Investigations on the role of base excision repair and non-homologous end-joining pathways in sodium selenite-induced toxicity and mutagenicity in Saccharomyces cerevisiae

Abstract

Selenium (Se) belongs to nutrients that are essential for human health. Biological activity of this compound, however, mainly depends on its dose, with a potential of Se to induce detrimental effects at high doses. Although mechanisms lying behind detrimental effects of Se are poorly understood yet, they involve DNA damage induction. Consequently, DNA damage response and repair pathways may play a crucial role in cellular response to Se. Using Saccharomyces cerevisiae we showed that sodium selenite (SeL), an inorganic form of Se, can be toxic and mutagenic in this organism due to its ability to induce DNA double-strand breaks (DSBs). Moreover, we reported that a spectrum of mutations induced by this compound in the stationary phase of growth is mainly represented by 1-4 bp deletions. Consequently, we proposed that SeL acts as an oxidizing agent in yeast producing oxidative damage to DNA. As short deletions could be anticipated to arise as a result of action of non-homologous end-joining (NHEJ) and oxidative damage to DNA is primarily coped with base excision repair (BER), a contribution of these two pathways towards survival, DSB induction, mutation frequency and types of mutations following SeL exposure was examined in present study. First, we show that while NHEJ plays no role in repairing toxic DNA lesions induced by SeL, cells with impairment in BER are sensitized towards this compound. Of BER activities examined, those responsible for processing of 3'-blocking DNA termini seem to be the most crucial for manifestation of the toxic effects of SeL in yeast. Second, an impact of NHEJ and BER on DSB induction after SeL exposure turned to be inappreciable, as no increase in DNA double-strand breakage in NHEJ and BER single or NHEJ BER double mutant upon SeL exposure was observed. Finally, we demonstrate that impairment in both these pathways does not importantly change mutation frequency after SeL exposure and that NHEJ is not responsible for generation of short deletions after SeL treatment, as these were comparably induced in the wild-type and NHEJ-defective cells.

Potential ofPleurotus ostreatusMycelium for Selenium Absorption

“…DNA double-strand breaks and cell death were also associated with the toxic and mutagenic effects of Na 2 SeO 3 on S. cerevisiae [28, 39]. However, in contrast to selenites, Ip [27] and Letavayová et al [28] observed that Se-methylselenocysteine inhibited growth rate, and DNA synthesis only modestly caused no break of DNA strands and induced cell death predominantly by apoptosis.…”

Neurobehavioral changes in mice offspring induced by prenatal exposure to acute toxicity of sodium selenite

“…There is a large body of evidence implicating oxidative stress and reactive oxygen species (ROS) in the mechanism of selenium toxicity (Isai et al 2009;Misra & Niyogi 2009). In oxidative stress, the metabolism of oxygen leads to generation of ROS which are able to oxidize almost all classes of macromolecules, including proteins, lipids and nucleic acids (Zachara et al 2006;Fujimoto et al 2009;Mániková et al 2010). It was proved that selenite ions have the potential to induce oxidative DNA damage in the liver cell culture through either an increase in ROS formation (Fujimoto et al 2009) or probably by inducing the imbalance of intracellular glutathione redox (Misra & Niyogi 2009).…”

“…They can involve DNA damage induction and consequently, DNA damage response and repair pathways may play a crucial role in cellular response to selenium (Mániková et al 2010). Toxicity of selenium, however, depends on many factors like the selenium species, amount ingested, age, physiological status, and dietary interaction with other nutrients (Mataix Verdu & Llopis 2002).…”

Sulfate Assimilation Mediates Tellurite Reduction and Toxicity in Saccharomyces cerevisiae

“…In higher eukaryotes, telluriuminduced cell death has been suggested to occur by an oxidative mechanism that at least partially involves oxidation-induced DNA damage (44). Se(IV) exposure is, in fact, well known to lead to DNA double-strand breaks (27,32). In yeast, however, viable knockout mutants lacking genes involved in DNA repair and replication and in cell cycle checkpoints showed normal Te phenotypes, suggesting that DNA damage contributes little to Te toxicity.…”