Yeast Genomics and Drug Target Identification

Bharucha, Nike; Kumar, Anuj

doi:10.2174/138620707782507340

Cited by 28 publications

(16 citation statements)

References 62 publications

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“…Yeast cells are useful in the identification of genes important in drug toxicity (Bharucha & Kumar, 2007). An advantage of yeast over mammalian cellular systems is the relatively straightforward way of performing genetic modifications.…”

Section: Discussionmentioning

confidence: 99%

Subunits Rip1p and Cox9p of the respiratory chain contribute to diclofenac-induced mitochondrial dysfunction

et al. 2011

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The widely used drug diclofenac can cause serious heart, liver and kidney injury, which may be related to its ability to cause mitochondrial dysfunction. Using Saccharomyces cerevisiae as a model system, we studied the mechanisms of diclofenac toxicity and the role of mitochondria therein. We found that diclofenac reduced cell growth and viability and increased levels of reactive oxygen species (ROS). Strains increasingly relying on respiration for their energy production showed enhanced sensitivity to diclofenac. Furthermore, oxygen consumption was inhibited by diclofenac, suggesting that the drug inhibits respiration. To identify the site of respiratory inhibition, we investigated the effects of deletion of respiratory chain subunits on diclofenac toxicity. Whereas deletion of most subunits had no effect, loss of either Rip1p of complex III or Cox9p of complex IV resulted in enhanced resistance to diclofenac. In these deletion strains, diclofenac did not increase ROS formation as severely as in the wild-type. Our data are consistent with a mechanism of toxicity in which diclofenac inhibits respiration by interfering with Rip1p and Cox9p in the respiratory chain, resulting in ROS production that causes cell death.

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Section: Discussionmentioning

confidence: 99%

Subunits Rip1p and Cox9p of the respiratory chain contribute to diclofenac-induced mitochondrial dysfunction

et al. 2011

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“…To identify the cellular targets of any bioactive compounds is a very difficult task. In the last years, however, all the genome resources that were developed for S. cerevisiae (www.yeastgenome.org) provided an excellent genomic platform for drug development and drug target identification (7,28,50,85). In addition, all these genetic tools have made it possible to study and construct genetic interaction networks for identification of specific drug targets (9,16).…”

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confidence: 99%

Molecular Characterization of Propolis-Induced Cell Death in Saccharomyces cerevisiae

et al. 2011

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Propolis, a natural product of plant resins, is used by the bees to seal holes in their honeycombs and protect the hive entrance. However, propolis has also been used in folk medicine for centuries. Here, we apply the power of Saccharomyces cerevisiae as a model organism for studies of genetics, cell biology, and genomics to determine how propolis affects fungi at the cellular level. Propolis is able to induce an apoptosis cell death response. However, increased exposure to propolis provides a corresponding increase in the necrosis response. We showed that cytochrome c but not endonuclease G (Nuc1p) is involved in propolis-mediated cell death in S. cerevisiae. We also observed that the metacaspase YCA1 gene is important for propolis-mediated cell death. To elucidate the gene functions that may be required for propolis sensitivity in eukaryotes, the full collection of about 4,800 haploid S. cerevisiae deletion strains was screened for propolis sensitivity. We were able to identify 138 deletion strains that have different degrees of propolis sensitivity compared to the corresponding wild-type strains. Systems biology revealed enrichment for genes involved in the mitochondrial electron transport chain, vacuolar acidification, negative regulation of transcription from RNA polymerase II promoter, regulation of macroautophagy associated with protein targeting to vacuoles, and cellular response to starvation. Validation studies indicated that propolis sensitivity is dependent on the mitochondrial function and that vacuolar acidification and autophagy are important for yeast cell death caused by propolis.

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“…Enhancer studies identify a multiplied phenotype resulting from overexpression of a gene in a mutant strain. Genetic interaction networks, epistatic relationships and even drug targets [59] can be examined with overexpression strains. This section will discuss several collections that can be utilized to overexpress both essential and nonessential genes (Table 1).…”

Section: Gene Overexpression Libraries For Large-scale Analysismentioning

confidence: 99%

Mutant power: using mutant allele collections for yeast functional genomics

Norman¹,

Kumar²

2015

Briefings in Functional Genomics

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The budding yeast has long served as a model eukaryote for the functional genomic analysis of highly conserved signaling pathways, cellular processes and mechanisms underlying human disease. The collection of reagents available for genomics in yeast is extensive, encompassing a growing diversity of mutant collections beyond gene deletion sets in the standard wild-type S288C genetic background. We review here three main types of mutant allele collections: transposon mutagen collections, essential gene collections and overexpression libraries. Each collection provides unique and identifiable alleles that can be utilized in genome-wide, high-throughput studies. These genomic reagents are particularly informative in identifying synthetic phenotypes and functions associated with essential genes, including those modeled most effectively in complex genetic backgrounds. Several examples of genomic studies in filamentous/pseudohyphal backgrounds are provided here to illustrate this point. Additionally, the limitations of each approach are examined. Collectively, these mutant allele collections in Saccharomyces cerevisiae and the related pathogenic yeast Candida albicans promise insights toward an advanced understanding of eukaryotic molecular and cellular biology.

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Yeast Genomics and Drug Target Identification

Cited by 28 publications

References 62 publications

Subunits Rip1p and Cox9p of the respiratory chain contribute to diclofenac-induced mitochondrial dysfunction

Subunits Rip1p and Cox9p of the respiratory chain contribute to diclofenac-induced mitochondrial dysfunction

Molecular Characterization of Propolis-Induced Cell Death in Saccharomyces cerevisiae

Mutant power: using mutant allele collections for yeast functional genomics

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