Complex Mechanisms of Antimony Genotoxicity in Budding Yeast Involves Replication and Topoisomerase I-Associated DNA Lesions, Telomere Dysfunction and Inhibition of DNA Repair.

Ireneusz Litwin,Seweryn Mucha,Ewa Maciaszczyk-Dziubinska,Ewa Pilarczyk,Robert Wysocki

doi:10.3390/ijms22094510

Ireneusz Litwin, Seweryn Mucha + Show 3 more

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https://doi.org/10.3390/ijms22094510

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Abstract

Antimony is a toxic metalloid with poorly understood mechanisms of toxicity and uncertain carcinogenic properties. By using a combination of genetic, biochemical and DNA damage assays, we investigated the genotoxic potential of trivalent antimony in the model organism Saccharomyces cerevisiae. We found that low doses of Sb(III) generate various forms of DNA damage including replication and topoisomerase I-dependent DNA lesions as well as oxidative stress and replication-independent DNA breaks accompanied by activation of DNA damage checkpoints and formation of recombination repair centers. At higher concentrations of Sb(III), moderately increased oxidative DNA damage is also observed. Consistently, base excision, DNA damage tolerance and homologous recombination repair pathways contribute to Sb(III) tolerance. In addition, we provided evidence suggesting that Sb(III) causes telomere dysfunction. Finally, we showed that Sb(III) negatively effects repair of double-strand DNA breaks and distorts actin and microtubule cytoskeleton. In sum, our results indicate that Sb(III) exhibits a significant genotoxic activity in budding yeast.

Highlights

Antimony is a toxic metalloid that ubiquitously occurs in the environment at very low concentrations [1]
Filling of ssDNA gaps is performed by the DNA damage tolerance (DDT) pathway that operates in two modes
In S phase, ssDNA gaps are preferentially repaired by a recombination-like mechanism called template switch (TS) that depends on the Rad18 and Rad5 E3 ubiquitin ligases, recombination proteins, including Rad51 and Rad52, and nucleases such as the

Summary

Introduction

Antimony is a toxic metalloid that ubiquitously occurs in the environment at very low concentrations [1]. Antimony has multiple industrial applications leading to occupational exposure and environmental pollution, especially in the mining and smelting areas [2,3,4]. Inappropriate storage conditions, mainly exposure to high temperature and prolonged storage, result in antimony leaching from plastic materials and contamination of drinking water and foods [5,6,7,8]. Accumulating evidence suggests that exposure to antimony leads to various adverse health effects in humans [2,9]. Antimony trioxide is classified as possibly carcinogenic to humans by the International Agency for Research on Cancer (IARC) and a pollutant of priority interest by the United States Environment Protection Agency (USEPA) [10,11]. Antimony compounds show a promising anticancer activity [13,14,15]

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