title: The oxidative stress responsive transcription factor Pap1 confers DNA damage resistance on checkpoint-deficient fission yeast cells.
abstract: Eukaryotic cells invoke mechanisms to promote survival when confronted with cellular stress or damage to the genome. The protein kinase Chk1 is an integral and conserved component of the DNA damage response pathway. Mutation or inhibition of Chk1 results in mitotic death when cells are exposed to DNA damage. Oxidative stress activates a pathway that results in nuclear accumulation of the bZIP transcription factor Pap1. We report the novel finding that fission yeast Pap1 confers resistance to drug- and non-drug-induced DNA damage even when the DNA damage checkpoint is compromised. Multi-copy expression of Pap1 restores growth to chk1-deficient cells exposed to camptothecin or hydroxyurea. Unexpectedly, increased Pap1 expression also promotes survival of chk1-deficient cells with mutations in genes encoding DNA ligase (cdc17) or DNA polymerase δ (cdc6), but not DNA replication initiation mutants. The ability of Pap1 to confer resistance to DNA damage was not specific to chk1 mutants, as it also improved survival of rad1- and rad9-deficient cells in the presence of CPT. To confer resistance to DNA damage Pap1 must localize to the nucleus and be transcriptionally active.
authors.affiliation: Department of Pharmacology, Rutgers Robert Wood Johnson Medical School, Piscataway, New Jersey, United States of America ; Graduate Program in Cellular and Molecular Pharmacology, Rutgers Graduate School of Biomedical Sciences, Piscataway, New Jersey, United States of America.
authors.forename: Carrie
authors.initials: C
authors.lastname: Belfield
authors.affiliation: Department of Pharmacology, Rutgers Robert Wood Johnson Medical School, Piscataway, New Jersey, United States of America.
authors.forename: Craig
authors.initials: C
authors.lastname: Queenan
authors.affiliation: Department of Pharmacology, Rutgers Robert Wood Johnson Medical School, Piscataway, New Jersey, United States of America.
authors.forename: Hui
authors.initials: H
authors.lastname: Rao
authors.affiliation: Center for Gene Science, Hiroshima University, Higashi-Hiroshima, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Kitamura
authors.affiliation: Department of Pharmacology, Rutgers Robert Wood Johnson Medical School, Piscataway, New Jersey, United States of America ; Graduate Program in Cellular and Molecular Pharmacology, Rutgers Graduate School of Biomedical Sciences, Piscataway, New Jersey, United States of America ; Member, Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey, United States of America.
authors.forename: Nancy C
authors.initials: NC
authors.lastname: Walworth
mesh_terms: D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism*; D002166:Camptothecin; D002467:Cell Nucleus / Q000378:metabolism*; D000071877:Checkpoint Kinase 1; D004249:DNA Damage / Q000235:genetics*; D011088:DNA Ligases / Q000235:genetics; D006918:Hydroxyurea; D008856:Microscopy, Fluorescence; D018384:Oxidative Stress / Q000235:genetics / Q000502:physiology*; D000073718:Pancreatitis-Associated Proteins; D011494:Protein Kinases / Q000172:deficiency*; D012568:Schizosaccharomyces / Q000235:genetics / Q000502:physiology*; D029702:Schizosaccharomyces pombe Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors; D000073718:Pancreatitis-Associated Proteins; C105096:Pap1 protein, S pombe; C000612141:REG3A protein, human; D029702:Schizosaccharomyces pombe Proteins; C491233:cdc6 protein, S pombe; D011494:Protein Kinases; D000071877:Checkpoint Kinase 1; C000605873:Chk1 protein, S pombe; D011088:DNA Ligases; C483777:Cdc17 protein, S pombe; D006918:Hydroxyurea; D002166:Camptothecin