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A novel yeast cell-based screen identifies flavone as a tankyrase inhibitor |
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| Authors: | Yoko Yashiroda Reika Okamoto Kaori Hatsugai Yasushi Takemoto Tamio Saito Yoshikazu Sugimoto Hiroyuki Seimiya |
| Affiliation: | a Chemical Genomics Research Group/Chemical Genetics Laboratory, RIKEN Advanced Science Institute, Wako, Saitama 351-0198, Japan b Japan Biological Informatics Consortium (JBIC), Koto-ku, Tokyo 135-8073, Japan c Division of Molecular Biotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Koto-ku, Tokyo 135-8550, Japan d Division of Chemotherapy, Graduate School of Pharmaceutical Sciences, Keio University, Minato-ku, Tokyo 105-8512, Japan e National Institute of Advanced Industrial Science and Technology, Koto-ku, Tokyo 135-0064, Japan f Chemical Biology Core Facility/Antibiotics Laboratory, RIKEN Advanced Science Institute, Wako, Saitama 351-0198, Japan g Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki, Kanagawa 214-8571, Japan h CREST Research Project, Japan Science and Technology Corporation, Saitama 332-0012, Japan |
| Abstract: | The telomere-associated protein tankyrase 1 is a poly(ADP-ribose) polymerase and is considered to be a promising target for cancer therapy, especially for BRCA-associated cancers. However, an efficient assay system for inhibitor screening has not been established, mainly due to the difficulty of efficient preparation of the enzyme and its substrate. Here, we report a cell-based assay system for detecting inhibitory activity against tankyrase 1. We found that overexpression of the human tankyrase 1 gene causes a growth defect in the fission yeast Schizosaccharomyces pombe. Chemicals that restore the growth defect phenotype can be identified as potential tankyrase 1 inhibitors. We performed a high-throughput screen using this system, and identified flavone as a compound that restores the growth of yeast cells overexpressing tankyrase 1. Indeed, flavone inhibited poly(ADP-ribosyl)ation of proteins caused by overexpression of tankyrase 1 in yeast cells. This system allows rapid identification of inhibitory activity against tankyrase 1 and is amenable to high-throughput screening using robotics. |
| Keywords: | Tankyrase 1 Inhibitor High-throughput screening Schizosaccharomyces pombe |
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