Drug-induced phenotypes provide a tool for the functional analysis of yeast genes

Launhardt, Heike; Hinnen, Albert; Münder, Thomas

doi:10.1002/(sici)1097-0061(199807)14:10<935::aid-yea289>3.0.co;2-9

Cited by 32 publications

(16 citation statements)

References 29 publications

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“…These results identified the Alg7p protein as the known target and the uncharacterized proteins encoded by YMR266W and YMR007W as hypersensitive to tunicamycin. article whereby targets are identified by their ability to confer resistance to a strain when present at high copy 3,4 . In this technique, a more sensitive target present at wild-type levels may mask any resistance conferred by overexpression of an additional target.…”

Section: Figmentioning

confidence: 99%

“…Although comprehensive genome-wide surveys of gene dosage in yeast have not been performed, evidence that gene dosage can alter drug sensitivity has been demonstrated. Specifically, increased gene dosage (on the order of ten copies per cell) of a drug target has been shown to increase resistance of a yeast strain to the corresponding drug 3,4 . Here, the converse is demonstrated: decreased gene dosage of a drug target from two copies to one copy in heterozygous strains results in increased sensitivity, or drug-induced haploinsufficiency.…”

Section: Introductionmentioning

confidence: 99%

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Genomic profiling of drug sensitivities via induced haploinsufficiency

et al. 1999

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Lowering the dosage of a single gene from two copies to one copy in diploid yeast results in a heterozygote that is sensitized to any drug that acts on the product of this gene. This haploinsufficient phenotype thereby identifies the gene product of the heterozygous locus as the likely drug target. We exploited this finding in a genomic approach to drug-target identification. Genome sequence information was used to generate molecularly tagged heterozygous yeast strains that were pooled, grown competitively in drug and analysed for drug sensitivity using high-density oligonucleotide arrays. Individual heterozygous strain analysis verified six known drug targets. Parallel analysis identified the known target and two hypersensitive loci in a mixed culture of 233 strains in the presence of the drug tunicamycin. Our discovery that both drug target and hypersensitive loci exhibit drug-induced haploinsufficiency may have important consequences in pharmacogenomics and variable drug toxicity observed in human populations.

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Section: Figmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Genomic profiling of drug sensitivities via induced haploinsufficiency

et al. 1999

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“…Traditionally, these gain-of-function studies were performed with genetic screens using yeast genomic libraries in multicopy plasmids [16]. Among the transformants obtained, those overexpressing the target grew and formed colonies in a plate containing the drug of interest [17]. The molecular nature of the target was then determined by plasmid rescue and subsequent sequencing.…”

Section: Gene Overexpression Approachesmentioning

confidence: 99%

Yeast on drugs: Saccharomyces cerevisiae as a tool for anticancer drug research

Menacho‐Marquez

Murguía

2007

Clin Transl Oncol

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The budding yeast Saccharomyces cerevisiae is being widely used as a model for investigating fundamental processes relevant to all living organisms. Many of these processes are affected by genetic and epigenetic alterations in cancer such as cell cycle progression, DNA replication and segregation, maintenance of genomic integrity and stress responses. Therefore, yeast emerges as an attractive model for anticancer drug research. The genetic tractability of budding yeast, its ease of manipulation and the wealth of functional genomics tools available in this organism makes it ideal for genome-wide analysis of biological functions and chemical screenings. The present review will discuss some of the innovative advantages based on yeast genetics and genomics for antitumour drug target identification and drug discovery.

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“…In a more recent study, Launhardt et al used an overexpression library to identify genes conferring resistance to ketoconazole, an antifungal agent that blocks the synthesis of ergosterol, which is a major component of fungal membranes [47]. Here, the authors introduced a high-copy genomic DNA library into a drug-sensitive yeast strain and subsequently screened for drug-resistant revertants.…”

Section: Overexpression Screening For Drug Re-sistancementioning

confidence: 99%

“…Furthermore, by these approaches, the initial screen does not necessitate the construction of specific yeast mutants. Also, in most cases, a single agar plate can be used to screen at least a million transformants [47]. Overexpression screens simplify the process of identifying the resistance gene, since this can be accomplished by simply sequencing plasmid DNA from drug-resistant colonies [43].…”

Section: Overexpression Screening For Drug Re-sistancementioning

confidence: 99%

Yeast Genomics and Drug Target Identification

Bharucha¹,

Kumar²

2007

CCHTS

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The budding yeast Saccharomyces cerevisiae is well recognized as a preferred eukaryote for the development of genomic technologies and approaches. Accordingly, a sizeable complement of genomic resources has been developed in yeast, and this genomic foundation is now informing a wide variety of disciplines. In particular, yeast genomic methodologies are gaining an expanding foothold in drug development studies, most notably as a preliminary tool towards drug target identification. In this review, we highlight many applications of yeast genomics in the identification of targeted genes and pathways of small molecules or therapeutic drugs. The applicability of genome-wide resources of yeast disruption and deletion mutants for drug-sensitivity/resistance screening is presented here, along with a summary of microarray technologies for drug-based transcriptional profiling and synthetic interaction mapping. Applications of protein-interaction traps for potential drug target identification are also considered. Collectively, this overview of yeast genomics emphasizes the growing intersection between high-throughput model organism biology and medicinal chemistry an intersection promising tangible advances for both academic and pharmaceutical fields alike.

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Drug-induced phenotypes provide a tool for the functional analysis of yeast genes

Cited by 32 publications

References 29 publications

Genomic profiling of drug sensitivities via induced haploinsufficiency

Genomic profiling of drug sensitivities via induced haploinsufficiency

Yeast on drugs: Saccharomyces cerevisiae as a tool for anticancer drug research

Yeast Genomics and Drug Target Identification

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