Uranyl Acetate as a Direct Inhibitor of DNA-Binding Proteins

Hartsock, Wendy J; Cohen, Jennifer D.; Segal, David J.

doi:10.1021/tx600347k

Cited by 42 publications

(26 citation statements)

References 45 publications

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“…Xeroderma Pigmentosum, Complementation Group A (XPA) has a single C4 zinc finger that is sensitive to other carcinogenic metals such as arsenic (Piatek et al, 2008; Zhou et al, 2011; Hudson et al, 2015) and zinc content of XPA was reduced after treatment with UA. UA was previously reported to interfere with the DNA binding capacity of the C 2 H 2 zinc finger protein specificity protein 1 (Sp1) (Hartsock et al, 2007) and UA treatment caused zinc loss from this protein as well as another C2H2 zinc finger protein, aprataxin (APTX). The IC 50 values for zinc loss were between 1 and 3 μM for each of these zinc finger proteins suggesting that UA may interfere with DNA repair at much lower concentrations than required to cause DNA damage and cytotoxicity.…”

Section: Resultsmentioning

confidence: 99%

“…There is limited evidence that uranium may interact with zinc finger proteins. One study demonstrated that at concentrations equal to or greater than 10 μM, uranyl acetate (UA) disrupted the DNA binding activity of two purified zinc finger proteins, Aart and specificity protein (Sp)1 in vitro (Hartsock et al, 2007). Furthermore, poly(ADP-ribose) polymerase-1 (PARP-1) was identified as a uranium binding protein using affinity chromatography and mass spectrometry approaches (Dedieu et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of poly(ADP-ribose)polymerase-1 and DNA repair by uranium

Cooper

Dashner

Tsosie

et al. 2016

Toxicology and Applied Pharmacology

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Uranium has radiological and non-radiological effects within biological systems and there is increasing evidence for genotoxic and carcinogenic properties attributable to uranium through its heavy metal properties. In this study, we report that low concentrations of uranium (as uranyl acetate; <10 μM) is not cytotoxic to human embryonic kidney cells or normal human keratinocytes; however, uranium exacerbates DNA damage and cytotoxicity induced by hydrogen peroxide, suggesting that uranium may inhibit DNA repair processes. Concentrations of uranyl acetate in the low micromolar range inhibited the zinc finger DNA repair protein poly(ADP-ribose) polymerase (PARP)-1 and caused zinc loss from PARP-1 protein. Uranyl acetate exposure also led to zinc loss from the zinc finger DNA repair proteins Xeroderma Pigmentosum, Complementation Group A (XPA) and aprataxin (APTX). In keeping with the observed inhibition of zinc finger function of DNA repair proteins, exposure to uranyl acetate enhanced retention of induced DNA damage. Co-incubation of uranyl acetate with zinc largely overcame the impact of uranium on PARP-1 activity and DNA damage. These findings present evidence that low concentrations of uranium can inhibit DNA repair through disruption of zinc finger domains of specific target DNA repair proteins. This may provide a mechanistic basis to account for the published observations that uranium exposure is associated with DNA repair deficiency in exposed human populations.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Inhibition of poly(ADP-ribose)polymerase-1 and DNA repair by uranium

Cooper

Dashner

Tsosie

et al. 2016

Toxicology and Applied Pharmacology

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“…AP1 and NF-κB, through a nonspecific protein domain interaction manner. 57 Cadmium (Cd 2+ ) has been reported to inhibit the activity of mismatch repair (MMR) complex Msh2-Msh6 via binding at multiple nonspecific binding sites of this MMR complex. 58 This directly and indirectly damaged DNA must be repaired correctly to allow it to duplicate accurately.…”

Section: Dna Damage Responses To Genotoxicantsmentioning

confidence: 99%

Autophagy as the effector and player in DNA damage response of cells to genotoxicants

2015

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Autophagy is a highly conserved pathway in eukaryotic cells induced by a variety of stimuli to remove superfluous or damaged organelles or abnormally aggregated proteins to maintain cellular homeostasis.A remarkable progress in our understanding of autophagy has been made in the past decade, not only regarding the molecular mechanism, but also its fundamental roles in the biological effects of various environmental stresses or the development of some human diseases. The genome of eukaryotic cells is constantly threatened by endogenous and exogenous genotoxic factors. Research in recent years has demonstrated that autophagy is not only one of the fundamental effects of genotoxicants but also a critical player in DNA damage response to genotoxic stress. A series of DNA damage response (DDR) proteins including ATM, p53, PARP-1, DNA-PKcs, TIP60, and so on have been demonstrated to play important roles in DNA damage induced autophagy, which functions as a protective measure to promote cell survival. Autophagy was also shown to play roles in the cellular responses to DNA damage, e.g. cell cycle regulation, apoptosis. Although the importance of autophagy in DDR has been recognized, there are still a lot of questions to answer. For example, how does the cell transduce the nuclei DDR signal to the cytosol to initiate autophagy; what is the mechanism of DDR related autophagy determining cell survival or cell death pathway; and what is the mechanism associating the autophagy and carcinogenesis potential of chronic low dose exposure of toxicants? In this review, we provide an overview and discuss the molecular mechanism of DNA damage induced autophagy, and their mutual regulation and its role in cell fate determination in response to genotoxic effects of environmental toxicants.1. Autophagy as a ubiquitous cellular response to environmental alterations and genotoxic stress Autophagy was described in mammalian cells more than 50 years ago as a machinery to deliver the components and organelles of the cell to lysosomes for degradation. 1 As a highly conserved ubiquitous pathway among eukaryotic cells from yeast to human, autophagy can be induced by a variety of stimuli, such as nutrient starvation, 2 growth factor withdrawal, 3 energetic deprivation, 4 oxidative stress, 5 and pathogen infection. 6-8 Many environmental toxicants have already been demonstrated to induce autophagy through the generation of endoplasmic reticulum (ER)-stress, oxidative stress, and DNA damage induction. Depending on the type of toxicant, and the exposure concentration and duration, autophagy induction could act as coordinated signaling for either death or survival determination in the processes of acute toxic response or late effects.A group of environmental metal pollutants, including cadmium, chromium, mercury, iron and arsenic, has been shown to induce autophagy. 9-13 Autophagy has been considered as the initial response of cells to metal toxicants, which may confer protection against cellular damage or act as a potential biomarker of toxic metal...

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“…Previous studies have suggested that the type II secretion system has an essential role in localizing several metal-containing proteins on the outer surface of the cell Mehta et al, 2006). Uranium has a high affinity for DNA, which can result in DNA strand breakage and inhibition of DNA-protein interactions (Hartsock et al, 2007;Matsuda & Nakajima, 2012;Yazzie et al, 2003;Zobel & Beer, 1961). Thus, exposure to U(VI) could be expected to result in DNA damage.…”

Section: Protein and Dna Damagementioning

confidence: 99%

Proteome of Geobacter sulfurreducens in the presence of U(VI)

et al. 2014

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Geobacter species often play an important role in the in situ bioremediation of uranium-contaminated groundwater, but little is known about how these microbes avoid uranium toxicity. To evaluate this further, the proteome of Geobacter sulfurreducens exposed to 100 µM U(VI) acetate was compared to control cells not exposed to U(VI). Of the 1363 proteins detected from these cultures, 203 proteins had higher abundance during exposure to U(VI) compared with the control cells and 148 proteins had lower abundance. U(VI)-exposed cultures expressed lower levels of proteins involved in growth, protein and amino acid biosynthesis, as well as key central metabolism enzymes as a result of the deleterious effect of U(VI) on the growth of G. sulfurreducens. In contrast, proteins involved in detoxification, such as several efflux pumps belonging to the RND (resistance–nodulation–cell division) family, and membrane protection, and other proteins, such as chaperones and proteins involved in secretion systems, were found in higher abundance in cells exposed to U(VI). Exposing G. sulfurreducens to U(VI) resulted in a higher abundance of many proteins associated with the oxidative stress response, such as superoxide dismutase and superoxide reductase. A strain in which the gene for superoxide dismutase was deleted grew more slowly than the WT strain in the presence of U(VI), but not in its absence. The results suggested that there is no specific mechanism for uranium detoxification. Rather, multiple general stress responses are induced, which presumably enable Geobacter species to tolerate high uranium concentrations.

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Uranyl Acetate as a Direct Inhibitor of DNA-Binding Proteins

Cited by 42 publications

References 45 publications

Inhibition of poly(ADP-ribose)polymerase-1 and DNA repair by uranium

Inhibition of poly(ADP-ribose)polymerase-1 and DNA repair by uranium

Autophagy as the effector and player in DNA damage response of cells to genotoxicants

Proteome of Geobacter sulfurreducens in the presence of U(VI)

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