Arsenite induces DNA-protein crosslinks and cytokeratin expression in the WRL-68 human hepatic cell line

Ramírez, Patricia; Razo, Luz M. Del; Gutiérrez-Ruı́z, Ma.Concepción; Gonsebatt, María E.

doi:10.1093/carcin/21.4.701

Cited by 71 publications

(37 citation statements)

References 23 publications

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“…Similarly UVR, particularly UVA, generates ROS in the skin also leading to oxidative DNA damage (11). Oxidative stress plays a significant role in UVR-induced skin carcinogenesis (12), and excessive ROS generation causes a range of DNA damages, including DNA strand breaks (13), DNA-protein cross-links (14), deletion mutations (15), and 8-hydroxyl-2Ј-deoxyguanine (8-OHdG) (16). 8-OHdG is a biomarker of oxidative stress and the major mutagenic form of oxidative DNA damage (17).…”

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confidence: 99%

Inhibition of Poly(ADP-ribose) Polymerase-1 by Arsenite Interferes with Repair of Oxidative DNA Damage

Ding

Liu

Cooper

et al. 2009

Journal of Biological Chemistry

134

139

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Arsenic enhances skin tumor formation when combined with other carcinogens, including UV radiation (UVR). In this study we report that low micromolar concentrations of arsenite synergistically increases UVR-induced oxidative DNA damage in human keratinocytes as detected by 8-hydroxyl-2-deoxyguanine (8-OHdG) formation. Poly(ADP-ribose) polymerase-1 (PARP-1) is involved in base excision repair, a process that repairs 8-OHdG lesions. Arsenite suppresses UVR-induced PARP-1 activation in a concentration-dependent manner. Inhibition of PARP-1 activity by 3-aminobenzamide or small interfering RNA silencing of PARP-1 expression significantly increases UVR-induced 8-OHdG formation, suggesting that inhibition of PARP-1 activity by arsenite contributes to oxidative DNA damage. PARP-1 is a zinc finger protein, and mass spectrometry analysis reveals that arsenite can occupy a synthetic apopeptide representing the first zinc finger of PARP-1 (PARPzf). When the PARPzf peptide is preincubated with Zn(II) followed by incubation with increasing concentrations of arsenite, the ZnPARPzf signal is decreased while the AsPARPzf signal intensity is increased as a function of arsenite dose, suggesting a competition between zinc and arsenite for the same binding site. Addition of Zn(II) abolished arsenite enhancement of UVR-stimulated 8-OHdG generation and restored PARP-1 activity. Our findings demonstrate that arsenite inhibits oxidative DNA damage repair and suggest that interaction of arsenite with the PARP-1 zinc finger domain contributes to the inhibition of PARP-1 activity by arsenite. Arsenite inhibition of poly-(ADP-ribosyl)ation is one likely mechanism for the reported cocarcinogenic activities of arsenic in UVR-induced skin carcinogenesis.Arsenic is a naturally occurring element that is present in food, soil, and water (1, 2). Environmental or occupational exposures to arsenic are associated with both acute and chronic toxic effects in humans, including increased incidence of skin, lung, liver, and urinary tract cancers (3). Although human epidemiological data link inorganic arsenic in drinking water with an elevated risk of non-melanoma skin cancer (4), arsenic as a sole agent is not an effective skin carcinogen in animal models (5). However, arsenite enhances tumor development in animals pretreated with other carcinogens (6), chronically stimulated by growth factors (7), or co-treated with UV radiation (UVR) 2 (8). It has been reported that sodium arsenite concentration as low as 1.25 mg/liter (10 M) in drinking water enhances UVRinduced tumorigenicity in mice (8), but the mechanisms underlying this observation are not fully understood.Arsenite exposure generates reactive oxygen species (ROS), and we have directly demonstrated that the production of O 2. , H 2 O 2 , and ⅐ OH in arsenite-exposed keratinocytes is associated with DNA damage (9, 10). Similarly UVR, particularly UVA, generates ROS in the skin also leading to oxidative DNA damage (11). Oxidative stress plays a significant role in UVR-induced skin carcinogenesis (12...

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mentioning

confidence: 99%

Inhibition of Poly(ADP-ribose) Polymerase-1 by Arsenite Interferes with Repair of Oxidative DNA Damage

Ding

Liu

Cooper

et al. 2009

Journal of Biological Chemistry

134

139

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“…Many endogenous compounds (e.g., metabolites of lipid peroxidation) as well as environmental agents are reactive with both DNA and proteins and thus can produce covalent linkage between these two types of macromolecules (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13). DNA-protein crosslinks (DPCs) represent a relatively abundant form of DNA damage as evidenced by data indicating that the background level of DPCs in human white blood cells ranged from 0.5 to 4.5 per 10 7 bases (1).…”

mentioning

confidence: 99%

Incision of DNA–protein crosslinks by UvrABC nuclease suggests a potential repair pathway involving nucleotide excision repair

Minko

Zou

Lloyd

2002

Proc. Natl. Acad. Sci. U.S.A.

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DNA-protein crosslinks (DPCs) arise in biological systems as a result of exposure to a variety of chemical and physical agents, many of which are known or suspected carcinogens. The biochemical pathways for the recognition and repair of these lesions are not well understood in part because of methodological difficulties in creating site-specific DPCs. Here, a strategy for obtaining site-specific DPCs is presented, and in vitro interactions of the Escherichia coli nucleotide excision repair (NER) UvrABC nuclease at sites of DPCs are investigated. To create site-specific DPCs, the catalytic chemistry of the T4 pyrimidine dimer glycosylase͞apurinic͞apyrimidinic site lyase (T4-pdg) has been exploited, namely, its ability to be covalently trapped to apurinic͞apyrimidinic sites within duplex DNA under reducing conditions. Incubation of the DPCs with UvrABC proteins resulted in DNA incision at the 8th phosphate 5 and the 5th and 6th phosphates 3 to the protein-adducted site, generating as a major product of the reaction a 12-mer DNA fragment crosslinked with the protein. The incision occurred only in the presence of all three protein subunits, and no incisions were observed in the nondamaged complementary strand. The UvrABC nuclease incises DPCs with a moderate efficiency. The proper assembly and catalytic function of the NER complex on DNA containing a covalently attached 16-kDa protein suggest that the NER pathway may be involved in DPC repair and that at least some subset of DPCs can be removed by this mechanism without prior proteolytic degradation.I n cells, DNA is tightly associated with a variety of proteins that serve both to maintain the structural organization of the genetic material and to coordinate cellular processes including replication, repair, recombination, and transcription. Many endogenous compounds (e.g., metabolites of lipid peroxidation) as well as environmental agents are reactive with both DNA and proteins and thus can produce covalent linkage between these two types of macromolecules (1-13). DNA-protein crosslinks (DPCs) represent a relatively abundant form of DNA damage as evidenced by data indicating that the background level of DPCs in human white blood cells ranged from 0.5 to 4.5 per 10 7 bases (1). An age-related accumulation of DPCs has also been observed in mouse organs (2), supporting the hypothesis that oxidative mechanisms contribute to the formation of these DNA damages (2, 3). DPC levels increase dramatically upon exposure to a variety of physical or chemical agents, including UV light (4), ionizing radiation (5), ␤-propiolactone (6), aldehydes (1, 7-9), arsenite (10), ferric nitrilotriacetate (11), chromate (12), nickel (13), and others. Chemotherapeutic agents, such as cisplatin (12,14), bisplatinum (15), and neocarcinostatin (16), have also been shown to induce DPC formation. Exposure to several DPC-inducing agents gives rise to genotoxic and carcinogenic effects, and for some agents, such as formaldehyde, their primary mutagenic effects are believed to be mediated through the ...

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“…Seven of these proteins were identified as various cytokeratin isoforms. It has been reported that cytokeratins were among the proteins cross-linked to DNA after exposure to arsenite in WRL-68 human hepatic cells (Ramírez et al, 2000), suggesting the existence of DNAcytokeratin cross-links. Strikingly, we found that more proteins migrated to the bottom of the tube after the CsCl gradient centrifugation.…”

Section: Discussionmentioning

confidence: 99%

Cytokeratin-RNA Cross-Linking Mediated by the Antitumor Aminoflavone, 5-Amino-2,3-fluorophenyl-6,8-difluoro-7-methyl-4H-1-benzopyran-4-one

Meng¹,

Meng²,

Veenstra³

et al. 2008

J Pharmacol Exp Ther

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Aminoflavone (AF) is an anticancer drug in early clinical trials, and its antiproliferative activity involves the induction of DNA-protein cross-links. To identify the proteins cross-linked to nucleic acids, cesium chloride (CsCl) gradient centrifugation was used to isolate proteins tightly bound to nucleic acids in AF-treated human breast carcinoma MCF-7 cells. The identified proteins included structural proteins (several cytokeratins), transcription regulators, and stress response proteins. The identification of the cytokeratins was validated using direct immunoblotting of the high-density CsCl (nucleic acid) fractions isolated from AF-treated cells. Ribonuclease A pretreatment caused the cytokeratin signal in the heaviest CsCl fractions to disappear, suggesting that AF mediates RNA-cytokeratin cross-links. Additional experiments using radiolabeled AF showed that AF formed adducts with total RNA and mRNA with similar affinity to that of DNA. Moreover, 18S RNA was selectively pulled down using an anti-cytokeratin antibody after AF treatment. Consistent with the formation of these adducts, we found that AF inhibits RNA and protein synthesis in a dose-and time-dependent manner. This study provides evidence for the formation of AF-mediated cytokeratin-RNA cross-links and the presence of cytokeratin-RNA complexes. Thus, in addition to its anticancer activity, AF might be a useful molecular probe to study the potential role of cytokeratins in the subcellular localization and metabolism of RNA.

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Arsenite induces DNA-protein crosslinks and cytokeratin expression in the WRL-68 human hepatic cell line

Cited by 71 publications

References 23 publications

Inhibition of Poly(ADP-ribose) Polymerase-1 by Arsenite Interferes with Repair of Oxidative DNA Damage

Inhibition of Poly(ADP-ribose) Polymerase-1 by Arsenite Interferes with Repair of Oxidative DNA Damage

Incision of DNA–protein crosslinks by UvrABC nuclease suggests a potential repair pathway involving nucleotide excision repair

Cytokeratin-RNA Cross-Linking Mediated by the Antitumor Aminoflavone, 5-Amino-2,3-fluorophenyl-6,8-difluoro-7-methyl-4H-1-benzopyran-4-one

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