title: A functional variomics tool for discovering drug-resistance genes and drug targets.
abstract: Comprehensive discovery of genetic mechanisms of drug resistance and identification of in vivo drug targets represent significant challenges. Here we present a functional variomics technology in the model organism Saccharomyces cerevisiae. This tool analyzes numerous genetic variants and effectively tackles both problems simultaneously. Using this tool, we discovered almost all genes that, due to mutations or modest overexpression, confer resistance to rapamycin, cycloheximide, and amphotericin B. Most significant among the resistance genes were drug targets, including multiple targets of a given drug. With amphotericin B, we discovered the highly conserved membrane protein Pmp3 as a potent resistance factor and a possible target. Widespread application of this tool should allow rapid identification of conserved resistance mechanisms and targets of many more compounds. New genes and alleles that confer resistance to other stresses can also be discovered. Similar tools in other systems, such as human cell lines, will also be useful.
authors: Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
authors: Zhiwei
authors: Z
authors: Huang
authors: Kaifu
authors: K
authors: Chen
authors: Jianhuai
authors: J
authors: Zhang
authors: Yongxiang
authors: Y
authors: Li
authors: Hui
authors: H
authors: Wang
authors: Dandan
authors: D
authors: Cui
authors: Jiangwu
authors: J
authors: Tang
authors: Yong
authors: Y
authors: Liu
authors: Xiaomin
authors: X
authors: Shi
authors: Wei
authors: W
authors: Li
authors: Dan
authors: D
authors: Liu
authors: Rui
authors: R
authors: Chen
authors: Richard S
authors: RS
authors: Sucgang
authors: Xuewen
authors: X
authors: Pan
mesh_terms: D000483:Alleles; D000666:Amphotericin B / Q000494:pharmacology; D000935:Antifungal Agents / Q000494:pharmacology*; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D003513:Cycloheximide / Q000494:pharmacology; D004352:Drug Resistance, Microbial / Q000235:genetics*; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011510:Proteolipids / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D012269:Ribosomal Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology
chemical_list: D000666:Amphotericin B; D000935:Antifungal Agents; D018797:Cell Cycle Proteins; D003513:Cycloheximide; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011510:Proteolipids; D012269:Ribosomal Proteins; D029701:Saccharomyces cerevisiae Proteins; D020123:Sirolimus; C410735:PMP3 protein, S cerevisiae; C489321:RPL28 protein, S cerevisiae; C081135:TOR2 protein, S cerevisiae