NDLI: The synthetic genetic interaction network reveals small molecules that target specific pathways in Sacchromyces cerevisiae

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Molecular BioSystems Vol - 7 Issue - 5

Molecular BioSystems Vol - 7 Issue - 4

Molecular BioSystems Vol - 7 Issue - 3

Molecular BioSystems Vol - 7 Issue - 2

Molecular BioSystems Vol -6

Molecular BioSystems Vol -5

Molecular BioSystems Vol -4

Molecular BioSystems Vol -3

Molecular BioSystems Vol -2

The synthetic genetic interaction network reveals small molecules that target specific pathways in Sacchromyces cerevisiae

Content Provider	Royal Society of Chemistry (RSC)
Author	Nislow, Corey Giaever, Guri Tamble, Craig M. Lokey, R. Scott Williams, Alexander G. Stuart, Joshua M. Onge, Robert P. St.
Copyright Year	2011
Abstract	High-throughput elucidation of synthetic genetic interactions (SGIs) has contributed to a systems-level understanding of genetic robustness and fault-tolerance encoded in the genome. Pathway targets of various compounds have been predicted by comparing chemical-genetic synthetic interactions to a network of SGIs. We demonstrate that the SGI network can also be used in a powerful reverse pathway-to-drug approach for identifying compounds that target specific pathways of interest. Using the SGI network, the method identifies an indicator gene that may serve as a good candidate for screening a library of compounds. The indicator gene is selected so that compounds found to produce sensitivity in mutants deleted for the indicator gene are likely to abrogate the target pathway. We tested the utility of the SGI network for pathway-to-drug discovery using the DNA damage checkpoint as the target pathway. An analysis of the compendium of synthetic lethal interactions in yeast showed that superoxide dismutase 1 (SOD1) has significant SGI connectivity with a large subset of DNA damage checkpoint and repair (DDCR) genes in Saccharomyces cerevisiae, and minimal SGIs with non-DDCR genes. We screened a sod1Δ strain against three National Cancer Institute (NCI) compound libraries using a soft agar high-throughput halo assay. Fifteen compounds out of ∼3100 screened showed selective toxicity toward sod1Δ relative to the isogenic wild type (wt) strain. One of these, 1A08, caused a transient increase in growth in the presence of sublethal doses of DNA damaging agents, suggesting that 1A08 inhibits DDCR signaling in yeast. Genome-wide screening of 1A08 against the library of viable homozygous deletion mutants further supported DDCR as the relevant targeted pathway of 1A08. When assayed in human HCT-116 colorectal cancer cells, 1A08 caused DNA-damage resistant DNA synthesis and blocked the DNA-damage checkpoint selectively in S-phase.
Starting Page	2019
Ending Page	2030
Page Count	12
File Format	HTM / HTML PDF
ISSN	1742206X
Volume Number	7
Issue Number	6
Journal	Molecular BioSystems
DOI	10.1039/c0mb00298d
Language	English
Publisher	Royal Society of Chemistry
Access Restriction	Open
Subject Keyword	Colorectal cancer Agar Superoxide dismutase Saccharomyces DDCR Silicon Graphics SGI Gene NCI DNA Cell cycle National Cancer Institute Library Mutation Genome Saccharomyces cerevisiae NCI-60
Content Type	Text
Resource Type	Article
Subject	Molecular Biology Biotechnology

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The Synthetic Genetic Interaction Network Reveals Small Molecules that Target Specific Pathways in Sacchromyces cerevisiae

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