Overexpression of humanmutT homologue gene messenger RNA in renal-cell carcinoma: Evidence of persistent oxidative stress in cancer

Okamoto, Keigo; Toyokuni, Shinya; Kim, Wun-Jae; Ogawa, Osamu; Kakehi, Yoshiyuki; Arao, Shinji; Hayashi, Hiroshi; Yoshida, Osamu

doi:10.1002/(sici)1097-0215(19960208)65:4<437::aid-ijc7>3.0.co;2-y

Cited by 88 publications

(41 citation statements)

References 29 publications

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“…Consistently, in mth1-deficient mice, the incidence of spontaneous carcinogenesis in lung, liver, and stomach increases up to severalfold in comparison to that in wild type mice (19). Furthermore, the increased accumulation of 8-oxo-dG in human cancerous tissues including brain tumors is generally coincidental with the increased expression of hMTH1 protein (44,45). As well as for carcinogenesis, oxidative damage has been considered to be one of the major causes for neurodegenerative diseases, and we found the regional accumulation of 8-oxo-dG and altered expression of hMTH1 in patients with various neurodegenerative diseases.…”

Section: Discussionsupporting

confidence: 73%

A Molecular Basis for the Selective Recognition of 2-Hydroxy-dATP and 8-Oxo-dGTP by Human MTH1

Sakai¹,

Furuichi²,

Takahashi³

et al. 2002

Journal of Biological Chemistry

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MTH1 hydrolyzes oxidized purine nucleoside triphosphates such as 8-oxo-dGTP, 8-oxo-dATP, 2-hydroxydATP, and 2-hydroxy rATP to monophosphates, and thus avoids errors caused by their misincorporation during DNA replication or transcription, which may result in carcinogenesis or neurodegeneration. This substrate specificity for oxidized purine nucleoside triphosphates was investigated by mutation analyses based on the sequence comparison with the Escherichia coli homolog, MutT, which hydrolyzes only 8-oxo-dGTP and 8-oxo-rGTP but not oxidized forms of dATP or ATP. Neither a replacement of the phosphohydrolase module of MTH1 with that of MutT nor deletions of the C-terminal region of MTH1, which is unique for MTH1, altered the substrate specificity of MTH1. In contrast, the substitution of residues at position Trp-117 and Asp-119 of MTH1, which showed apparent chemical shift perturbations with 8-oxo-dGDP in NMR analyses but are not conserved in MutT, affected the substrate specificity. Trp-117 is essential for MTH1 to recognize both 8-oxodGTP and 2-hydroxy-dATP, whereas Asp-119 is only essential for recognizing 2-hydroxy-dATP, thus suggesting that origins of the substrate-binding pockets for MTH1 and MutT are different.Endogenous oxidation of nucleic acids, such as DNA, RNA, and their precursors by reactive oxygen species generated under normal metabolic conditions, appear to induce spontaneous mutagenesis and cell death, which have been implicated in aging and various diseases including cancer and neuronal degeneration (1). It has been established that 8-oxoguanine (8-oxoG), an oxidized form of guanine, is highly mutagenic and one of the main endogenous sources for spontaneous mutagenesis. During DNA replication, 8-oxo-deoxyguanosine triphosphate (8-oxo-dGTP) can be inserted into the nascent strand opposite adenine and cytosine in the template, with almost equal efficiency, thus resulting in an A:T to C:G transversion mutation (2, 3). Accumulation of 8-oxoG in double-stranded DNA is caused by direct oxidization of guanine in DNA or incorporation of precursor nucleotide, 8-oxo-dGTP, which is generated in nucleotide pools with oxidation of dGTP (4). A misincorporation of oxidized nucleotides also occurs during transcription, thus leading to an accumulation of abnormal proteins (5, 6).To eliminate such deleterious oxidized nucleotides, organisms come equipped with elaborate mechanisms. In Escherichia coli the MutT protein hydrolyzes 8-oxo-dGTP and 8-oxoguanosine triphosphate (8-oxo-rGTP) to the monophosphate form, thus avoiding the misincorporation of mutagenic nucleotides into DNA and mRNA during replication and transcription (7,8). The absence of the mutT gene increases the spontaneous occurrence of A:T to C:G transversion a thousandfold over the wild type level (7, 9), and further increases the occurrence of transcriptional errors (6). Enzymatic activities similar to that of MutT had been identified in both human and other mammalian cells (10 -13). Based on the similarity in their amino acid sequences to that of Mut...

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Section: Discussionsupporting

confidence: 73%

A Molecular Basis for the Selective Recognition of 2-Hydroxy-dATP and 8-Oxo-dGTP by Human MTH1

Sakai¹,

Furuichi²,

Takahashi³

et al. 2002

Journal of Biological Chemistry

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“…This is confirmed by the finding that overexpression of MTH1 in embryonic fibroblasts derived from mismatch-repair-defective msh2 -/-mice restores their high spontaneous mutation rate to normal [138]. An increase in MTH1 expression has been observed in renal [139], brain [140], lung [141] and several other tumours and this is consistent with the concept that cancer cells suffer from persistent oxidative stress. Interestingly, a polymorphic variant of MTH1 (V83M) has been associated with an increased frequency of stomach cancer and correlates with p53 mutation [142].…”

Section: Human and Mouse Nudix Hydrolasessupporting

confidence: 69%

The Nudix hydrolase superfamily

McLennan

2005

Cell. Mol. Life Sci.

536

544

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Nudix hydrolases are found in all classes of organism and hydrolyse a wide range of organic pyrophosphates, including nucleoside di- and triphosphates, dinucleoside and diphosphoinositol polyphosphates, nucleotide sugars and RNA caps, with varying degrees of substrate specificity. Some superfamily members, such as Escherichia coli MicrotT, have the ability to degrade potentially mutagenic, oxidised nucleotides while others control the levels of metabolic intermediates and signalling compounds. In prokaryotes and simple eukaryo tes, the number of Nudix genes varies from 0 to over 30, reflecting the metabolic complexity and adaptability of the organism. Mammals have around 24 Nudix genes, several of which encode more than one variant. This review integrates the sizeable recent literature on these proteins with information from global functional genomic studies to provide some insights into the possible roles of different superfamily members in cellular metabolism and homeostasis and to stimulate discussion and further research into this ubiquitous protein family.

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“…Subsequently, human MTH1 (hMTH1) has been also shown to hydrolyze 2-hydroxy-2 -deoxyadenosine triphosphate and 8-hydroxy-2 -deoxyadenosine triphosphate [21,22]. A number of RAS-expressing human cancers such as lung cancer and renal carcinoma have been shown to overexpress MTH1 [23][24][25]. Suppression of the mutator phenotype in mismatch repair-defective colorectal cancer cells has been achieved by overexpressing MTH1 [26].…”

Section: Introductionmentioning

confidence: 99%

Addiction to MTH1 protein results in intense expression in human breast cancer tissue as measured by liquid chromatography-isotope-dilution tandem mass spectrometry

et al. 2015

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Overexpression of humanmutT homologue gene messenger RNA in renal-cell carcinoma: Evidence of persistent oxidative stress in cancer

Cited by 88 publications

References 29 publications

A Molecular Basis for the Selective Recognition of 2-Hydroxy-dATP and 8-Oxo-dGTP by Human MTH1

A Molecular Basis for the Selective Recognition of 2-Hydroxy-dATP and 8-Oxo-dGTP by Human MTH1

The Nudix hydrolase superfamily

Addiction to MTH1 protein results in intense expression in human breast cancer tissue as measured by liquid chromatography-isotope-dilution tandem mass spectrometry

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