Arrest of replication by mammalian DNA polymerases α and β caused by chromium-DNA lesions

Bridgewater, Laura C.; Manning, Francis C. R.; Patierno, Steven R.

doi:10.1002/(sici)1098-2744(199812)23:4<201::aid-mc2>3.0.co;2-6

Cited by 52 publications

(18 citation statements)

References 30 publications

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“…Cr(VI) is also known to undergo reductive activation to convert Cr(VI) into a stable end-product Cr(III); which is known to participate in a variety of reactions that can cause DNA damage (Arslan et al, 1987). Cr(III) has been shown to produce DNA-DNA strand cross-links (O’Brien et al, 2001), and the ion can arrest the activity of individually isolated DNA polymerases in vitro , (Bridgewater et al, 1998). Studies examining the ability of chromium ion to induce mutations during DNA synthesis have been performed using individually purified DNA polymerases (Snow, 1991, 1994; Jatinder and Snow, 1998), and these suggest that Cr (III) can alter the fidelity with which individually purified DNA polymerases synthesize DNA on primed artificial DNA templates.…”

Section: Discussionmentioning

confidence: 99%

“…DNA primase, which is associated with DNA polymerase α initiates synthesis (Waga and Stillman, 1998) by laying down a short RNA primer on the DNA template before being displaced by DNA polymerase δ. Increasing concentrations of Cr(III), or Cr(VI) in the presence of reducing agents such as ascorbic acid, result in the arrest of DNA synthesis mediated in vitro by DNA polymerase α (Bridgewater et al,1998). Furthermore, during the initiation of DNA synthesis, it has been proposed that polymerase α is displaced shortly after beginning synthesis of the nascent DNA strand on both the leading and lagging DNA template strands (Waga and Stillman, 1998), and is replaced by polymerase δ.…”

Section: Discussionmentioning

confidence: 99%

“…Cr(III) is known to promote DNA cross-linking and DNA polymerase arrest (O’Brien et al, 2001). Cr(III)-induced DNA lesions decrease the fidelity of DNA replication in vitro (Snow, 1991, 1994; Singh and Snow, 1998), and have been shown to arrest in vitro DNA replication via inhibition of the activity of DNA polymerases involved in the replication process, (Bridgewater et al, 1994a, 1998). Following its transfection into human cells, Cr(III)-treated plasmid DNA also generates specific types of mutations, while undergoing replication (Tsou et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

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Chromium reduces the in vitro activity and fidelity of DNA replication mediated by the human cell DNA synthesome

Dai

Liu

Malkas

et al. 2009

Toxicology and Applied Pharmacology

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Hexavalent chromium Cr(VI) is known to be a carcinogenic metal ion, with a complicated mechanism of action. It can be found within our environment in soil and water contaminated by manufacturing processes. Cr(VI) ion is readily taken up by cells, and is recognized to be both genotoxic and cytotoxic; following its reduction to the stable trivalent form of the ion, chromium(Cr(III)), within cells. This form of the ion is known to impede the activity of cellular DNA polymerase and polymerase-mediated DNA replication. Here, we report the effects of chromium on the activity and fidelity of the DNA replication process mediated by the human cell DNA synthesome. The DNA synthesome is a functional multiprotein complex that is fully competent to carry-out each phase of the DNA replication process. The IC 50 of Cr(III) toward the activity of DNA synthesome-associated DNA polymerases α, δ and ε is 15, 45 and 125 μM, respectively. Cr(III) inhibits synthesome-mediated DNA synthesis (IC 50 =88 μM), and significantly reduces the fidelity of synthesome-mediated DNA replication. The mutation frequency induced by the different concentrations of Cr(III) ion used in our assays ranges from 2-13 fold higher than that which occurs spontaneously, and the types of mutations include single nucleotide substitutions, insertions, and deletions. Single nucleotide substitutions are the predominant type of mutation, and they occur primarily at GC base-pairs. Cr (III) ion produces a lower number of transition and a higher number of transversion mutations than occur spontaneously. Unlike Cr (III), Cr(VI) ion has little effect on the in vitro DNA synthetic activity and fidelity of the DNA synthesome, but does significantly inhibit DNA synthesis in intact cells. Cell growth and proliferation is also arrested by increasing concentrations of Cr(VI) ion. Our studies provide evidence indicating that the chromium ion induced decrease in the fidelity and activity of synthesome mediated DNA replication correlates with the genotoxic and cytotoxic effects of this metal ion; and promotes cell killing via inhibition of the DNA polymerase activity mediating the DNA replication and repair processes utilized by human cells.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Chromium reduces the in vitro activity and fidelity of DNA replication mediated by the human cell DNA synthesome

Dai

Liu

Malkas

et al. 2009

Toxicology and Applied Pharmacology

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“…Generally, inhalation of particulate chromium compounds results in lung injury and a marked inflammatory response in the lung [94–96]. Recently published studies from our laboratory show a pronounced inflammatory response in the lung to intranasal (IN) particulate zinc chromate administration [97,98]. Analysis of cells collected by bronchoalveolar lavage showed an increase in viable cells in the lung airways of BALB/cJ mice as early as 6 h after Cr(VI) exposure, which persisted for up to 24 h. Flow cytometric and cytospin studies determined that there was a significant 64.8% increase in neutrophils present after 6 h Cr(VI) exposure as compared to 9.6% in the saline-treated control mouse; while at the same time point, there was a significant decrease in the presence of macrophages from 90.4% in control mice, to 35.2% in Cr(VI)-treated animals [97].…”

Section: Mode Of Action Of Chromium Carcinogenesismentioning

confidence: 99%

Chromium genotoxicity: A double-edged sword

Nickens¹,

Patierno²,

Ceryak³

2010

Chemico-Biological Interactions

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321

175

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Certain forms of hexavalent chromium [Cr(VI)] are known respiratory carcinogens that induce a broad spectrum of DNA damage. Cr(VI)-carcinogenesis may be initiated or promoted through several mechanistic processes including, the intracellular metabolic reduction of Cr(VI) producing chromium species capable of interacting with DNA to yield genotoxic and mutagenic effects, Cr(VI)-induced inflammatory/immunological responses, and alteration of survival signaling pathways. Cr(VI) enters the cell through nonspecific anion channels, and is metabolically reduced by agents including ascorbate, glutathione, and cysteine to Cr(V), Cr(IV), and Cr(III). Cr(III) has a weak membrane permeability capacity and is unable to cross the cell membrane, thereby trapping it within the cell where it can bind to DNA and produce genetic damage leading to genomic instability. Structural genetic lesions produced by the intracellular reduction of Cr(VI) include DNA adducts, DNA strand breaks, DNA-protein crosslinks, oxidized bases, abasic sites, and DNA inter-and intrastrand crosslinks. The damage induced by Cr(VI) can lead to dysfunctional DNA replication and transcription, aberrant cell cycle checkpoints, dysregulated DNA repair mechanisms, microsatelite instability, inflammatory responses, and the disruption of key regulatory gene networks responsible for the balance of cell survival and cell death, which may all play an important role in Cr(VI) carcinogenesis. Several lines of evidence have indicated that neoplastic progression is a result of consecutive genetic/epigenetic changes that provide cellular survival advantages, and ultimately lead to the conversion of normal human cells to malignant cancer cells. This review is based on studies that provide a glimpse into Cr(VI) carcinogenicity via mechanisms including Cr(VI)-induced death-resistance, the involvement of DNA repair mechanisms in survival after chromium exposure, and the activation of survival signaling cascades in response to Cr(VI) genotoxicity.

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“…Furthermore, Cr treated caused the decrease of nucleotide excision repair mechanism, which develops cytotoxicity (36).…”

Section: Comet Proceduresmentioning

confidence: 99%

Chromium Inhibits in Vitro Viability and Steroidogenic in Ram Leydig Cells

Al-Bayati¹

2017

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One of an ecological hazardous agent Chromium; Cr (VI), The present experiment in vitro design to examine the mechanism of Leydig cell functions of Cr (VI) in ram testis, Cr (VI) treated groups demising cell growth behavior of exponential phase was upset of feeding time to Leydig cell in a dose-dependent manner, and induced mitochondria-dependent ATP depletion and subsequently apoptosis. Cr (VI) effect may be attributed, at least in part to DNA fragmentation increase DNA tail number and tail length of COMET as compared with control group. Furthermore, the properties of cell-specific regulation of cell membrane integrity had reduced and determinant cell concentration drop an.d reflected on the testosterone concentration were decreased as concentration-dependent manner, In conclusion, our results display the Cr (VI) is cytotoxic and impairs both viability and steroidogenic functions of Leydig cells in ram testis via actually different pathway direct affecting of viability and indirect on steroidogenic activity, succeeding in testicular performance. However, the definite modes of action of harmfulness are not evidently unknown and must be rechecked and studied in a different aspect.

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Arrest of replication by mammalian DNA polymerases α and β caused by chromium-DNA lesions

Cited by 52 publications

References 30 publications

Chromium reduces the in vitro activity and fidelity of DNA replication mediated by the human cell DNA synthesome

Chromium reduces the in vitro activity and fidelity of DNA replication mediated by the human cell DNA synthesome

Chromium genotoxicity: A double-edged sword

Chromium Inhibits in Vitro Viability and Steroidogenic in Ram Leydig Cells

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