Tucker Chandra L, Fields Stanley
Department of Genome Sciences, Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA.
Comp Funct Genomics. 2004;5(3):216-24. doi: 10.1002/cfg.391.
Understanding the actions of drugs and toxins in a cell is of critical importance to medicine, yet many of the molecular events involved in chemical resistance are relatively uncharacterized. In order to identify the cellular processes and pathways targeted by chemicals, we took advantage of the haploid Saccharomyces cerevisiae deletion strains (Winzeler et al., 1999). Although ~4800 of the strains are viable, the loss of a gene in a pathway affected by a drug can lead to a synthetic lethal effect in which the combination of a deletion and a normally sublethal dose of a chemical results in loss of viability. WE carried out genome-wide screens to determine quantitative sensitivities of the deletion set to four chemicals: hydrogen peroxide, menadione, ibuprofen and mefloquine. Hydrogen peroxide and menadione induce oxidative stress in the cell, whereas ibuprofen and mefloquine are toxic to yeast by unknown mechanisms. Here we report the sensitivities of 659 deletion strains that are sensitive to one or more of these four compounds, including 163 multichemicalsensitive strains, 394 strains specific to hydrogen peroxide and/or menadione, 47 specific to ibuprofen and 55 specific to mefloquine.We correlate these results with data from other large-scale studies to yield novel insights into cellular function.
了解药物和毒素在细胞中的作用对医学至关重要，但许多与化学抗性相关的分子事件相对尚未得到充分表征。为了确定化学物质所靶向的细胞过程和途径，我们利用了单倍体酿酒酵母缺失菌株（Winzeler等人，1999年）。尽管约4800个菌株是有活力的，但受药物影响的途径中一个基因的缺失可导致合成致死效应，即缺失与正常亚致死剂量的化学物质相结合会导致活力丧失。我们进行了全基因组筛选，以确定缺失菌株对四种化学物质的定量敏感性：过氧化氢、甲萘醌、布洛芬和甲氟喹。过氧化氢和甲萘醌在细胞中诱导氧化应激，而布洛芬和甲氟喹对酵母有毒性，但其作用机制尚不清楚。在此，我们报告了对这四种化合物中的一种或多种敏感的659个缺失菌株的敏感性，包括163个多化学敏感菌株、394个对过氧化氢和/或甲萘醌特异的菌株、47个对布洛芬特异的菌株和55个对甲氟喹特异的菌株。我们将这些结果与其他大规模研究的数据相关联，以对细胞功能产生新的见解。
