1997 Fiscal Year Final Research Report Summary
Search for Novel Anti-cancer Drugs Targetting DNA Replication and Repair
| Project/Area Number |
08557131
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 展開研究 |
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| Research Field |
Biological pharmacy
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| Research Institution | Osaka University |
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Principal Investigator |
HANAOKA Fumio Osaka Univ., IMCB,Professor, 細胞生体工学センター, 教授 (50012670)
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| Co-Investigator(Kenkyū-buntansha) |
KAKEYA Hideaki REKEN,Antibiotics Lab., Research Scientist, 抗生物質研究室, 研究員 (00270596)
MAEKAWA Takafumi Osaka Univ., IMCB,Research Assistant, 細胞生体工学センター, 助手 (90273721)
MASUTANI Chikahide Osaka Univ., IMCB,Research Assistant, 細胞生体工学センター, 助手 (40241252)
OHKUMA Yoshiaki Osaka Univ., IMCB,Associate Professor, 細胞生体工学センター, 助教授 (70192515)
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| Project Period (FY) |
1996 – 1997
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| Keywords | DNA replication / DNA repair / cell-free system / inhibitors / anti-cancer drugs / saponin / DNA helicase / SV40T antigen |
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| Research Abstract |
We have screened more than one hundred of culture supernatants of Actinomycetes and Eumycetes using cell-free systems for SV40 DNA replication and the nucleotide excision repair (NER) with UV-irradiated SV40 minichromosomes to obtain either inhibitors or stimulators for DNA replication and repair. As s result of these screening, we obtained a couple of samples for replication inhibitors and NER inhibitors.
One of the replication inhibitors (RK606) was purified, and its structure was identified as a kind of soybean saponin (soyasaponin II). RK606 also inhibited SV40 DNA replication with purified proteins, therefore, we examined the effect of RK606 on individual enzymes and proteins. It turned out that RK606 specifically inhibited DNA helicase activity of SV40 T antigen. Interestingly, a cellular DNA helicase was not inhibited by this compound, indicating that RK606 might be a specific inhibitor of T antigen helicase. To our knowledge, this is the first inhibitor besides ATP analogues for any DNA helicase.
One of the repair inhibitors (RK679) was examined for its stability at different pH and for its extractability by several solvents. The behaviors of the repair inhibitor were similar to those of some kinds of tyrosine kinase inhibitors, genistein and daizein, therefore, we checked the effect of these tyrosine kinase inhibitors on cell-free NER assay. However, we could not find any effect of these compounds on NER,suggesting that RK679 is not either genistein or daizein but is rather different compound.
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[Publications] van der Spek, P.J., Visser, C.E., Hanaoka, F., Smit, B., Hagemeijer, A., Bootsma, D., and Hoeijmakers, J.H.J.: "Cloning, comparative mapping, and RNA expression of the mouse homologues of the Saccharomyces cerevisiae nucleotide excision repair gene RAD23." Genomics. 31. 20-27 (1996)
Description
「研究成果報告書概要(欧文)」より
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[Publications] Sugasawa, K., Masutani, C., Uchida, A., Maekawa, T., van der Spek, P.J., Bootsma, D., Hoeijmakers, J.H.J., and Hanaoka, F.: "HHR23B,a human Rad23 homolog, stimulates XPC protein in nucleotide excision repair in vitro." Mol.Cell.Biol.16. 4852-4861 (1996)
Description
「研究成果報告書概要(欧文)」より
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[Publications] Ito, K., Asano, M., Highes, P., Kohzaki, H., Masutani, C., Hanaoka, F., Curran, T., and Ito, Y.: "c-Jun stimutates origin-dependent DNA unwinding by polyomavirus large T antigen." EMBO J.15. 5636-5646 (1996)
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「研究成果報告書概要(欧文)」より
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[Publications] Withers-Ward, E.S., Jowett, J.B., Stewart, S.A., Xie, Y.M., Garfinkel, A., Shibagaki, Y., Chow, S.A., Shah, N., Hanaoka, F., Sawitz, D.G., Armstrong, R.W., Souza, L.M., and Chen, I.S.: "Human immunodeficiency virus type 1 Vpr interacts with HHR23A,a cellular protein implicated in nucleotide excision DNA repair." J.Virol.71. 9732-9742 (1997)
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「研究成果報告書概要(欧文)」より
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[Publications] Masutani, C., Araki, M., Sugasawa, K., van der Spek, P.J., Yamada, A., Uchida, A., Maekawa, T., Bootsma, D., Hoeijmakers, J.H.J., and Hanaoka, F.: "Identification and characterization of XPC-binding domain of hHR23B." Mol.Cell.Biol.17. 6915-6923 (1997)
Description
「研究成果報告書概要(欧文)」より
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[Publications] Sugasawa, K., Ng, J.M.Y., Masutani, C., Maekawa, T., Uchida, A., van der Spek, P.J., Eker, A.P.M., Rademakers, S., Visser, C., Aboussekhra, A., Wood, R.D., Hanaoka, F., Bootsma, D., and Hoeijmakers, J.H.J.: "Two human homologues of Rad23 are functionally interchangeable in complex formation and stimulation of XPC repair activity." Mol.Cell.Biol.17. 6924-6931 (1997)
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「研究成果報告書概要(欧文)」より
