1998 Fiscal Year Final Research Report Summary
Transcription-coupled repair and its deficiency
| Project/Area Number |
09044304
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| Research Category |
Grant-in-Aid for international Scientific Research
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| Allocation Type | Single-year Grants |
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| Section | Joint Research |
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| Research Field |
Molecular biology
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| Research Institution | Osaka University |
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Principal Investigator |
TANAKA Kiyoji Osaka University, Institute for Molecular and Cellular Biology, Professor, 細菌生体工学センター, 教授 (80144450)
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| Co-Investigator(Kenkyū-buntansha) |
YASUI Akira Tohoku University, Institute of Development, Aging and Cancer, Professor, 加齢医学研究所, 教授 (60191110)
BOHR V.A. 国立老化機構研究所, 分子遺伝学研究部, 部長
THOMALE J. エッセン大学, 医学部, 主任研究員
HOEIJMAKERS ジェイ エイチ ジェ エラスムス大学 医学部, 教授
HANAOKA Fumio Osaka University, Institute for Molecular and Cellular Biology, Professor, 細菌生体工学センター, 教授 (50012670)
THOMALE Juergen Essen University, School of Medicine, Senior Scietist
BOHR Vilhelm A. National Institute of Health, National Institute on Aging, Chief
HOEIJMAKERS Jan H.J. Erasmus University, Faculty of Medicine and Health Sciences, Professor
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| Project Period (FY) |
1997 – 1998
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| Keywords | DNA repair / trascription / xeroderma pigmentosum / Cockayne syndrome / microinjection / ultraviolet light / skin cancer / gene targeting |
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| Research Abstract |
Nucleotide excision repair (NER) removes a wide variety of lesions from the genome and is defective in the genetic disorders xeroderma pigmentosum (XP) and Cockayne syndrome (CS). Complementation studies revealed that 7 genes are involved in XP (XPA-XPG) and 2 in CS (CSA, CSB). There are two subpathways in NER : transcription-coupled (TC-)NER accomplishing efficient removal of lesions blocking transcription and the slower global genome (GG-)NER.(1) We recently discovered a novel 855-amino acid protein, XAB2 (XPA-binding protein 2), containing 18 tetratricopeptide repeats, by virtue of its ability to interact with XPA in yeast two hybrid system. Immunoprecipitation analysis demonstrated that XAB2 is associated with the TC-NER-specific proteins CSA, CSB and RNA polymerase II in vivo. Antibodies against XAB2 inhibited both TCR and transcription when microinjected into living fibroblasts. These results indicate that XAB2 is a novel component involved in TC-NER and transcription. (2) XPA- o
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r CSB-deflcient mice were generated. A very important discovery was made when XPA-deficient micethat develop normally was crossed with the CSB-deflcient mice to generate double knockout mice. The double knockout mice appear to exhibit very severe synergistic developmental impairment resulting in extremely early ceasing of developmenta and death 4-6 weeks after birth. These results indicate that CSB and XPA belong to the different epistatic groups and that DNA damage and transcriptional competance contribute to the process of aging. (3) To find out whether NER contributes to preferential removal of 06-EtGua from active genes (asobserved in mammary cells of the rat and thymus cells of the mouse) repair kinetics for this a dduct have been measured in DNA from different tissues of EtNU-exposed XPA +/- and XPA -/- mice. For tissue-specific global repair of 06-EtGua no significant differences were observed between XPA knock out and heterozygote mice. However, this lesion was removed 3-4 times faster from active genes than from total genomic DNA in liver and brain cells of XPA +/- animals. This preferential repair was not observed in the XPA knock out mice. These results indicate that 06-EtGua in the active gene is repaired by NER. Less
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Research Products
(20 results)
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[Publications] Takeuchi, S., Nakatsu, Y., Nakane, H., Murai, H., Hirota, S., Kitamura, Y., Okuyama, A., & Tanaka, K.: "Strand specificity and absence of hotspots for p53 mutations in UVB-induced skin tumors of XPA-deficient mice." Cancer Research. 58. 641-646 (1998)
Description
「研究成果報告書概要(欧文)」より
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[Publications] Winter, D.B., Phung, Q.H., Umar, A., Baker, S.M., Tarone, R.E., Tanaka.K., Liskay, R.M., Kunkel, T.A., Bohr, V.A., & Gearhart, P.J.: "Altered spectra of hypermutation in antibodies from mice deficient for theDNA mismatch repair protein PMS2." Proc.Natl.Acad.Sci.USA.95. 6953-6958 (1998)
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「研究成果報告書概要(欧文)」より
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[Publications] Ikegami, T., Kuraoka, L., Saijo, M., Kodo, N., Y.Kyogoku, Morikawa, K., Tanaka, K., & Shirakawa, M.: "Solution structure of the DNA- and RPA-binding domain of the human repair factor XPA." Nature Structural Biology. 5. 701-706 (1998)
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「研究成果報告書概要(欧文)」より
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[Publications] Kobayashi, T., Takeuchi, S., Saijo, M., Nakatsu, Y., Morioka, H., Otsuka, E., Wakasugi, M., Nikaido, O., & Tanaka, K.: "Mutational analysis of a function of xeroderma pigmentosum group A (XPA) protein in strand specific DNA repair." Nucleic Acid Research. 26. 4662-4668 (1998)
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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., Hoejimakers, J.H.J., and Hanaoka, F.: "Identification and characterization of XPC-binding domain of hHR23B." Mol.Cell.Biol.17. 6915-6923 (1997)
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「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., vander Spek, P.J., Eker, A.P.M., Rademakers, S., Visser, C., Aboussekhra, A., Wood, R.D., Hanaoka, F., Bootsma, D., and Hoejimakers, 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)
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., Iwai, S., van der Spek, P., Eker, A.P.M., Hanaoka, F., Bootsma, D., and Hoeijimakers, J.H.J.: "Xeroderma pigmentosum group C protein complex is the initiator of global gnome nucleotide excision repair." Mol.Cell. 2. 223-232 (1998)
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「研究成果報告書概要(欧文)」より
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[Publications] van der Horst, G.T.J., Muijtjes, M., Kobayashi, K.Takano, R., Kanno, S-1, Takao, M., de Wit, J., Verkerk, A., Eker, A.P.M., van Leenen, D., Buijs, R., Bootsma, D., Hoeijmakers, J.H.J., and Yasui, A.: "Mammalian blue-light receptor homologs CRY1 and CRY2 are essential for maintenance of the biological clock." Nature. (in press.).
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「研究成果報告書概要(欧文)」より
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[Publications] G.T.J.van der Horst, H.van Steeg, R.J.W.Berg, A.J.van Gool, J.de Wit, G.Weeda, H.Morreau, R.B.Beems, C.F.van Kreijl, F.R.de Gruijl, D.Bootsma & J.H.J.Hoeijmakers.: "Defective transcription-coupled repair in Cockayne syndrome B mice is associated with skin cancer predisposition." Cell. 89. 425-435 (1997)
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「研究成果報告書概要(欧文)」より
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