New York University School of Medicine, Nelson Institute of Environmental Medicine, NY 10987, USA.
BMC Genomics. 2009 Nov 15;10:524. doi: 10.1186/1471-2164-10-524.
The understanding of the biological function, regulation, and cellular interactions of the yeast genome and proteome, along with the high conservation in gene function found between yeast genes and their human homologues, has allowed for Saccharomyces cerevisiae to be used as a model organism to deduce biological processes in human cells. Here, we have completed a systematic screen of the entire set of 4,733 haploid S. cerevisiae gene deletion strains (the entire set of nonessential genes for this organism) to identify gene products that modulate cellular toxicity to nickel sulfate (NiSO(4)).
We have identified 149 genes whose gene deletion causes sensitivity to NiSO(4) and 119 genes whose gene deletion confers resistance. Pathways analysis with proteins whose absence renders cells sensitive and resistant to nickel identified a wide range of cellular processes engaged in the toxicity of S. cerevisiae to NiSO(4). Functional categories overrepresented with proteins whose absence renders cells sensitive to NiSO(4) include homeostasis of protons, cation transport, transport ATPases, endocytosis, siderophore-iron transport, homeostasis of metal ions, and the diphthamide biosynthesis pathway. Functional categories overrepresented with proteins whose absence renders cells resistant to nickel include functioning and transport of the vacuole and lysosome, protein targeting, sorting, and translocation, intra-Golgi transport, regulation of C-compound and carbohydrate metabolism, transcriptional repression, and chromosome segregation/division. Interactome analysis mapped seven nickel toxicity modulating and ten nickel-resistance networks. Additionally, we studied the degree of sensitivity or resistance of the 111 nickel-sensitive and 72 -resistant strains whose gene deletion product has a similar protein in human cells.
We have undertaken a whole genome approach in order to further understand the mechanism(s) regulating the cell's toxicity to nickel compounds. We have used computational methods to integrate the data and generate global models of the yeast's cellular response to NiSO(4). The results of our study shed light on molecular pathways associated with the cellular response of eukaryotic cells to nickel compounds and provide potential implications for further understanding the toxic effects of nickel compounds to human cells.
对酵母基因组和蛋白质组的生物学功能、调控和细胞相互作用的理解，以及酵母基因与其人类同源物之间基因功能的高度保守性，使得酿酒酵母能够被用作模型生物，以推断人类细胞中的生物学过程。在这里，我们完成了对整个 4733 个单倍体酿酒酵母基因缺失株系（该生物的全部非必需基因）的系统筛选，以鉴定出调节细胞对硫酸镍（NiSO4）毒性的基因产物。
我们已经确定了 149 个基因，其基因缺失导致对 NiSO4敏感，119 个基因缺失赋予对镍的抗性。对缺失蛋白使细胞对镍敏感和耐受的蛋白质进行途径分析，确定了一系列参与酿酒酵母对 NiSO4毒性的细胞过程。缺失蛋白使细胞对 NiSO4敏感的功能类别包括质子、阳离子运输、运输 ATP 酶、内吞作用、铁载体-铁运输、金属离子内稳态和二氢喋呤生物合成途径。缺失蛋白使细胞对镍有抗性的功能类别包括液泡和溶酶体的功能和运输、蛋白质靶向、分拣和易位、高尔基体内运输、C 化合物和碳水化合物代谢的调节、转录抑制和染色体分离/分裂。互作分析映射了七个镍毒性调节和十个镍抗性网络。此外，我们还研究了其基因缺失产物在人类细胞中有类似蛋白的 111 个镍敏感株系和 72 个镍抗性株系的敏感性或抗性程度。
我们采用了全基因组方法，以进一步了解调节细胞对镍化合物毒性的机制。我们使用计算方法整合数据并生成酵母细胞对 NiSO4反应的全局模型。我们研究的结果揭示了与真核细胞对镍化合物的细胞反应相关的分子途径，并为进一步理解镍化合物对人类细胞的毒性作用提供了潜在的启示。
