2005 Fiscal Year Final Research Report Summary
From G1 regulators to Replication machinery
| Project/Area Number |
12141101
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| Research Category |
Grant-in-Aid for Scientific Research on Priority Areas
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| Allocation Type | Single-year Grants |
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| Review Section |
Biological Sciences
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| Research Institution | Tokyo Metropolitan Institute of Medical Science |
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Principal Investigator |
MASAI Hisao Tokyo Metropolitan Institute of Medical Science, Genome Dynamics Project, Project Leader, 東京都臨床医学総合研究所, 副参事研究員 (40229349)
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| Co-Investigator(Kenkyū-buntansha) |
OHTANI Kiyoshi Tokyo Medical and Dental University, Human Gene Sciences Center, Instrutor, 疾患遺伝子実験センター, 講師 (30201974)
FUJITA Masatoshi National Cancer Center Reseach Institute, Virology Division, General Manager, ウイルス部, 室長 (30270713)
MURAKAMI Yota Kyoto University, Institute for Virus Research, Department of Viral Oncology, Associate Professor, ウイルス研究所, 助教授 (20260622)
TSURIMOTO Toshiki Kyusyu University, School of Sciences, Department of Biology, Professor, 理学研究院, 教授 (30163885)
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| Project Period (FY) |
2000 – 2005
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| Keywords | G1-S transition / E2F transcription factor / prereplicative complex / MCM complex / Cdc7 kinase / Cyclin-dependent kinase / Nuclear Matrix Attachment / Clamp-Clamp loader |
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| Research Abstract |
G1 signals activate Cdk4-CyclinD, which in turn activates E2F by phosphorylation of Rb. Our results show that E2F induces not only factors required for G1-S transition but also S phase regulators, checkpoint proteins, repair factors and G2-M transition factors. This will lead to activation of growth cycle and brings about coordinated progression of S phase as well as subsequent mitotic events. Replication factors induced by E2F promote generation of prereplicative complexes on the chromatin. This process may be intimately linked to interaction of replication machinery with nuclear matrix through transcription factors. Cdk and Cdc7 phosphorylates the N-terminal tails of MCM2 and MCM4 proteins and this phosphorylation results in recruitment of additional replication factors including Cdc45. MCM helicase is activated specifically by the single-stranded thimine-rich sequences which may be exposed during this step. Multiple clamp-clamp loader systems operate during the operation of replication forks, permitting the coordinated execution of fork-related activities including DNA synthesis, sister chromatid cohesion, and chromatin assembly. Tauti-potent stem cells undergo specific cell cycle program which may be achieved by overexpression of a subset of crucial replication/ cell cycle regulators. In cancer cells, the steady-state expression levels of the replication factors are distinctively different from the normal cells, and downregulation of replication factors in cancer cells often leads to induction of cell death, raising a possibility that replication factors could be novel targets for cancer therapy. On the other hand, deregulation of some critical factors including Cdt1 leads to induced genetic instability which may results in malignant growth.
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[Journal Article] RNA polymerase II is required for siRNA generation and peri-centromeric heterochromatin formation in fission yeast.2005
Author(s)
Kato, H., Goto, D.B., Martienssen, R.A., Urano, T., Furukawa, K., Murakami, Y.
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Journal Title
Science 309
Pages: 467-469
Description
「研究成果報告書概要(和文)」より
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[Journal Article] RNA polymerase II is required for siRNA generation and peri-centromeric heterochromatin formation in fission yeast.2005
Author(s)
Kato, H., Goto, D.B., Martienssen, R.A., Urano, T., Furukawa, K, Murakami, Y.
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Journal Title
Science. 309
Pages: 467-469
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Cdt1 phosphorylation by cyclin A-dependent kinases negatively regulates its function without affecting geminin binding.2004
Author(s)
Sugimoto, N., Tatsumi, Y., Tsurumi, T., Matsukage, A., Kiyono, T., Nishitani, H., Fujita, M.
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Journal Title
J.Biol.Chem. 279
Pages: 19691-19697
Description
「研究成果報告書概要(和文)」より
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[Journal Article] Cdt1 phosphorylation by cyclin A-dependent kinases negatively regulates its function without affecting geminin binding.2004
Author(s)
Sugimoto, N., Tatsumi, Y., Tsurumi, T., Matsukage, A., Kiyono, T., Nishitani, H, Fujita, M.
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Journal Title
J. Biol. Chem. 279
Pages: 19691-19697
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Thymine-rich single-stranded DNA activates Mcm4/6/7 helicase on Y-fork and bubble-like substrates.2003
Author(s)
You, Z., Ishimi, Y., Mizuno T., Sugasawa, K., Hanaoka, F., Masai, H.
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Journal Title
EMBO J 22
Pages: 6148-6160
Description
「研究成果報告書概要(和文)」より
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[Journal Article] Thymine-rich single-stranded DNA activates Mcm4/6/7 helicase on Y-fork and bubble-like substrates.2003
Author(s)
You, Z., Ishimi, Y., Mizuno T., Sugasawa, K., Hanaoka, F, Masai, H.
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Journal Title
EMBO J. 22
Pages: 6148-6160
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Inactivation of Cdc7 kinase in mouse embryonic stem cells results in S phase arrest and p53-dependent cell death.2002
Author(s)
Kim, J.M., Nakao, K., Nakamura, K., Saito, I., Katsuki, M., Arai, K., Masai, H.
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Journal Title
EMBO J. 21
Pages: 2168-2179
Description
「研究成果報告書概要(和文)」より
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[Journal Article] Inactivation of Cdc7 kinase in mouse embryonic stem cells results in S phase arrest and p53-dependent cell death.2002
Author(s)
Kim, J.M., Nakao, K., Nakamura, K., Saito, I., Katsuki, M., Arai, K, Masai, H.
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Journal Title
EMBO J. 21
Pages: 2168-2179
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] ATP-dependent structural change of the eukaryotic clamp loader protein, RFC.2000
Author(s)
Shiomi, Y., Usukura, J., Masamura, Y., Takeyasu, K., Nakayama, Y., Obuse, C., Yoshikawa, H., Tsurimoto, T.
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Journal Title
Proc.Natl.Acad.Sci.USA 97
Pages: 14127-14132
Description
「研究成果報告書概要(和文)」より
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[Journal Article] ATP-dependent structural change of the eukaryotic clamp loader protein, RFC.2000
Author(s)
Shiomi, Y., Usukura, J., Masamura, Y., Takeyasu, K, Nakayama, Y., Yoshikawa, H, Tsurimoto, T.
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Journal Title
Proc.Natl.Acad.Sci.USA. 97: Obuse, C.
Pages: 14127-14132
Description
「研究成果報告書概要(欧文)」より
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