title: Genome-wide functional profiling reveals genes required for tolerance to benzene metabolites in yeast.
abstract: Benzene is a ubiquitous environmental contaminant and is widely used in industry. Exposure to benzene causes a number of serious health problems, including blood disorders and leukemia. Benzene undergoes complex metabolism in humans, making mechanistic determination of benzene toxicity difficult. We used a functional genomics approach to identify the genes that modulate the cellular toxicity of three of the phenolic metabolites of benzene, hydroquinone (HQ), catechol (CAT) and 1,2,4-benzenetriol (BT), in the model eukaryote Saccharomyces cerevisiae. Benzene metabolites generate oxidative and cytoskeletal stress, and tolerance requires correct regulation of iron homeostasis and the vacuolar ATPase. We have identified a conserved bZIP transcription factor, Yap3p, as important for a HQ-specific response pathway, as well as two genes that encode putative NAD(P)H:quinone oxidoreductases, PST2 and YCP4. Many of the yeast genes identified have human orthologs that may modulate human benzene toxicity in a similar manner and could play a role in benzene exposure-related disease.
authors.affiliation: Department of Nutritional Science and Toxicology, University of California, Berkeley, California, United States of America.
authors.forename: Matthew
authors.initials: M
authors.lastname: North
authors.forename: Vickram J
authors.initials: VJ
authors.lastname: Tandon
authors.forename: Reuben
authors.initials: R
authors.lastname: Thomas
authors.forename: Alex
authors.initials: A
authors.lastname: Loguinov
authors.forename: Inna
authors.initials: I
authors.lastname: Gerlovina
authors.forename: Alan E
authors.initials: AE
authors.lastname: Hubbard
authors.forename: Luoping
authors.initials: L
authors.lastname: Zhang
authors.forename: Martyn T
authors.initials: MT
authors.lastname: Smith
authors.forename: Chris D
authors.initials: CD
authors.lastname: Vulpe
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000595:Amino Acid Sequence; D000818:Animals; D001554:Benzene / Q000378:metabolism*; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D016000:Cluster Analysis; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D005656:Fungal Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D005800:Genes, Fungal / Q000235:genetics*; D023281:Genomics; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D007501:Iron / Q000378:metabolism; D008563:Membrane Lipids / Q000378:metabolism; D008969:Molecular Sequence Data; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D009249:NADP / Q000378:metabolism; D010636:Phenols / Q000378:metabolism* / Q000633:toxicity*; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000187:drug effects* / Q000235:genetics* / Q000254:growth & development; D013045:Species Specificity; D013997:Time Factors; D025262:Vacuolar Proton-Translocating ATPases / Q000235:genetics / Q000378:metabolism; D014617:Vacuoles / Q000187:drug effects / Q000378:metabolism
chemical_list: D005656:Fungal Proteins; D008563:Membrane Lipids; D010636:Phenols; D009249:NADP; D007501:Iron; D016660:NAD(P)H Dehydrogenase (Quinone); D025262:Vacuolar Proton-Translocating ATPases; D001554:Benzene