Giaever Guri, Flaherty Patrick, Kumm Jochen, Proctor Michael, Nislow Corey, Jaramillo Daniel F, Chu Angela M, Jordan Michael I, Arkin Adam P, Davis Ronald W
Stanford Genome Technology Center, 855 California Avenue, Palo Alto, CA 94304-1103, USA.
Proc Natl Acad Sci U S A. 2004 Jan 20;101(3):793-8. doi: 10.1073/pnas.0307490100. Epub 2004 Jan 12.
We demonstrate the efficacy of a genome-wide protocol in yeast that allows the identification of those gene products that functionally interact with small molecules and result in the inhibition of cellular proliferation. Here we present results from screening 10 diverse compounds in 80 genome-wide experiments against the complete collection of heterozygous yeast deletion strains. These compounds include anticancer and antifungal agents, statins, alverine citrate, and dyclonine. In several cases, we identified previously known interactions; furthermore, in each case, our analysis revealed novel cellular interactions, even when the relationship between a compound and its cellular target had been well established. In addition, we identified a chemical core structure shared among three therapeutically distinct compounds that inhibit the ERG24 heterozygous deletion strain, demonstrating that cells may respond similarly to compounds of related structure. The ability to identify on-and-off target effects in vivo is fundamental to understanding the cellular response to small-molecule perturbants.
我们展示了一种在酵母中进行全基因组实验的方法的有效性，该方法能够识别那些与小分子发生功能相互作用并导致细胞增殖受到抑制的基因产物。在此，我们呈现了在80次全基因组实验中针对完整的杂合酵母缺失菌株集合筛选10种不同化合物的结果。这些化合物包括抗癌和抗真菌药物、他汀类药物、枸橼酸阿尔维林和达克罗宁。在一些情况下，我们鉴定出了先前已知的相互作用；此外，在每种情况下，我们的分析都揭示了新的细胞相互作用，即使一种化合物与其细胞靶点之间的关系已经明确确立。此外，我们鉴定出了三种治疗作用不同的化合物之间共有的化学核心结构，这些化合物能够抑制ERG24杂合缺失菌株，这表明细胞可能对相关结构的化合物有相似的反应。在体内识别靶标和非靶标效应的能力对于理解细胞对小分子干扰物的反应至关重要。
