Chemogenomic profiling: Identifying the functional interactions of small molecules in yeast

Giaever, Guri; Flaherty, Patrick; Kumm, Jochen; Proctor, Michael; Nislow, Corey; Jaramillo, Daniel; Chu, Angela M.; Jordan, Michael I.; Arkin, Adam P.; Davis, Ronald W.

doi:10.1073/pnas.0307490100

Cited by 462 publications

(433 citation statements)

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“…For one data set of dispensability estimates, labeled SGTC for Stanford Genome Technology Center, growth rates were measured by the array-based method described in ref. 17. Six replicate growth experiments were conducted for each of two independently constructed pools of all viable homozygous yeast deletion strains.…”

Section: Methodsmentioning

confidence: 99%

Functional genomic analysis of the rates of protein evolution

Wall

Hirsh²,

Fraser³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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259

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The evolutionary rates of proteins vary over several orders of magnitude. Recent work suggests that analysis of large data sets of evolutionary rates in conjunction with the results from high-throughput functional genomic experiments can identify the factors that cause proteins to evolve at such dramatically different rates. To this end, we estimated the evolutionary rates of >3,000 proteins in four species of the yeast genus Saccharomyces and investigated their relationship with levels of expression and protein dispensability. Each protein's dispensability was estimated by the growth rate of mutants deficient for the protein. Our analyses of these improved evolutionary and functional genomic data sets yield three main results. First, dispensability and expression have independent, significant effects on the rate of protein evolution. Second, measurements of expression levels in the laboratory can be used to filter data sets of dispensability estimates, removing variates that are unlikely to reflect real biological effects. Third, structural equation models show that although we may reasonably infer that dispensability and expression have significant effects on protein evolutionary rate, we cannot yet accurately estimate the relative strengths of these effects

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Section: Methodsmentioning

confidence: 99%

Functional genomic analysis of the rates of protein evolution

Wall

Hirsh²,

Fraser³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

259

256

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“…Qdr3 belongs to cluster I of the DHA1 drug efflux family, including putative drug : H + antiporters with 12 predicted membrane-spanning segments (Paulsen et al, 1998), and confers yeast resistance against the antiarrhythmic and antimalarial drug quinidine, the herbicide barban and the antitumour agents bleomycin and cisplatin (Tenreiro et al, 2005). Through genome-wide screenings, QDR3 gene deletion was also found to increase yeast susceptibility towards magnesium dichloride (Rieger et al, 1999), selenomethionine (Bockhorn et al, 2008), the antiarrhythmic drug amiodarone (Yadav et al, 2007) and the antifungal drug fluconazole (Giaever et al, 2004). Remarkably, at least six other members of the DHA1 family of S. cerevisiae drug : H + antiporters are individually required for quinidine resistance (do Valle Matta et al, 2001; Felder et al, 2002;Nunes et al, 2001;Tenreiro et al, 2002Tenreiro et al, , 2005.…”

Section: Introductionmentioning

confidence: 99%

Yeast response and tolerance to polyamine toxicity involving the drug : H+ antiporter Qdr3 and the transcription factors Yap1 and Gcn4

et al. 2011

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The yeast QDR3 gene encodes a plasma membrane drug : H + antiporter of the DHA1 family that was described as conferring resistance against the drugs quinidine, cisplatin and bleomycin and the herbicide barban, similar to its close homologue QDR2. In this work, a new physiological role for Qdr3 in polyamine homeostasis is proposed. QDR3 is shown to confer resistance to the polyamines spermine and spermidine, but, unlike Qdr2, also a determinant of resistance to polyamines, Qdr3 has no apparent role in K + homeostasis. QDR3 transcription is upregulated in yeast cells exposed to spermine or spermidine dependent on the transcription factors Gcn4, which controls amino acid homeostasis, and Yap1, the main regulator of oxidative stress response. Yap1 was found to be a major determinant of polyamine stress resistance in yeast and is accumulated in the nucleus of yeast cells exposed to spermidine-induced stress. QDR3 transcript levels were also found to increase under nitrogen or amino acid limitation; this regulation is also dependent on Gcn4. Consistent with the concept that Qdr3 plays a role in polyamine homeostasis, QDR3 expression was found to decrease the intracellular accumulation of [ 3 H]spermidine, playing a role in the maintenance of the plasma membrane potential in spermidine-stressed cells. INTRODUCTIONMultidrug efflux transporters are found in all living cells and are thought to recognize a wide variety of structurally and pharmacologically unrelated drugs. They are proposed to actively extrude or compartmentalize drugs and other xenobiotics, thus providing protection from these compounds (Jungwirth & Kuchler, 2006;Paulsen, 2003;Prasad et al., 2002;Roepe et al., 1996;. The activity of these proteins underlies the manifestation of cellular drug resistance, seriously limiting the therapeutic potential of drugs (Hayes & Wolf, 1997). The in silico analysis of the yeast genome revealed the existence of 23 putative drug : H + antiporters of the multiple drug resistance (MDR) family of the major facilitator superfamily (MFS). Although many of these proteins have been shown to confer resistance to a wide variety of drugs and chemicals (Paulsen et al., 1998;, the molecular mechanisms behind their apparent promiscuity remain elusive and a topic of debate (Jungwirth & Kuchler, 2006;Paulsen, 2003;Prasad et al., 2002;Roepe et al., 1996;.In the present work, we have further examined the biological function of the MFS-MDR transporter encoded by the QDR3 gene, which is present in the plasma membrane of Saccharomyces cerevisiae (Huh et al., 2003;Tenreiro et al., 2005). Qdr3 belongs to cluster I of the DHA1 drug efflux family, including putative drug : H + antiporters with 12 predicted membrane-spanning segments (Paulsen et al., 1998), and confers yeast resistance against the antiarrhythmic and antimalarial drug quinidine, the herbicide barban and the antitumour agents bleomycin and cisplatin (Tenreiro et al., 2005). Through genome-wide screenings, QDR3 gene deletion was also found to increase yeast susceptibility towards ma...

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“…However, combining this classic approach with genomics-era technologies that accelerate discovery time lines is essential. For example, forward genetics platforms such as the S. cerevisiae haploinsufficiency profiling (HOP) (Shoemaker et al 1996;Giaever et al 1999Giaever et al , 2002Giaever et al , 2004Roemer et al 2011a) or C. albicans fitness test (Xu et al 2007;Jiang et al 2008;Roemer et al 2011b) offer whole cell target-specific assays for essentially all possible drug targets in yeast and has proven enormously successful in the discovery and mechanism of action (MOA) determination of novel antifungal agents (Roemer et al 2011a(Roemer et al , 2012. As routinely performed in antibacterial discovery Roemer and Boone 2013;Wang et al 2013), next-generation sequencing also offers greater speed and resolution in determining the MOA of potential antifungal leads.…”

Section: Future Directionsmentioning

confidence: 99%

Antifungal Drug Development: Challenges, Unmet Clinical Needs, and New Approaches

Roemer

Krysan

2014

Cold Spring Harbor Perspectives in Medicine

475

353

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Invasive, life-threatening fungal infections are an important cause of morbidity and mortality, particularly for patients with compromised immune function. The number of therapeutic options for the treatment of invasive fungal infections is quite limited when compared with those available to treat bacterial infections. Indeed, only three classes of molecules are currently used in clinical practice and only one new class of antifungal drugs has been developed in the last 30 years. Here we summarize the unmet clinical needs of current antifungal therapy, discuss challenges inherent to antifungal drug discovery and development, and review recent developments aimed at addressing some of these challenges.

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Chemogenomic profiling: Identifying the functional interactions of small molecules in yeast

Cited by 462 publications

References 20 publications

Functional genomic analysis of the rates of protein evolution

Functional genomic analysis of the rates of protein evolution

Yeast response and tolerance to polyamine toxicity involving the drug : H+ antiporter Qdr3 and the transcription factors Yap1 and Gcn4

Antifungal Drug Development: Challenges, Unmet Clinical Needs, and New Approaches

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