title: Loss of SOD1 and LYS7 sensitizes Saccharomyces cerevisiae to hydroxyurea and DNA damage agents and downregulates MEC1 pathway effectors.
abstract: Aerobic metabolism produces reactive oxygen species, including superoxide anions, which cause DNA damage unless removed by scavengers such as superoxide dismutases. We show that loss of the Cu,Zn-dependent superoxide dismutase, SOD1, or its copper chaperone, LYS7, confers oxygen-dependent sensitivity to replication arrest and DNA damage in Saccharomyces cerevisiae. We also find that sod1Delta strains, and to a lesser extent lys7Delta strains, when arrested with hydroxyurea (HU) show reduced induction of the MEC1 pathway effector Rnr3p and of Hug1p. The HU sensitivity of sod1Delta and lys7Delta strains is suppressed by overexpression of TKL1, a transketolase that generates NADPH, which balances redox in the cell and is required for ribonucleotide reductase activity. Our results suggest that the MEC1 pathway in sod1Delta mutant strains is sensitive to the altered cellular redox state due to increased superoxide anions and establish a new relationship between SOD1, LYS7, and the MEC1-mediated checkpoint response to replication arrest and DNA damage in S. cerevisiae.
authors.affiliation: Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, National Naval Medical Center, Building 8, Room 5101, 8901 Wisconsin Ave., Bethesda, MD 20889-5105, USA.
authors.forename: Carole D
authors.initials: CD
authors.lastname: Carter
authors.forename: Lauren E
authors.initials: LE
authors.lastname: Kitchen
authors.forename: Wei-Chun
authors.initials: WC
authors.lastname: Au
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Babic
authors.forename: Munira A
authors.initials: MA
authors.lastname: Basrai
mesh_terms: D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D064447:Checkpoint Kinase 2; D003470:Culture Media / Q000737:chemistry; D004249:DNA Damage / Q000187:drug effects*; D004261:DNA Replication / Q000235:genetics; D004271:DNA, Fungal / Q000187:drug effects / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics; D017353:Gene Deletion; D015966:Gene Expression Regulation, Fungal / Q000235:genetics; D006918:Hydroxyurea / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D010100:Oxygen / Q000378:metabolism / Q000494:pharmacology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013482:Superoxide Dismutase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000072105:Superoxide Dismutase-1; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014174:Transketolase / Q000235:genetics / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D003470:Culture Media; D004271:DNA, Fungal; D004268:DNA-Binding Proteins; C403293:HUG1 protein, S cerevisiae; D047908:Intracellular Signaling Peptides and Proteins; D018832:Molecular Chaperones; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; C115052:SML1 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; C095735:LYS7 protein, S cerevisiae; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; C084088:TKL1 protein, S cerevisiae; D014174:Transketolase; D064447:Checkpoint Kinase 2; C088937:MEC1 protein, S cerevisiae; D017346:Protein Serine-Threonine Kinases; C067022:RAD53 protein, S cerevisiae; D010100:Oxygen; D006918:Hydroxyurea