title: Hydroxyurea Induces Cytokinesis Arrest in Cells Expressing a Mutated Sterol-14α-Demethylase in the Ergosterol Biosynthesis Pathway.
abstract: Hydroxyurea (HU) has been used for the treatment of multiple diseases, such as cancer. The therapeutic effect is generally believed to be due to the suppression of ribonucleotide reductase (RNR), which slows DNA polymerase movement at replication forks and induces an S phase cell cycle arrest in proliferating cells. Although aberrant mitosis and DNA damage generated at collapsed forks are the likely causes of cell death in the mutants with defects in replication stress response, the mechanism underlying the cytotoxicity of HU in wild-type cells remains poorly understood. While screening for new fission yeast mutants that are sensitive to replication stress, we identified a novel mutation in the erg11 gene encoding the enzyme sterol-14α-demethylase in the ergosterol biosynthesis pathway that dramatically sensitizes the cells to chronic HU treatment. Surprisingly, HU mainly arrests the erg11 mutant cells in cytokinesis, not in S phase. Unlike the reversible S phase arrest in wild-type cells, the cytokinesis arrest induced by HU is relatively stable and occurs at low doses of the drug, which likely explains the remarkable sensitivity of the mutant to HU. We also show that the mutation causes sterol deficiency, which may predispose the cells to the cytokinesis arrest and lead to cell death. We hypothesize that in addition to the RNR, HU may have a secondary unknown target(s) inside cells. Identification of such a target(s) may greatly improve the chemotherapies that employ HU or help to expand the clinical usage of this drug for additional pathological conditions.
authors: Department of Pharmacology and Toxicology, Boonshoft School of Medicine, Wright State University, Dayton, Ohio 45435 yong-jie.xu@wright.edu.
authors: Yong-Jie
authors: YJ
authors: Xu
authors: Department of Pharmacology and Toxicology, Boonshoft School of Medicine, Wright State University, Dayton, Ohio 45435.
authors: Amanpreet
authors: A
authors: Singh
authors: Department of Biochemistry and Molecular Biology, Boonshoft School of Medicine, Wright State University, Dayton, Ohio 45435.
authors: Gerald M
authors: GM
authors: Alter
mesh_terms: D048749:Cytokinesis; D004875:Ergosterol / Q000096:biosynthesis*; D006918:Hydroxyurea / Q000633:toxicity*; D009154:Mutation; D019384:Nucleic Acid Synthesis Inhibitors / Q000633:toxicity*; D012568:Schizosaccharomyces / Q000166:cytology / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D029702:Schizosaccharomyces pombe Proteins / Q000235:genetics* / Q000378:metabolism; D058886:Sterol 14-Demethylase / Q000235:genetics* / Q000378:metabolism
chemical_list: D019384:Nucleic Acid Synthesis Inhibitors; D029702:Schizosaccharomyces pombe Proteins; D058886:Sterol 14-Demethylase; D006918:Hydroxyurea; D004875:Ergosterol
keywords: cell cycle; cytokinesis; fission yeast; hydroxyurea; the replication checkpoint