Overexpression of <i>hMTH1</i> mRNA: a molecular marker of oxidative stress in lung cancer cells

Kennedy, Christopher H.; Cueto, Rafael; Belinsky, Steven A.; Lechner, John F.; Pryor, William A.

doi:10.1016/s0014-5793(98)00505-5

Cited by 82 publications

(54 citation statements)

References 22 publications

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“…Structure of MTH1-MTH1 adopts an ␣ϩ␤ fold with four long loops consisting of seven ␤-strands and two ␣-helices as follows: ␤A (residues 5-11), ␤B (17)(18)(19)(20)(21)(22), ␤C (67-74), ␤D (80 -87), ␤E (102-107), ␤F (132-139), ␤G (146 -153), ␣I (44 -58), and ␣II (120 -130) (Fig. 1B and Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Mice lacking the Mth1 gene exhibit an increase in the occurrence of spontaneous carcinogenesis in liver and, to a lesser extent, in lung and stomach, suggesting that an accumulation of 8-oxo-dGTP, which is a substrate of MTH1, may trigger malignant transformation in vivo (16). The detrimental effect of 8-oxo-dGTP in eukaryotes is also implied from the observation that an increase in the accumulation of 8-oxo-G in DNA, together with an increase in the expression of MTH1, is found not only in human cancer tissue (17,18) but also in degenerating neurons, as determined by immunohistochemical analyses (19,20).…”

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confidence: 99%

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Structure of Human MTH1, a Nudix Family Hydrolase That Selectively Degrades Oxidized Purine Nucleoside Triphosphates

Mishima

Sakai

Itoh

et al. 2004

Journal of Biological Chemistry

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Oxygen radicals generated through normal cellular respiration processes can cause mutations in genomic and mitochondrial DNA. Human MTH1 hydrolyzes oxidized purine nucleoside triphosphates, such as 8-oxodGTP and 2-hydroxy-dATP, to monophosphates, thereby preventing the misincorporation of these oxidized nucleotides during replication. Here we present the solution structure of MTH1 solved by multidimensional heteronuclear NMR spectroscopy. The protein adopts a fold similar to that of Escherichia coli MutT, despite the low sequence similarity between these proteins outside the conserved Nudix motif. The substrate-binding pocket of MTH1, deduced from chemical shift perturbation experiments, is located at essentially the same position as in MutT; however, a pocket-forming helix is largely displaced in MTH1 (ϳ9 Å) such that the shape of the pocket differs between the two proteins. Detailed analysis of the pocket-forming residues enabled us to identify Asn 33 as one of the key residues in MTH1 for discriminating the oxidized form of purine, and mutation of this residue modifies the substrate specificity. We also show that MTH1 catalyzes hydrolysis of 8-oxo-dGTP through nucleophilic substitution of water at the ␤-phosphate.Cellular DNA continually suffers assault from exogenous and endogenous agents that cause a wide variety of DNA modifications. Such modifications are often detrimental to the cell, leading to mutagenesis and carcinogenesis. Numerous enzymes have the important task of maintaining the integrity of DNA. These enzymes are generally well conserved from bacteria to humans.Oxygen radicals, which are spontaneously generated during normal cellular metabolism or by ionizing radiation or various chemicals, often attack nucleic acids, thereby generating modified bases in DNA (1, 2). Among these modified bases, the most abundant species, 8-oxo-7,8-dihydroguanine (8-oxo-G), 1 can pair with both cytosine and adenine with almost equal efficiency and consequently can induce A:T to C:G and G:C to T:A transversion mutations (3-5).Organisms are equipped with elaborate mechanisms to counteract the mutagenic effects of 8-oxo-G. In Escherichia coli, two glycosylases encoded by the mutM and mutY genes function to prevent mutation caused by the presence of 8-oxo-G in DNA. MutM protein removes 8-oxo-G paired with cytosine, whereas MutY protein removes adenine paired with 8-oxo-G (6 -9). To prevent further mutation through the presence of 8-oxo-dGTP, MutT hydrolyzes 8-oxo-dGTP to its monophosphate form, thereby preventing the oxidized purine from being misincorporated into genomic DNA. The importance of this enzyme has been underscored by the observation that deficiency of the mutT gene increases the occurrence of A:T to C:G transversion mutations 1000-fold (10, 11). The mechanism concerning the coordinated action of MutM, MutY, and MutT, which constitute the so-called "GO system," has been well characterized in prokaryotes. Protein factors with enzymatic activities similar to those of MutM, MutY, and MutT have been identified ...

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Structure of Human MTH1, a Nudix Family Hydrolase That Selectively Degrades Oxidized Purine Nucleoside Triphosphates

Mishima

Sakai

Itoh

et al. 2004

Journal of Biological Chemistry

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“…DNA damage may be done by ROS, like hydroxyl radicals formed by the Fenton´s reaction. Several studies have revealed an interesting correlation between tumor size and the amount of 8-OHdG (8-hydroxy-2'-desoxyguanosine; also known as 8-oxodeoxyguanosine, 8-oxo-dG), a nucleotide modified by the activity of free radicals (Kennedy et al, 1998;Yano et al, 2009). The promotion stage is characterized by the expansion of initiated cells, stimulating cell proliferation and/or apoptosis inhibition.…”

Section: Ros and Carcinogenesismentioning

confidence: 99%

Oxidative Therapy Against Cancer

Miguel¹,

Cordero²

2012

Oxidative Stress and Diseases

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“…The human protein, whose enzymatic activities and amino acid sequences are similar to those of MutT, was named human MutT homologue 1 (hMTH1) [6]. It has been reported that hMTH1 gene expression is a molecular marker of oxidative stress [7]. The level of hMTH1 protein was found to increase in mitochondria isolated from postmyocardial infarction hearts, as oxidative stress increased [8].…”

mentioning

confidence: 99%

Oxidative stress in lung epithelial cells from patients with idiopathic interstitial pneumonias

Kuwano¹,

Nakashima²,

Inoshima³

et al. 2003

Eur Respir J

113

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Overexpression of hMTH1 mRNA: a molecular marker of oxidative stress in lung cancer cells

Cited by 82 publications

References 22 publications

Structure of Human MTH1, a Nudix Family Hydrolase That Selectively Degrades Oxidized Purine Nucleoside Triphosphates

Structure of Human MTH1, a Nudix Family Hydrolase That Selectively Degrades Oxidized Purine Nucleoside Triphosphates

Oxidative Therapy Against Cancer

Oxidative stress in lung epithelial cells from patients with idiopathic interstitial pneumonias

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