RRC ID 48064
著者 Xu YJ, Singh A, Alter GM.
タイトル Hydroxyurea Induces Cytokinesis Arrest in Cells Expressing a Mutated Sterol-14α-Demethylase in the Ergosterol Biosynthesis Pathway.
ジャーナル Genetics
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.
巻・号 204(3)
ページ 959-973
公開日 2016-11-1
DOI 10.1534/genetics.116.191536
PII genetics.116.191536
PMID 27585850
PMC PMC5105871
MeSH Cytokinesis* Ergosterol / biosynthesis* Hydroxyurea / toxicity* Mutation Nucleic Acid Synthesis Inhibitors / toxicity* Schizosaccharomyces / cytology Schizosaccharomyces / drug effects Schizosaccharomyces / genetics Schizosaccharomyces / metabolism* Schizosaccharomyces pombe Proteins / genetics* Schizosaccharomyces pombe Proteins / metabolism Sterol 14-Demethylase / genetics* Sterol 14-Demethylase / metabolism
IF 4.015
引用数 4
リソース情報
酵母 FY13123 FY17338 FY17340 FY17341 FY17342