2003 Fiscal Year Final Research Report Summary
STUDY ON NOVEL REQULATORY MECHANISMA OF DNA REPAIR
| Project/Area Number |
13308041
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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 | 一般 |
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| Research Field |
Molecular biology
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| Research Institution | OSAKA UNIVERSITY |
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Principal Investigator |
HANAOKA Fumio OSAKA UNIVERSITY, GRAD. SCH. FRONT. BIOSCI., PROFESSOR, 大学院・生命機能研究科, 教授 (50012670)
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| Co-Investigator(Kenkyū-buntansha) |
YOKOI Masayuki OSAKA UNIVERSITY, GRAD. SCH. FRONT. BIOSCI., RESEACH ASSOCIATE, 大学院・生命機能研究科, 助手 (00322701)
MASUTANI Chikahide OSAKA UNIVERSITY, GRAD. SCH. FRONT. BIOSCI., RESEACH ASSOCIATE, 大学院・生命機能研究科, 助手 (40241252)
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| Project Period (FY) |
2001 – 2003
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| Keywords | nucleotide excision repair / translesion synthesis / XPC protein / HR23B protein / xeroderma pigmentosum / thymine DNA glycosylase / DNA polymerase η / DNA polymerase τ |
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| Research Abstract |
In order to investigate how DNA repair systems are regulated, we analysed molecular mechanisms of nucleotide excision repair (NER) and translesion synthesis (TLS) in eukaryotic cells, and obtained the following results.
1) The XPC-HR23B protein complex, the initiator of global genome NER, was found to associate with a centrosome protein centrin 2.
2) The XPC-HR23B strongly recognized specific secondary structures of DNA, involving a single-and double-strand junction. A DNase I footprint analysis, using a looped DNA substrate, revealed that a single XPC-HR23B complex protected a distorted site in an asymmetrical manner.
3) While mHR23A KO mice showed no abnormalities, mHR23B KO mice showed impaired embryonic development and a high rate of intrauterine or neonatal death. Surviving animals display a variety of abnormalities, including retarded growth, facial dysmorphology, and male sterility.
4) XPC was found to interact with thymine DNA glycosylase (TDG) in yeast two hybrid screening. By biochemical analyses, XPC interacted with TDG not only physically but also functionally.
5) We identified two fission yeast homologs of budding yeast Rad4 and human XPC, designated Rfp4A and Rhp4B. Rhp4A was found to play roles in GGR and TCR, while Rhp4B acts as an accessory protein in GGR.
6) Human DNA polymerase η (Pol η) catalyzed relatively efficient and accurate TLS past 5R-thymineglycol and 5S-thymineglycol.
7) Both alleles of DNA polymerase τ (Pol τ) gene was found to have null mutation in 129-derived strains of mice. Overall frequency and spectrum of mutation were normal in Pol τ-deficient mice.
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Research Products
(13 results)
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[Publications] Araki, M., Masutani, C., Takemura, M., Uchida, A., Sugasawa, K., Kondoh, J., Ohkuma, Y., Hanaoka, F.: "Centrosome protein centrin 2/caltractin l is part of the xeroderma pigmentosum group C complex that initiates global genome nucleotide excision repair."J. Biol. Chem.. 276. 18665-18672 (2001)
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「研究成果報告書概要(欧文)」より
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[Publications] Fukumoto, Y., Hiyama, H., Yokoi, M., Nakaseko, Y., Yanagida, M., Hanaoka,F.: "Two budding yeast RAD4 homologs in fission yeast play different roles in the repair of UV-induced damage."DNA Repair. 1. 833-845 (2002)
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[Publications] McDonald, J.P., Frank, E.G., Plosky, B.S., Rogozin, I.B., Masutani, C., Hanaoka, F., Woodgate, R., Gearhart,P.J.: "129-derived strains of mice are deficient in DNA polymerase t and have normal immunoglobulin hypermutation."J. Exp. Med.. 198. 635-643 (2003)
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[Publications] McCulloch, S.D., Kokoska, R.J., Masutani, C., Iwai, S., Hanaoka, F., Kunkel,T.A.: "Preferential cis-syn thymine dimer bypass by DNA polymerase occurs with biased fidelity."Nature. 428. 97-100 (2004)
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「研究成果報告書概要(欧文)」より
