title: Heme deficiency sensitizes yeast cells to oxidative stress induced by hydroxyurea.
abstract: Hydroxyurea (HU) has a long history of clinical and scientific use as an antiviral, antibacterial, and antitumor agent. It inhibits ribonucleotide reductase and reversibly arrests cells in S phase. However, high concentrations or prolonged treatment with low doses of HU can cause cell lethality. Although the cytotoxicity of HU may significantly contribute to its therapeutic effects, the underlying mechanisms remain poorly understood. We have previously shown that HU can induce cytokinesis arrest in theerg11-1mutant of fission yeast, which has a partial defect in the biosynthesis of fungal membrane sterol ergosterol. Here, we report the identification of a new mutant in heme biosynthesis,hem13-1, that is hypersensitive to HU. We found that the HU hypersensitivity of thehem13-1mutant is caused by oxidative stress and not by replication stress or a defect in cellular response to replication stress. The mutation is hypomorphic and causes heme deficiency, which likely sensitizes the cells to the HU-induced oxidative stress. Because the heme biosynthesis pathway is highly conserved in eukaryotes, this finding, as we show in our separate report, may help to expand the therapeutic spectrum of HU to additional pathological conditions.
authors.affiliation: From the Department of Pharmacology and Toxicology, Boonshoft School of Medicine, Wright State University, Dayton, Ohio 45435 and.|the Wadsworth Center, New York State Department of Health, Albany, New York 12208.
authors.forename: Amanpreet
authors.initials: A
authors.lastname: Singh
authors.affiliation: From the Department of Pharmacology and Toxicology, Boonshoft School of Medicine, Wright State University, Dayton, Ohio 45435 and yong-jie.xu@wright.edu.
authors.forename: Yong-Jie
authors.initials: YJ
authors.lastname: Xu
mesh_terms: D006418:Heme / Q000096:biosynthesis* / Q000235:genetics; D006918:Hydroxyurea / Q000494:pharmacology*; D009154:Mutation; D018384:Oxidative Stress / Q000187:drug effects* / Q000235:genetics; D012568:Schizosaccharomyces / Q000235:genetics / Q000378:metabolism*; D029702:Schizosaccharomyces pombe Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D029702:Schizosaccharomyces pombe Proteins; D006418:Heme; D006918:Hydroxyurea
keywords: DNA replication; cell cycle; checkpoint control; heme; oxidative stress; ribonucleotide reductase