Formation, Detection, and Role In Carcinogenesis of Ethenobases in Dna

Bartsch, Helmut; Barbin, Alain; Marion, Marie‐Jeanne; Nair, J. Somarajan; Guichard, Yves

doi:10.3109/03602539409029802

Cited by 144 publications

(101 citation statements)

References 58 publications

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“…In contrast, analysis of healthy human and rodent liver samples by immunoaffinity-P 32 -postlabeling methods revealed the presence of only low background levels of these etheno-DNA adducts. 24,25 Furthermore, using a highly sensitive immunoenrichment-high-pressure liquid chromatography method for quantifying etheno-DNA adducts excreted in urine, a significantly higher amount of ⑀dA was found in ALD patients compared with healthy subjects (H. Bartsch, J. Nair, unpublished observation).…”

Section: Discussionmentioning

confidence: 99%

Ethanol‐induced cytochrome P4502E1 causes carcinogenic etheno‐DNA lesions in alcoholic liver disease†‡

et al. 2009

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Oxidative stress is thought to play a major role in the pathogenesis of hepatocellular cancer (HCC), a frequent complication of alcoholic liver disease (ALD). However, the underlying mechanisms are poorly understood. In hepatocytes of ALD patients, we recently detected by immunohistochemistry significantly increased levels of carcinogenic etheno-DNA adducts that are formed by the reaction of the major lipid peroxidation product, 4-hydroxynonenal (4-HNE) with nucleobases. In the current study, we show that protein-bound 4-HNE and etheno-DNA adducts both strongly correlate with cytochrome P450 2E1 (CYP2E1) expression in patients with ALD (r ‫؍‬ 0.9, P < 0.01). Increased levels of etheno-DNA adducts were also detected in the liver of alcohol-fed lean ( E xcess consumption of alcohol is widespread inWestern countries and, in the United States, alcohol abuse affects approximately 18 million adults. 1 The consumption of more than 80 g ethanol per day for more than 10 years increases the risk for hepatocellular carcinoma (HCC) by approximately fivefold. 2 Worldwide, HCC is one of the most common malignant tumors, ranking as the seventh most prevalent in men and the ninth in women. The risk for HCC in decompensated alcohol-induced cirrhosis is approximately 1% to 2% per year. 2 Although the evolution of alcohol-related HCC involves several factors, 3,4 including the presence of cirrhosis, oxidative stress, disturbed DNA methylation, and defective retinoic acid signaling, the precise mechanisms at a molecular level by which alcohol causes HCC are poorly understood. Recently, the International Agency for Research on Cancer has classified ethanol as a human (group 1) carcinogen, because it induces HCC (among other tumors) in animals and increases the risk for developing HCC in humans. 3,5,6

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Section: Discussionmentioning

confidence: 99%

Ethanol‐induced cytochrome P4502E1 causes carcinogenic etheno‐DNA lesions in alcoholic liver disease†‡

et al. 2009

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“…These chemicals include vinyl compounds, haloaldehydes, ␣-haloketones, haloalkanes, halothioketenes, haloketenes, and products of lipid peroxidation (17,18). After the work presented above was completed, Saparbaev and Laval purified a protein from E. coli that removes 3,N 4 -ethenocytosine (⑀C) from DNA and showed that it was Mug (11).…”

Section: Resultsmentioning

confidence: 99%

The Role of the Escherichia coli Mug Protein in the Removal of Uracil and 3,N 4-Ethenocytosine from DNA

Lutsenko

Bhagwat

1999

Journal of Biological Chemistry

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The human thymine-DNA glycosylase has a sequence homolog in Escherichia coli that is described to excise uracils from U⅐G mismatches (Gallinari, P., and Jiricny, J. (1996) Nature 383, 735-738) and is named mismatched uracil glycosylase (Mug). It has also been described to remove 3,N 4 -ethenocytosine (⑀C) from ⑀C⅐G mismatches (Saparbaev, M., and Laval, J. (1998) Proc. Natl. Acad. Sci. U. S. A. 95, 8508 -8513). We used a mug mutant to clarify the role of this protein in DNA repair and mutation avoidance. We find that inactivation of mug has no effect on C to T or 5-methylcytosine to T mutations in E. coli and that this contrasts with the effect of ung defect on C to T mutations and of vsr defect on 5-methylcytosine to T mutations. Even under conditions where it is overproduced in cells, Mug has little effect on the frequency of C to T mutations. Because uracil-DNA glycosylase (Ung) and Vsr are known to repair U⅐G and T⅐G mismatches, respectively, we conclude that Mug does not repair U⅐G or T⅐G mismatches in vivo. A defect in mug also has little effect on forward mutations, suggesting that Mug does not play a role in avoiding mutations due to endogenous damage to DNA in growing E. coli. Cell-free extracts from mug ؉ ung cells show very little ability to remove uracil from DNA, but can excise ⑀C. The latter activity is missing in extracts from mug cells, suggesting that Mug may be the only enzyme in E. coli that can remove this mutagenic adduct. Thus, the principal role of Mug in E. coli may be to help repair damage to DNA caused by exogenous chemical agents such as chloroacetaldehyde.Cytosine is the most unstable of the four bases in DNA and deaminates hydrolytically to create U⅐G mismatches. If unrepaired, uracil can pair with an adenine during replication causing a C to T mutation. For this reason, cells contain uracil-DNA glycosylase (Ung), an enzyme that removes the uracil and initiates its replacement with cytosine. The importance of Ung in mutation avoidance is evidenced by the observation that ung strains of Escherichia coli (1) and yeast (2) accumulate C to T mutations.Cytosines methylated at position 5 similarly deaminate to create T⅐G mismatches, which are not subject to repair by Ung. In E. coli, a specialized mismatch correction process called very short patch repair corrects these mispairs to C⅐G (3). The key enzyme in this repair pathway is a sequence-specific, mismatch-specific endonuclease, Vsr, which hydrolyzes the phosphodiester linkage preceding the mismatched T (4). No eukaryotic sequence homologs of this enzyme have been reported; instead a DNA glycosylase is thought to serve the same function (5). This enzyme excises thymines from T⅐G mismatches (6) and prefers mismatches that are followed by a G⅐C pairs (7,8). This enzyme, thymine-DNA glycosylase (TDG), 1 could prevent mutations when 5-methylcytosines within CG dinucleotides deaminate to thymine.The cDNA for TDG was cloned and its sequence was determined (9). Remarkably, a sequence homolog of this protein was found in E. coli and Serratia ma...

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“…6 -Ethenoadenine (⑀A) 1 and other exocyclic DNA adducts such as 3,N 4 -ethenocytosine (⑀C) or N 2 ,3-ethenoguanine (⑀G) are introduced to DNA by the human carcinogen vinyl chloride and related compounds (1). These DNA lesions are also formed during interaction with DNA of the peroxidation products of -6-polyunsaturated fatty acids (2).…”

Section: Nmentioning

confidence: 99%

“…In the same studies only 0.3% of 7,8-dihydro-8-oxoguanine (8-oxoG) residues induced GC 3 TA transversions (11). Treatment of mammalian cells with compounds inducing etheno-DNA adducts additionally triggers chromosomal aberrations and sister chromatid exchanges (1).…”

Section: Nmentioning

confidence: 99%

The Pyrimidine Ring-opened Derivative of 1,N 6-Ethenoadenine Is Excised from DNA by theEscherichia coli Fpg and Nth Proteins

Speina

Cieśla

Wójcik

et al. 2001

Journal of Biological Chemistry

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It was previously shown that 1,N 6 -ethenoadenine (⑀A) in DNA rearranges into a pyrimidine ring-opened derivative of 20-fold higher mutagenic potency in Escherichia coli (AB1157 lac⌬U169) than the parental ⑀A (Basu, A. K., Wood, M. L., Niedernhofer, L. J., Ramos, L. A., and Essigmann, J. M. (1993) Biochemistry 32, 12793-12801). We have found that at pH 7.0, the stability of the N-glycosidic bond in ⑀dA is 20-fold lower than in dA. In alkaline conditions, but also at neutrality, ⑀dA depurinates or converts into products: ⑀dA 3 B 3 C 3 D. Compound B is a product of water molecule addition to the C(2)-N(3) bond, which is in equilibrium with a product of N(1)-C(2) bond rupture in ⑀dA. Compound C is a deformylated derivative of ring-opened compound B, which further depurinates yielding compound D. Ethenoadenine degradation products are not recognized by human N-alkylpurine-DNA glycosylase, which repairs ⑀A. Product B is excised from oligodeoxynucleotides by E. coli formamidopyrimidine-DNA glycosylase (Fpg) and endonuclease III (Nth). Repair by the Fpg protein is as efficient as that of 7,8-dihydro-8-oxoguanine when the excised base is paired with dT and dC but is less favorable when paired with dG and dA. Ethenoadenine rearrangement products are formed in oligodeoxynucleotides also at neutral pH at the rate of about 2-3% per week at 37°C, and therefore they may contribute to ⑀A mutations.

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Formation, Detection, and Role In Carcinogenesis of Ethenobases in Dna

Cited by 144 publications

References 58 publications

Ethanol‐induced cytochrome P4502E1 causes carcinogenic etheno‐DNA lesions in alcoholic liver disease†‡

Ethanol‐induced cytochrome P4502E1 causes carcinogenic etheno‐DNA lesions in alcoholic liver disease†‡

The Role of the Escherichia coli Mug Protein in the Removal of Uracil and 3,N 4-Ethenocytosine from DNA

The Pyrimidine Ring-opened Derivative of 1,N 6-Ethenoadenine Is Excised from DNA by theEscherichia coli Fpg and Nth Proteins

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