title: The synthetic genetic interaction network reveals small molecules that target specific pathways in Sacchromyces cerevisiae.
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.
authors.affiliation: Department of Chemistry and Biochemistry, University of California Santa Cruz, 1156 High St., Santa Cruz, CA 95064, USA.
authors.forename: Craig M
authors.initials: CM
authors.lastname: Tamble
authors.forename: Robert P
authors.initials: RP
authors.lastname: St Onge
authors.forename: Guri
authors.initials: G
authors.lastname: Giaever
authors.forename: Corey
authors.initials: C
authors.lastname: Nislow
authors.forename: Alexander G
authors.initials: AG
authors.lastname: Williams
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Stuart
authors.forename: R Scott
authors.initials: RS
authors.lastname: Lokey
mesh_terms: D000465:Algorithms; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D017353:Gene Deletion; D055106:Genome-Wide Association Study; D045325:HCT116 Cells; D006801:Humans; D053858:Metabolic Networks and Pathways / Q000235:genetics; D016196:S Phase / Q000187:drug effects; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000201:enzymology / Q000235:genetics*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics* / Q000378:metabolism; D054852:Small Molecule Libraries / Q000494:pharmacology*; D013482:Superoxide Dismutase / Q000235:genetics* / Q000378:metabolism; D000072105:Superoxide Dismutase-1
chemical_list: C000606290:SOD1 protein, human; D029701:Saccharomyces cerevisiae Proteins; D054852:Small Molecule Libraries; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1