Lipid peroxidation as a potential endogenous source for the formation of exocyclic DNA adducts

Chung, Fung‐Lung; Chen, Hauh‐Jyun Candy; Nath, Raghu G.

doi:10.1093/carcin/17.10.2105

Cited by 331 publications

(284 citation statements)

References 39 publications

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“…However, initial experiments in our laboratory have indicated only a barely detectable, if any, interaction between ANPG and hHR23A and -B under the conditions used. 2 A, schematic representation of the 5Ј-flap structure DNA template containing either a C⅐G or a ⑀C⅐G base pair and possible elongation products: 41-mer, full-sized product; 25-mer, ⑀C termination product; 20-mer, ANPG⅐⑀C termination product; 13-mer, 5Ј-32 P-labeled primer. B, 10 nM 5Ј-32 P-labeled C⅐G (lanes 1-8) and/or ⑀C⅐G (lanes 9 -16) primer/ template were incubated with (lanes 3-8 and lanes [11][12][13][14][15][16] or without (lanes 1-2 and lanes 9 -10) 1 unit of Klenow fragment, and the primer extension reaction was performed for 5 min at 37°C.…”

Section: Discussionmentioning

confidence: 99%

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Hijacking of the Human Alkyl-N-purine-DNA Glycosylase by 3,N4-Ethenocytosine, a Lipid Peroxidation-induced DNA Adduct

Gros¹,

Maksimenko

Privezentzev³

et al. 2004

Journal of Biological Chemistry

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Lipid peroxidation generates aldehydes, which react with DNA bases, forming genotoxic exocyclic etheno(⑀)-adducts. E-bases have been implicated in vinyl chlorideinduced carcinogenesis, and increased levels of these DNA lesions formed by endogenous processes are found in human degenerative disorders. E-adducts are repaired by the base excision repair pathway. Here, we report the efficient biological hijacking of the human alkyl-N-purine-DNA glycosylase (ANPG) by 3,N 4 -ethenocytosine (⑀C) when present in DNA. Unlike the ethenopurines, ANPG does not excise, but binds to ⑀C when present in either double-stranded or single-stranded DNA. We developed a direct assay, based on the fluorescence quenching mechanism of molecular beacons, to measure a DNA glycosylase activity. Molecular beacons containing modified residues have been used to demonstrate that the ⑀C⅐ANPG interaction inhibits excision repair both in reconstituted systems and in cultured human cells. Furthermore, we show that the ⑀C⅐ANPG complex blocks primer extension by the Klenow fragment of DNA polymerase I. These results suggest that ⑀C could be more genotoxic than 1,N 6 -ethenoadenine (⑀A) residues in vivo. The proposed model of ANPG-mediated genotoxicity of ⑀C provides a new insight in the molecular basis of lipid peroxidation-induced cell death and genome instability in cancer.

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Section: Discussionmentioning

confidence: 99%

“…tion, which target DNA bases forming genotoxic exocyclic adducts such as 1,N 6 -ethenoadenine (⑀A) and 3,N 4 -ethenocytosine (⑀C) (1)(2)(3). Etheno(⑀)-adducts are also formed by reaction with epoxides that result from the metabolism of various industrial pollutants such as vinyl chloride and vinyl carbamate (4).…”

mentioning

confidence: 99%

Hijacking of the Human Alkyl-N-purine-DNA Glycosylase by 3,N4-Ethenocytosine, a Lipid Peroxidation-induced DNA Adduct

Gros¹,

Maksimenko

Privezentzev³

et al. 2004

Journal of Biological Chemistry

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“…The etheno bridges completely block normal Watson-Crick base pairing and are cytotoxic and potentially mutagenic [27]. These DNA adducts can arise endogeneously under oxidative stress in human cells, in particular when DNA is exposed to side products of lipid peroxidation [64][65][66]. The accumulation of these DNA lesions has been linked to aging and various diseases.…”

Section: Oxidative Repair Of Exocyclic Dna Adductsmentioning

confidence: 99%

Oxidative dealkylation DNA repair mediated by the mononuclear non-heme iron AlkB proteins

Mishina

2006

Journal of Inorganic Biochemistry

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DNA can be damaged by various intracellular and environmental alkylating agents to produce alkylation base lesions. These base damages, if not repaired promptly, may cause genetic changes that lead to diseases such as cancer. Recently, it was discovered that some of the alkylation DNA base damage can be directly removed by a family of proteins called the AlkB proteins that utilize a mononuclear non-heme iron(II) and α-ketoglutarate as cofactor and cosubstrate. These proteins activate dioxygen and perform an unprecedented oxidative deal-kylation of the alkyl adducts on DNA heteroatoms. This review summarizes the discovery of this activity and the recent research advances in studying this unique DNA repair pathway. The focus is placed on the chemical mechanism and function of these proteins. KeywordsDNA repair; AlkB; ABH; Direct repair; Mononuclear non-heme iron; Dioxygenase; Oxidative dealkylation; Demethylation Direct repair of alkylation DNA damageCellular DNA is subject to nonenzymatic alkylation (methylation) by environmental or chemical mutagens, resulting in adducts that are toxic and mutagenic [1][2][3][4][5][6]. Organisms have evolved a variety of mechanisms to repair these mutagenic damages. Escherichia coli (E. coli) responds to this threat by activating an adaptive responsive pathway, mediated by the E. coli Ada protein [7]. Upon receiving a methyl group from the damaged DNA, Ada turns into a transcriptional activator and activates its own expression and that of the alkB gene and two other genes, alkA and aidB ( Fig. 1(a)) [4,7,8]. The upregulated Ada is a bifunctional protein, which uses a N-terminal Cys38 residue to remove a methyl group fromS p -methylphosphotriester and a C-terminal Cys321 residue to remove a methyl adduct from O 6 -methylguanaine ( Fig. 1(b)) [9][10][11]. Both repair functions are irreversible and represent rare examples of direct repair of DNA damage. AlkA is a glycosylase that cleaves methylated bases from DNA and performs the first step of the well-known base excision repair of base lesions [12][13][14]. The precise function of AidB is still unknown. The function of the last member of this adaptive response, AlkB, also remained unknown until recently despite extensive research efforts. E. coli AlkBSince the first genetic study in 1983 isolating the E. coli mutant with specific sensitivity to the alkylating agent methylmethane sulfonate, MMS [15], the activity of AlkB was undisclosed The Fe II /αKG-dependent dioxygenase superfamily is widespread from bacteria to humans [19] and is the largest known non-heme iron protein family [20][21][22][23]. It represents a wide diversity of enzymes that catalyze the hydroxylation of unactivated C-H groups of a variety of substrates by coupling reductive activation of dioxygen with a decarbox-ylation of αKG, the co-substrate, to succinate. In the event of oxidation one of the oxygen atoms from O 2 is incorporated into the succinate and the other as a hydroxyl in the product [24]. This group of enzymes is known for their importance in ...

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“…These DNA-reactive aldehydes in turn form mutagenic exocyclic DNA adducts, including 1,N 6 -ethenodeoxyadenosine (⑀dA) and 3,N 4 -ethenodeoxycytidine (⑀dC). [8][9][10] Several enzyme systems are capable of producing ROS, including the mitochondrial respiratory chain, the cytosolic enzymes xanthine oxidase, and aldehyde oxidase, as well as the microsomal cytochrome P450 -dependent mono-oxygenases. Among the latter, cytochrome P450 2E1 (CYP2E1) is involved in alcohol-mediated generation of oxidative stress.…”

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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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Lipid peroxidation as a potential endogenous source for the formation of exocyclic DNA adducts

Cited by 331 publications

References 39 publications

Hijacking of the Human Alkyl-N-purine-DNA Glycosylase by 3,N4-Ethenocytosine, a Lipid Peroxidation-induced DNA Adduct

Hijacking of the Human Alkyl-N-purine-DNA Glycosylase by 3,N4-Ethenocytosine, a Lipid Peroxidation-induced DNA Adduct

Oxidative dealkylation DNA repair mediated by the mononuclear non-heme iron AlkB proteins

Ethanol-induced cytochrome P4502E1 causes carcinogenic etheno-DNA lesions in alcoholic liver disease

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