Prevention of the Mutagenicity and Cytotoxicity of Oxidized Purine Nucleotides

Nakabeppu, Yusaku; Behmanesh, Mehrdad; Yamaguchi, Hideyo; Yoshimura, Daisuke; Sakumi, Kunihiko

doi:10.1007/978-0-387-72974-9_3

Cited by 10 publications

(11 citation statements)

References 64 publications

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“…ROS are highly reactive molecules that can attack various biomolecules such as lipids, proteins, and nucleic acids. Among all nucleobases, guanine is the most susceptible to oxidation by ROS 7 resulting in the generation of 8-oxoguanine (8-oxoG). 8-oxoG is the major oxidised base in both nucleotide pools and polymerised DNA or RNA 8 9 .…”

mentioning

confidence: 99%

8-Oxoguanine accumulation in mitochondrial DNA causes mitochondrial dysfunction and impairs neuritogenesis in cultured adult mouse cortical neurons under oxidative conditions

Leon

Sakumi

Castillo

et al. 2016

Sci Rep

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Oxidative stress and mitochondrial dysfunction are implicated in aging-related neurodegenerative disorders. 8-Oxoguanine (8-oxoG), a common oxidised base lesion, is often highly accumulated in brains from patients with neurodegenerative disorders. MTH1 hydrolyses 8-oxo-2′-deoxyguanosine triphosphate (8-oxo-dGTP) to 8-oxo-dGMP and pyrophosphate in nucleotide pools, while OGG1 excises 8-oxoG paired with cytosine in DNA, thereby minimising the accumulation of 8-oxoG in DNA. Mth1/Ogg1-double knockout (TO-DKO) mice are highly susceptible to neurodegeneration under oxidative conditions and show increased accumulation of 8-oxoG in mitochondrial DNA (mtDNA) in neurons, suggesting that 8-oxoG accumulation in mtDNA causes mitochondrial dysfunction. Here, we evaluated the contribution of MTH1 and OGG1 to the prevention of mitochondrial dysfunction during neuritogenesis in vitro. We isolated cortical neurons from adult wild-type and TO-DKO mice and maintained them with or without antioxidants for 2 to 5 days and then examined neuritogenesis. In the presence of antioxidants, both TO-DKO and wild-type neurons exhibited efficient neurite extension and arborisation. However, in the absence of antioxidants, the accumulation of 8-oxoG in mtDNA of TO-DKO neurons was increased resulting in mitochondrial dysfunction. Cells also exhibited poor neurite outgrowth with decreased complexity of neuritic arborisation, indicating that MTH1 and OGG1 are essential for neuritogenesis under oxidative conditions.

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confidence: 99%

8-Oxoguanine accumulation in mitochondrial DNA causes mitochondrial dysfunction and impairs neuritogenesis in cultured adult mouse cortical neurons under oxidative conditions

Leon

Sakumi

Castillo

et al. 2016

Sci Rep

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“…A:T to T:A or T:A to A:T substitutions are distinctly independent of the regions with a high density of 8-oxoG (Supplemental Table 2), suggesting that 8-oxoG is somehow involved in base substitutions from or toward a G:C base pair. The accumulation of 8-oxoG in DNA is a result of the incorporation of 8-oxo-dGTP generated in nucleotide pools as well as of the direct oxidation of guanine in DNA, thus primarily causing A:T to C:G or G:C to T:A transversions (Egashira et al 2002;Arai et al 2003;Nakabeppu et al 2006). Recently, it has been shown that 8-oxoG in DNA induces various substitutions not only at the 8-oxoG site, but also in the neighboring regions through error-prone DNA replication in addition to the typical transversions (Efrati et al 1999).…”

Section: Discussionmentioning

confidence: 99%

A genome-wide distribution of 8-oxoguanine correlates with the preferred regions for recombination and single nucleotide polymorphism in the human genome

Ohno¹,

et al. 2006

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8-Oxoguanine (8-oxoG), a major spontaneous form of oxidative DNA damage, is considered to be a natural cause of genomic diversity in organisms because of its mutagenic potential. The steady-state level of 8-oxoG in the nuclear genome of a human cell has been estimated to be several residues per 10 6 guanines. In the present study, to clarify the genome-wide distribution of 8-oxoG in the steady state, we performed fluorescence in situ detection of 8-oxoG on human metaphase chromosomes using a monoclonal antibody. Multiple dot-like signals were observed on each metaphase chromosome. We then mapped the position of the signal at megabase resolution referring to the cytogenetically identified chromosomal band, and demonstrated that 8-oxoG is unevenly distributed in the normal human genome and that the distribution pattern is conserved among different individuals. Moreover, we found that regions with a high frequency of recombination and single nucleotide polymorphisms (SNPs) are preferentially located within chromosomal regions with a high density of 8-oxoG. Our findings suggest that 8-oxoG is one of the main causes of frequent recombinations and SNPs in the human genome, which largely contribute to the genomic diversity in human beings.

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“…In addition to 8‐oxo‐dGTP, MTH1 efficiently hydrolyzes other oxidized purine nucleoside triphosphates (Nakabeppu et al, 2006a), so MTH1‐null mice accumulated a larger amount of these triphosphates in dopaminergic nerve terminals after MPTP administration, resulting in an increased accumulation of oxidized purines in mitochondrial DNA (Fig. 10).…”

Section: Mth1 Deficiency Increased Degeneration Of Striatal Nerve Termentioning

confidence: 99%

“…MTH1 efficiently hydrolyzes oxidized purine ribonucleotides such as 2‐OH‐ATP, 8‐oxo‐ATP, and to a lesser extent 8‐oxo‐GTP (Nakabeppu et al, 2006a). As a result, cellular dysfunction might also be caused by their incorporation into RNA.…”

Section: Future Perspectivesmentioning

confidence: 99%

Oxidative damage in nucleic acids and Parkinson's disease

Nakabeppu

Tsuchimoto

Yamaguchi

et al. 2007

J of Neuroscience Research

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Oxidative DNA lesions, such as 8-oxoguanine (8-oxoG), accumulate in nuclear and mitochondrial genomes during aging, and such accumulation can increase dramatically in patients with Parkinson's disease (PD). To counteract oxidative damage to nucleic acids, human and rodents are equipped with three distinct enzymes. One of these, MTH1, hydrolyzes oxidized purine nucleoside triphosphates, such as 8-oxo-2'-deoxyguanosine triphosphate and 2-hydroxy-2'-deoxyadenosine triphosphate, to their monophosphate forms. The other two enzymes are 8-oxoG DNA glycosylase encoded by the OGG1 gene and adenine/2-hydroxyadenine DNA glycosylase encoded by the MUTYH gene. We have shown a significant increase in 8-oxoG in mitochondrial DNA as well as an elevated expression of MTH1, OGG1, and MUTYH in nigrostriatal dopaminergic neurons of PD patients, suggesting that the buildup of these lesions may cause dopamine neuron loss. We established MTH1-null mice and found that MTH1-null fibroblasts were highly susceptible to cell death caused by H(2)O(2) characterized by pyknosis and electron-dense deposits in the mitochondria, and that this was accompanied by an ongoing accumulation of 8-oxoG in nuclear and mitochondrial DNA. We also showed that MTH1-null mice exhibited an increased accumulation of 8-oxoG in striatal mitochondrial DNA, followed by more extreme neuronal dysfunction after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine administration than that of wild-type mice. In conclusion, oxidative damage in nucleic acids is likely to be a major risk factor for Parkinson's disease, indicating that a solid understanding of the defense mechanisms involved will enable us to develop new strategies for protecting the brain against oxidative stress.

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Prevention of the Mutagenicity and Cytotoxicity of Oxidized Purine Nucleotides

Cited by 10 publications

References 64 publications

8-Oxoguanine accumulation in mitochondrial DNA causes mitochondrial dysfunction and impairs neuritogenesis in cultured adult mouse cortical neurons under oxidative conditions

8-Oxoguanine accumulation in mitochondrial DNA causes mitochondrial dysfunction and impairs neuritogenesis in cultured adult mouse cortical neurons under oxidative conditions

A genome-wide distribution of 8-oxoguanine correlates with the preferred regions for recombination and single nucleotide polymorphism in the human genome

Oxidative damage in nucleic acids and Parkinson's disease

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