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Dynamic Regulation of Copper Uptake and Detoxification Genes in Saccharomyces cerevisiae

机译：酿酒酵母中铜吸收和解毒基因的动态调控

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The essential yet toxic nature of copper demands tight regulation of the copper homeostatic machinery to ensure that sufficient copper is present in the cell to drive essential biochemical processes yet prevent the accumulation to toxic levels. In Saccharomyces cerevisiae, the nutritional copper sensor Mac1p regulates the copper-dependent expression of the high affinity Cu(I) uptake genesCTR1, CTR3, and FRE1, while the toxic copper sensor Ace1p regulates the transcriptional activation of the detoxification genes CUP1, CRS5, andSOD1 in response to copper. In this study, we characterized the tandem regulation of the copper uptake and detoxification pathways in response to the chronic presence of elevated concentrations of copper ions in the growth medium. Upon addition of CuSO4, mRNA levels of CTR3 were rapidly reduced to eightfold the original basal level whereas the Ace1p-mediated transcriptional activation of CUP1 was rapid and potent but transient.CUP1 expression driven by an Ace1p DNA binding domain-herpes simplex virus VP16 transactivation domain fusion was also transient, demonstrating that this mode of regulation occurs via modulation of the Ace1p copper-activated DNA binding domain. In vivo dimethyl sulfate footprinting analysis of the CUP1 promoter demonstrated transient occupation of the metal response elements by Ace1p which paralleled CUP1 mRNA expression. Analysis of a Mac1p mutant, refractile for copper-dependent repression of the Cu(I) transport genes, showed an aberrant pattern of CUP1expression and copper sensitivity. These studies (i) demonstrate that the nutritional and toxic copper metalloregulatory transcription factors Mac1p and Ace1p must sense and respond to copper ions in a dynamic fashion to appropriately regulate copper ion homeostasis and (ii) establish the requirement for a wild-type Mac1p for survival in the presence of toxic copper levels.
机译：铜的基本但有毒的性质要求严格调节铜稳态机制，以确保细胞中存在足够的铜以驱动基本的生化过程，同时又防止积累到毒性水平。在酿酒酵母中，营养铜传感器Mac1p调节高亲和力Cu（I）摄取基因 CTR1 ， CTR3 的铜依赖性表达，和 FRE1 ，而毒性铜传感器Ace1p调节排毒基因 CUP1 ， CRS5 和 SOD1 对铜的响应。在这项研究中，我们表征了铜的吸收和解毒途径的串联调节，以响应生长培养基中铜离子浓度的长期存在。加入CuSO 4 后， CTR3 的mRNA水平迅速降低至原始基础水平的八倍，而Ace1p介导的 CUP1 的转录激活被降低。 Ace1p DNA结合结构域-单纯疱疹病毒VP16反式激活结构域融合驱动的 CUP1 表达也是瞬态的，表明这种调节模式是通过调节Ace1p铜激活的DNA来实现的结合域。体内 CUP1 启动子的硫酸二甲酯足迹分析表明，Ace1p与 CUP1 mRNA表达平行，从而短暂占用了金属响应元件。对Mac1p突变体的分析表明，该突变体可依赖铜依赖性抑制Cu（I）转运基因，显示了 CUP1 表达的异常模式和铜敏感性。这些研究（i）表明营养和有毒的铜金属调控转录因子Mac1p和Ace1p必须以动态方式感应和响应铜离子，以适当地调节铜离子的稳态，并且（ii）建立野生型Mac1p的生存要求在有毒的铜水平下。

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