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  • 1
    Publication Date: 2014-04-12
    Description: Genome-wide characterization of the in vivo cellular response to perturbation is fundamental to understanding how cells survive stress. Identifying the proteins and pathways perturbed by small molecules affects biology and medicine by revealing the mechanisms of drug action. We used a yeast chemogenomics platform that quantifies the requirement for each gene for resistance to a compound in vivo to profile 3250 small molecules in a systematic and unbiased manner. We identified 317 compounds that specifically perturb the function of 121 genes and characterized the mechanism of specific compounds. Global analysis revealed that the cellular response to small molecules is limited and described by a network of 45 major chemogenomic signatures. Our results provide a resource for the discovery of functional interactions among genes, chemicals, and biological processes.〈br /〉〈br /〉〈a href="" target="_blank"〉〈img src="" border="0"〉〈/a〉   〈a href="" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lee, Anna Y -- St Onge, Robert P -- Proctor, Michael J -- Wallace, Iain M -- Nile, Aaron H -- Spagnuolo, Paul A -- Jitkova, Yulia -- Gronda, Marcela -- Wu, Yan -- Kim, Moshe K -- Cheung-Ong, Kahlin -- Torres, Nikko P -- Spear, Eric D -- Han, Mitchell K L -- Schlecht, Ulrich -- Suresh, Sundari -- Duby, Geoffrey -- Heisler, Lawrence E -- Surendra, Anuradha -- Fung, Eula -- Urbanus, Malene L -- Gebbia, Marinella -- Lissina, Elena -- Miranda, Molly -- Chiang, Jennifer H -- Aparicio, Ana Maria -- Zeghouf, Mahel -- Davis, Ronald W -- Cherfils, Jacqueline -- Boutry, Marc -- Kaiser, Chris A -- Cummins, Carolyn L -- Trimble, William S -- Brown, Grant W -- Schimmer, Aaron D -- Bankaitis, Vytas A -- Nislow, Corey -- Bader, Gary D -- Giaever, Guri -- GM103504/GM/NIGMS NIH HHS/ -- GM44530/GM/NIGMS NIH HHS/ -- MOP-700724/Canadian Institutes of Health Research/Canada -- MOP-79368/Canadian Institutes of Health Research/Canada -- MOP-81340/Canadian Institutes of Health Research/Canada -- P01 HG000205/HG/NHGRI NIH HHS/ -- P41 GM103504/GM/NIGMS NIH HHS/ -- R01 003317-07/PHS HHS/ -- R01 CA157456/CA/NCI NIH HHS/ -- R01 GM044530/GM/NIGMS NIH HHS/ -- R01 HG003317/HG/NHGRI NIH HHS/ -- New York, N.Y. -- Science. 2014 Apr 11;344(6180):208-11. doi: 10.1126/science.1250217.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Donnelly Centre, University of Toronto, Toronto, Ontario M5S 3E1, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="" target="_blank"〉PubMed〈/a〉
    Keywords: Cell Line, Tumor ; Cells/*drug effects ; Drug Evaluation, Preclinical/*methods ; Drug Resistance/*genetics ; *Gene Regulatory Networks ; Genome-Wide Association Study/*methods ; Haploinsufficiency ; Humans ; Pharmacogenetics ; Saccharomyces cerevisiae/drug effects/genetics ; Small Molecule Libraries/*pharmacology
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2018-04-12
    Description: For decades, fungi have been a source of U.S. Food and Drug Administration–approved natural products such as penicillin, cyclosporine, and the statins. Recent breakthroughs in DNA sequencing suggest that millions of fungal species exist on Earth, with each genome encoding pathways capable of generating as many as dozens of natural products. However, the majority of encoded molecules are difficult or impossible to access because the organisms are uncultivable or the genes are transcriptionally silent. To overcome this bottleneck in natural product discovery, we developed the HEx (Heterologous EXpression) synthetic biology platform for rapid, scalable expression of fungal biosynthetic genes and their encoded metabolites in Saccharomyces cerevisiae . We applied this platform to 41 fungal biosynthetic gene clusters from diverse fungal species from around the world, 22 of which produced detectable compounds. These included novel compounds with unexpected biosynthetic origins, particularly from poorly studied species. This result establishes the HEx platform for rapid discovery of natural products from any fungal species, even those that are uncultivable, and opens the door to discovery of the next generation of natural products.
    Electronic ISSN: 2375-2548
    Topics: Natural Sciences in General
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