endonuclease Mice chemistry.chemical_compound History and Philosophy of Science MUTYH Neoplasms Nucleic Acids DNA-(Apurinic or Apyrimidinic Site) Lyase Animals Humans Genetic Predisposition to Disease N-Glycosyl Hydrolases General Neuroscience Deoxyguanosine Neurodegenerative Diseases Base excision repair Endonucleases Multifunctional Enzymes Oxidative Stress chemistry Biochemistry 8-Hydroxy-2'-Deoxyguanosine DNA glycosylase biology.protein Nucleic acid Reactive Oxygen Species Oxidation-Reduction DNA DNA Damage |
| Zdroj: | Annals of the New York Academy of Sciences. 1011:101-111 |
| ISSN: | 1749-6632 0077-8923 |
| DOI: | 10.1196/annals.1293.011 |
| Popis: | In mammalian cells, more than one genome in a single cell has to be maintained throughout the entire life of the cell, namely, one in the nucleus and the other in the mitochondria. The genomes and their precursor nucleotides are highly exposed to reactive oxygen species, which are inevitably generated as a result of the respiratory function in mitochondria. To counteract such oxidative damage in nucleic acids, cells are equipped with several defense mechanisms. Modified nucleotides in the nucleotide pools are hydrolyzed, thus avoiding their incorporation into DNA or RNA. Damaged bases in DNA with relatively small chemical alterations are mainly repaired by the base excision repair (BER) system, which is initiated by the excision of damaged bases by specific DNA glycosylases. MTH1 protein hydrolyzes oxidized purine nucleoside triphosphates, such as 8-oxo-dGTP, 8-oxo-dATP, and 2-hydroxy (OH)-dATP to the monophosphates, and MTH1 are located in the cytoplasm, mitochondria, and nucleus. We observed an increased susceptibility to spontaneous carcinogenesis in Mth1-deficient mice and an alteration of MTH1 expression along with the accumulation of 8-oxo-dG in patients with various neurodegenerative diseases. Enzymes for the BER pathway, namely, 8-oxoG DNA glycosylase (OGG1), 2-OH-A/adenine DNA glycosylase (MUTYH), and AP endonuclease (APEX2) are also located both in the mitochondria and in the nuclei, and the expression of mitochondrial OGG1 is altered in patients with various neurodegenerative diseases. We also observed increased susceptibilities to spontaneous carcinogenesis in OGG1 and MUTYH-deficient mice. The increased occurrence of lung tumor in OGG1-deficient mice was completely abolished by the concomitant disruption of the Mth1 gene. |
| Databáze: | OpenAIRE |
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