A functional variomics tool for discovering drug-resistance genes and drug targets.

TitleA functional variomics tool for discovering drug-resistance genes and drug targets.
Publication TypeJournal Article
Year of Publication2013
AuthorsHuang, Z, Chen, K, Zhang, J, Li, Y, Wang, H, Cui, D, Tang, J, Liu, Y, Shi, X, Li, W, Liu, D, Chen, R, Sucgang, RS, Pan, X
JournalCell Rep
Volume3
Issue2
Pagination577-85
Date Published2013 Feb 21
ISSN2211-1247
KeywordsAlleles, Amphotericin B, Antifungal Agents, Cell Cycle Proteins, Cycloheximide, Drug Resistance, Microbial, Mutation, Phosphatidylinositol 3-Kinases, Proteolipids, Ribosomal Proteins, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Sirolimus
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.

DOI10.1016/j.celrep.2013.01.019
Alternate JournalCell Rep
PubMed ID23416056
PubMed Central IDPMC3594652
Grant List1S10RR026550 / RR / NCRR NIH HHS / United States
F32EY19430 / EY / NEI NIH HHS / United States
HG004840 / HG / NHGRI NIH HHS / United States
P30 HD024064 / HD / NICHD NIH HHS / United States
P30CA125123 / CA / NCI NIH HHS / United States
P30HD024064 / HD / NICHD NIH HHS / United States
R01 HG004840 / HG / NHGRI NIH HHS / United States