A molecular barcoded yeast ORF library enables mode-of-action analysis of bioactive compounds

Ho, Cheuk Hei; Magtanong, Leslie; Barker, Sarah L.; Gresham, David; Nishimura, Shinichi; Natarajan, P.; Koh, Judice L.Y.; Porter, Justin; Gray, Christopher A.; Andersen, Raymond J.; Giaever, Guri; Nislow, Corey; Andrews, Brenda; Botstein, David; Graham, Todd R.; Yoshida, Minoru; Boone, Charles

doi:10.1038/nbt.1534

Cited by 277 publications

(270 citation statements)

References 59 publications

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“…S8 and S9). For each of these strains, the original gene deletion was reversed by adding the deleted ORF on a centromeric plasmid (21). H1-4 are evolution strains evolved at 39°C and in rich medium.…”

Section: Methodsmentioning

confidence: 99%

“…To measure the heat tolerance contribution of selected genes from chromosome III when inserted as extra copies into a diploid wild type, we used centromeric plasmids (21). Heat-shock tolerance was measured for each of these strains compared with a diploid wild type with an empty plasmid.…”

Section: Media Ypd (Yeast Extractmentioning

confidence: 99%

“…Next, we checked whether these genes can contribute to heat tolerance when introduced to a wild-type strain, one at a time. To this end, a diploid wild-type strain was transformed with centromeric plasmids (21), each containing one of these genes. As a negative control, 22 random genes from chromosome III that did not retain elevated expression were inserted in the same manner.…”

Section: Acquisition and Subsequent Elimination Of Chromosome III Trimentioning

confidence: 99%

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Chromosomal duplication is a transient evolutionary solution to stress

Yona

Manor

Herbst

et al. 2012

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

340

382

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Aneuploidy, an abnormal number of chromosomes, is a widespread phenomenon found in unicellulars such as yeast, as well as in plants and in mammalians, especially in cancer. Aneuploidy is a genomescale aberration that imposes a severe burden on the cell, yet under stressful conditions specific aneuploidies confer a selective advantage. This dual nature of aneuploidy raises the question of whether it can serve as a stable and sustainable evolutionary adaptation. To clarify this, we conducted a set of laboratory evolution experiments in yeast and followed the long-term dynamics of aneuploidy under diverse conditions. Here we show that chromosomal duplications are first acquired as a crude solution to stress, yet only as transient solutions that are eliminated and replaced by more efficient solutions obtained at the individual gene level. These transient dynamics of aneuploidy were repeatedly observed in our laboratory evolution experiments; chromosomal duplications gained under stress were eliminated not only when the stress was relieved, but even if it persisted. Furthermore, when stress was applied gradually rather than abruptly, alternative solutions appear to have emerged, but not aneuploidy. Our findings indicate that chromosomal duplication is a first evolutionary line of defense, that retains survivability under strong and abrupt selective pressures, yet it merely serves as a "quick fix," whereas more refined and sustainable solutions take over. Thus, in the perspective of genome evolution trajectory, aneuploidy is a useful yet short-lived intermediate that facilitates further adaptation.evolutionary dynamics | environmental stress | heat tolerance | pH tolerance

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Section: Methodsmentioning

confidence: 99%

Section: Media Ypd (Yeast Extractmentioning

confidence: 99%

Section: Acquisition and Subsequent Elimination Of Chromosome III Trimentioning

confidence: 99%

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Chromosomal duplication is a transient evolutionary solution to stress

Yona

Manor

Herbst

et al. 2012

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

340

382

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“…In signature-based approaches, a series of drug-induced molecular/phenotypic measurements are made in an experimental system. Collections of measurements from many small molecules form multivariate signatures that aim to fingerprint drugs based on their relative signature similarity (8)(9)(10)(11)(12)(13). In several landmark studies using Saccharomyces cerevisiae; gene expression compendia (8); and, later, barcoded loss of function/ORF libraries (9,10), large signatures were shown to characterize individual small molecule mechanisms of action effectively.…”

mentioning

confidence: 99%

Defining principles of combination drug mechanisms of action

Pritchard¹,

Bruno²,

Gilbert³

et al. 2012

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

156

137

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Combination chemotherapies have been a mainstay in the treatment of disseminated malignancies for almost 60 y, yet even successful regimens fail to cure many patients. Although their singledrug components are well studied, the mechanisms by which drugs work together in clinical combination regimens are poorly understood. Here, we combine RNAi-based functional signatures with complementary informatics tools to examine drug combinations. This approach seeks to bring to combination therapy what the knowledge of biochemical targets has brought to single-drug therapy and creates a statistical and experimental definition of "combination drug mechanisms of action." We show that certain synergistic drug combinations may act as a more potent version of a single drug. Conversely, unlike these highly synergistic combinations, most drugs average extant single-drug variations in therapeutic response. When combined to form multidrug regimens, averaging combinations form averaging regimens that homogenize genetic variation in mouse models of cancer and in clinical genomics datasets. We suggest surprisingly simple and predictable combination mechanisms of action that are independent of biochemical mechanism and have implications for biomarker discovery as well as for the development of regimens with defined genetic dependencies.chemotherapy | lymphoma | RNAi signature | systems biology C urrent rationales for the design of combination chemotherapy regimens were developed in the 1940s and 1950s (1-5) and, remarkably, were concurrent with the identification of DNA as the genetic material. The development of these regimens in the absence of any knowledge of cancer genomics was a remarkable achievement. However, although our knowledge of the genetic drivers of cancer and the mechanisms of drug action has increased dramatically over the past 30 y, this information has been difficult to adapt to clinical practice. As such, even very successful combination regimens often fail to cure many patients (6, 7). We hypothesize that part of this failure is due to the absence of mechanistic information about how drugs in regimens interact to promote combination effects (we term these effects "combination mechanisms of action"). We sought to address this gap by investigating specific hypotheses concerning the "mechanisms of action" of combination therapy.The classic term "drug mechanism of action" refers to the description of a specific biochemical event, which is often the activation or inhibition of an enzymatic effect. However, in recent years, "signature"-based prediction has provided a powerful new strategy for examining drug mechanism. In signature-based approaches, a series of drug-induced molecular/phenotypic measurements are made in an experimental system. Collections of measurements from many small molecules form multivariate signatures that aim to fingerprint drugs based on their relative signature similarity (8-13). In several landmark studies using Saccharomyces cerevisiae; gene expression compendia (8); and, later, barcoded loss o...

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“…The complex polyketide swinholide A and bistheonellide A are biologically active metabolites that show nanomolar potent against tumor cells [6,7]. There are actin disrupting compounds derived from lithistida like kabiramide, sphinxolide and reidispongiolide, callipeltoside but these are not meant for commercial purposes [11,12].…”

Section: Commercially Available Biochemical Probes From Lithistid Spomentioning

confidence: 99%

Lithistid Sponges Derived Compounds and Their Importance in Biological Research - A Review

Abirla

2018

Asian J Pharm Clin Res

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Lithistid sponges have an important source of complex natural compounds with biological activities. The lithistid sponges are of interest to biomedical science because of the great variety of pharmaceutically relevant biological activities of their chemical extracts and are considered as economically important. The compounds identified in these sponges have therapeutic potential and have been frequently hypothesized to contain compounds of bacterial origin. The peptides identified from these lithistid sponges are found to be the sources of antifungal activity. The active agents of these sponges also have cytotoxic and immunosuppressive activities. Many of the cyclic peptides of lithistid represent the anti-HIV activity. The different structure and biological activities of the compounds derived from these sponges have more chemical aspects too.

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A molecular barcoded yeast ORF library enables mode-of-action analysis of bioactive compounds

Cited by 277 publications

References 59 publications

Chromosomal duplication is a transient evolutionary solution to stress

Chromosomal duplication is a transient evolutionary solution to stress

Defining principles of combination drug mechanisms of action

Lithistid Sponges Derived Compounds and Their Importance in Biological Research - A Review

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