Comparative Functional Genomic Analysis Identifies Distinct and Overlapping Sets of Genes Required for Resistance to Monomethylarsonous Acid (MMAIII) and Arsenite (AsIII) in Yeast
Comparative Functional Genomic Analysis Identifies Distinct and Overlapping Sets of Genes Required for Resistance to Monomethylarsonous Acid (MMAIII) and Arsenite (AsIII) in Yeast
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DOI：
10.1093/toxsci/kfp162
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发表时间：
2009-10-01
影响因子：
3.8
通讯作者：
Vulpe, Chris D.
中科院分区：
文献类型：
--
作者：
Jo, William J.;Loguinov, Alex;Vulpe, Chris D.
砷是一种人类毒素和致癌物质，通常在饮用水中发现。亚砷酸盐（As-III）是毒性最大的无机形式，但最近的证据表明，代谢物一甲基亚胂酸（MMA（III））毒性更大。我们已经使用了化学基因组学的方法来确定的基因，调节细胞毒性的MMA（III）和As-III的酵母酿酒酵母。使用纯合缺失突变体的功能分析提供了对两种砷剂的反应中高度保守的生物过程的要求的证据，包括微管蛋白折叠，DNA双链断裂修复和染色质修饰。在150 μ M MMA（III）和300 μ M As-III的等毒剂量下，谷胱甘肽代谢相关基因仅对前者的抗性至关重要，这表明MMA（III）比As-III破坏谷胱甘肽代谢的效力更高。MMA（III）处理诱导野生型菌株中谷胱甘肽水平显著增加，这与硫和甲硫氨酸代谢途径基因的需求相关，并与氧化应激的诱导一致。基于GSH代谢和微管蛋白折叠过程中缺失菌株的相对敏感性，氧化应激似乎是MMA（III）毒性的主要机制，而在As-III的情况下是微管蛋白破坏的次要机制。许多已鉴定的酵母基因在人类中具有直系同源物，可能以与酵母对应物类似的方式调节砷毒性。
Arsenic is a human toxin and carcinogen commonly found as a contaminant in drinking water. Arsenite (As-III) is the most toxic inorganic form, but recent evidence indicates that the metabolite monomethylarsonous acid (MMA(III)) is even more toxic. We have used a chemical genomics approach to identify the genes that modulate the cellular toxicity of MMA(III) and As-III in the yeast Saccharomyces cerevisiae. Functional profiling using homozygous deletion mutants provided evidence of the requirement of highly conserved biological processes in the response against both arsenicals including tubulin folding, DNA double-strand break repair, and chromatin modification. At the equitoxic doses of 150 mu M MMA(III) and 300 mu M As-III, genes related to glutathione metabolism were essential only for resistance to the former, suggesting a higher potency of MMA(III) to disrupt glutathione metabolism than As-III. Treatments with MMA(III) induced a significant increase in glutathione levels in the wild-type strain, which correlated to the requirement of genes from the sulfur and methionine metabolic pathways and was consistent with the induction of oxidative stress. Based on the relative sensitivity of deletion strains deficient in GSH metabolism and tubulin folding processes, oxidative stress appeared to be the primary mechanism of MMA(III) toxicity whereas secondary to tubulin disruption in the case of As-III. Many of the identified yeast genes have orthologs in humans that could potentially modulate arsenic toxicity in a similar manner as their yeast counterparts.