MTH1, an oxidized purine nucleoside triphosphatase, prevents the cytotoxicity and neurotoxicity of oxidized purine nucleotides

Division of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Fukuoka 812-8582, Japan.
DNA Repair (Impact Factor: 3.11). 08/2006; 5(7):761-72. DOI: 10.1016/j.dnarep.2006.03.003
Source: PubMed


In human and rodent cells, MTH1, an oxidized purine nucleoside triphosphatase, efficiently hydrolyzes oxidized dGTP, GTP, dATP and ATP such as 2'-deoxy-8-oxoguanosine triphosphate (8-oxo-dGTP) and 2'-deoxy-2-hydroxyadenosine triphosphate (2-OH-dATP) in nucleotide pools, thus avoiding their incorporation into DNA or RNA. MTH1 is expressed in postmitotic neurons as well as in proliferative tissues, and it is localized both in the mitochondria and nucleus, thus suggesting that MTH1 plays an important role in the prevention of the mutagenicity and cytotoxicity of such oxidized purines as 8-oxoG which are known to accumulate in the cellular genome. Our recent studies with MTH1-deficient mice or cells revealed that MTH1 efficiently minimizes accumulation of 8-oxoG in both nuclear and mitochondrial DNA in the mouse brain as well as in cultured cells, thus contributing to the protection of the brain from oxidative stress.

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    • "Indeed, an increase in neuronal RNA oxidation is correlated with decreased expression of MTH1 in the hippocampus of senescenceaccelerated SAMP8 mice as well as patients with AD (Song et al. 2011). However, in other studies, an increased expression of MTH1 in the vulnerable neuronal populations has been reported in the brains of AD (Furuta et al. 2001) and PD (Shimura-Miura et al. 1999), which may indicate a compensatory up-regulation of the MTH1 against oxidative stress (Nakabeppu et al. 2006). "
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    ABSTRACT: An age-associated increase in oxidative damage to nucleic acids, predominantly to RNA, has been recently demonstrated in neurons of human and rodent brains, which may play a fundamental role in the development of age-associated neurodegeneration. Indeed, more prominent levels of neuronal RNA oxidation compared to normal aging have been described in neurodegenerative disorders including Alzheimer disease, Parkinson disease, dementia with Lewy bodies, and amyotrophic lateral sclerosis. Moreover, oxidative damage to RNA has been found also in cellular and animal model of neurodegeneration. Oxidative RNA modification can occur not only in protein-coding RNAs but also in non-coding RNAs that are recently revealed to contribute towards the complexity of the mammalian brain. It has been hypothesized that RNA oxidation causes aberrant expression of microRNAs and proteins and subsequently initiates inappropriate cell fate pathways. While less lethal than mutations in the genome and not inheritable, such sublethal damage to cells might be associated with underlying mechanisms of degeneration, especially age-associated neurodegeneration. Of particular interest, the accumulating evidence obtained from studies on either human samples or experimental models coincidentally suggests that RNA oxidation is a feature in neurons of aging brain and more prominently observed in vulnerable neurons at early-stage of age-associated neurodegenerative disorders, indicating that RNA oxidation actively contributes to the background, the onset, and the development of the disorders. Further investigations aimed at understanding of the processing mechanisms related to oxidative RNA damage and its consequences may provide significant insights into the pathogenesis of neurodegenerative disorders and lead to better therapeutic strategies.
    Full-text · Article · Jun 2012 · Neurotoxicity Research
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    • "Hydrolase MTH1 is other important enzyme preventing incorporation of oxidized purine nucleotide triphosphates in DNA (Nakabeppu et al., 2006). Knockout of this enzyme in mice resulted in increased frequency of lung, stomach and liver tumours with age (Halliwell, 2007). "

    Full-text · Chapter · Apr 2012
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    • "A solution structure of MTH1 has previously been reported [1]. MTH1 is present both in the nucleus and the mitochondria where it also minimizes accumulation of 8-oxo- guanine in DNA [2]. Indeed, MTH1À/À knockout mice or cells siR- NA depleted for MTH1 accumulate 8-oxo-G in their DNA and display a slight increase in mutation and cancer rates [3] [4] [5]. "
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    ABSTRACT: MTH1 hydrolyzes oxidized nucleotide triphosphates, thereby preventing them from being incorporated into DNA. We here present the structures of human MTH1 (1.9Å) and its complex with the product 8-oxo-dGMP (1.8Å). Unexpectedly MTH1 binds the nucleotide in the anti conformation with no direct interaction between the 8-oxo group and the protein. We suggest that the specificity depends on the stabilization of an enol tautomer of the 8-oxo form of dGTP. The binding of the product induces no major structural changes. The structures reveal the mode of nucleotide binding in MTH1 and provide the structural basis for inhibitor design.
    Full-text · Article · Aug 2011 · FEBS letters
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