Mechanisms protecting genomic integrity from damage caused by reactive oxygen species: Implications for carcinogenesis and neurodegeneration (第12回公開シンポジウム「活性酸素の分子病態学」)

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In mammalian cells, more than one genome in a single cell has to be maintained throughout the entire life of the cell, one in the nucleus and the other in the mitochondria. It seems likely that 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, these cells are equipped with several defense mechanisms. Modified nucleotides in the nucleotide pools are hydrolyzed, thus avoiding their incorporation during synthesis of 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. Human MTH1 (hMTH1) protein hydrolyzes oxidized purine nucleoside triphosphates, such as 8-oxo-dGTP, 8-oxo-dATP and 2-hydroxy (OH)-dATP to the monophosphates. In human cells, multi-forms of hMTH1 polypeptides are located in the cytoplasm, mitochondria and nucleus, and their synthesis is regulated by both alternative splicing of the transcripts and the alternative initiation of their translation, both of which are further altered by a single nucleotide polymorphism. We observed an increased susceptibility to spontaneous carcinogenesis in mth1 deficient mice, and alteration of MTH1 expression along with accumulation of 8-oxo-dG in patients with various neurodegenerative diseases. Human enzymes for the BER pathway, namely 8-oxoG DNA glycosylase (hOGG1) , 2-OH-A/adenine DNA glycosylase (hMYH) , and a novel AP endonuclease (hAPE2) are also located in the mitochondria as well as the nuclei in human cells, and the expression of mitochondrial OGG1 is altered in patients with various neurodegenerative diseases. Furthermore, MYH and APE2 have a functional PCNA binding motif, thus suggesting that the PCNA-dependent post-replicative BER plays an essential role in the repair of such misincorporated bases as 2-0H-dA or adenine opposite 8-oxoG in templates.
日本環境変異原学会の論文
2001-12-22

Mechanisms protecting genomic integrity from damage caused by reactive oxygen species: Implications for carcinogenesis and neurodegeneration (第12回公開シンポジウム「活性酸素の分子病態学」)

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