| Career Summary |
Education
1981 B.Sc., Department of Biochemistry and Biophysics, Faculty of Science, University of Tokyo
1981-1990 Graduate Student and Postdoctoral Fellow, DNAX Research Institute of Molecular and Cellular Biology, Palo Alto, California, USA
1983 M.Sc., University of Tokyo
1986 Ph.D., University of Tokyo
Professional Experience
1986 Postdoctoral Fellow, Department of Molecular Biology, DNAX Research Institute of Molecular and Cellular Biology, Palo Alto, California, USA
1990-1995 Assistant Professor, Department of Molecular and Developmental Biology, Institute of Medical Science, University of Tokyo
1995-2000 Associate Professor, Department of Molecular and Developmental Biology, Institute of Medical Science, University of Tokyo
Visiting Associate Professor, Bioresponse Regulation Laboratory, Virus Institute, University of Kyoto
2000-2005 Laboratory Head, Department of Cell Biology, Tokyo Metropolitan Institute of Medical Sciences
2003-present Visiting Professor, Tokyo Metropolitan University of Health Sciences
2005-present Project Leader, Genome Dynamics Project, Tokyo Metropolitan Institute of Medical Science
2004-present Visiting Professor, The University of Tokyo, Graduate School of Frontier Sciences
2004-present Visiting Professor, University of Tokyo, Graduate School of Frontier Sciences
2005-present Visiting Professor, Tokyo University of Science
2005-present Visiting Professor, Tokyo Medical and Dental University
2006-present Project Leader/ Head, Genome Dynamics Project, Tokyo Metropolitan Institute of Medical Sciences
2007-present Visiting Professor, Tokyo Metropolitan University
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| Educational Activities |
University of Tokyo Graduate School of Arts and Sciences (Summer semester, "Life Science")
University of Tokyo School of Medicine
Tokyo Medical and Dental University, Graduate School
Tokyo Metropolitan University, Graduate School
Tsukuba University, Graduate School
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| Research Activities |
Our goal is to understand the molecular mechanisms underlying the faithful inheritance of genetic materials and stable maintenance of the genome. Toward this goal, we are studying various aspects of chromosome dynamics, with particular focus on regulation during S phase, using E. coli, fission yeast, and mammalian cells. The elucidation of how chromosomes replicate and how the inheritance of the replicated chromosomes is regulated to enable stable maintenance of the genome through generations will shed a new light on how defects in these processes may contribute to the development of diseases, including cancers, and to senescence. It will also help to identify novel target proteins for cancer therapies.
Ongoing projects include the elucidation of i) the genetic program for specifying the locations and timing of replication origin activation, ii) the architecture and regulation of replication forks during the cell cycle, and iii) cellular responses to arrested replication forks for maintaining genetic integrity.
Initiation of eukaryotic DNA replication. Molecular pathway for assembly of prereplicative complex and firing of initiation is indicated. In the bottom of the figure, normal replication fork (right) and stalled replication fork (left) are indicated. Adapted from Masai et al. Annual Review of Biochemistry (2010, in press).
Molecular architecture of a eukaryotic replication fork and its interaction with various chromosome dynamics. Cdc7 kinase plays a major role in regulating replication forks.
Cdc7 network regulating various chromosome dynamics.
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Literature
Original papers (after 2006)
Ogino, K. and Masai, H. (2006) "Rad3-Cds1 mediates coupling of initiation of meiotic recombination with DNA replication: Mei4-dependent transcription as a potential target of meiotic checkpoint."
J. Biol. Chem. 281, 1338-1344.
Tanaka, T. and Masai, H. (2006) "Stabilization of a stalled replication fork by concerted actions of two helicases."
J. Biol. Chem. 281, 3484-3493.
Sasaki, K., Ose, T., Tanaka, T., Mizukoshi, T., Ishigaki, T., Maenaka,K., Masai, H., and Kohda, D. (2006) "Crystallization and preliminary crystallographic analysis of the N-terminal domain of PriA from Escherichia coli."
Biochim. Biophys. Acta. 1764, 157-160.
Kitamura, R., Sekimoto, T., Ito, S., Harada, S., Yamagata, H., Masai, H., Yoneda, H., and Yanagi, K. (2006) "Nuclear import of Epstein-Barr Virus Nuclear Antigen 1 mediated by NPI-1 (Importin 5) is up- and down-regulated by phosphorylation of the nuclear localization signal for which Lys379 and Arg380 are essential."
J. Virol. 80, 1979-1991.
Ogino, K., Hirota, K., Matsumoto, S., Takeda, T., Ohta, K., Arai, K., and Masai, H. (2006) "Hsk1 kinase is required for induction of meiotic double-stranded DNA breaks without involving checkpoint kinases in fission yeast."
Proc. Natl. Acad. Sci. USA 103, 8131-8136.
Hayashida, T., Oda, M., Ohsawa, K., Yamaguchi, A., Giacca, M., Locksley, R. M., Masai, H.*, and Miyatake, S.* (2006) "Replication initiation from a novel origin identified in the Th2 cytokine cluster locus requires a distant conserved non-coding sequence." (*co-communicating authors)
J. Immunol. 176, 5446-5454.
Masai, H., Taniyama, C., Ogino, K., Matsui, E., Kakusho, N., Matsumoto, M., Kim, J.-M., Ishii, A., Tanaka, T., Kobayashi, T., Tamai, K., Ohtani, K., and Arai, K. (2006) "Phosphorylation of MCM4 by Cdc7 kinase facilitates its interaction with Cdc45 on the chromatin."
J. Biol. Chem. 281, 39249-32961. Selected as "JBC paper of the week" and featured on cover of December 22 issue.
Yoshizawa-Sugata, N. and Masai, H. (2007) "Human Tim/Timeless-interacting protein, Tipin, is required for efficient progression of S phase and DNA replication checkpoint."
J. Biol. Chem. 282, 2729-2740.
Tanaka, T., Mizukoshi, T., Sasaki, K., Kohda, D., and Masai, H. (2007) "Escherichia coli PriA protein: Two modes of DNA binding and activation of ATP hydrolysis."
J. Biol. Chem. 282, 19917-19927.
Sasaki, K., Ose, T., Okamoto, N., Maenaka, K., Tanaka, T., Masai, H., Saito, M., Shirai, T., and Kohda, D. (2007) "Structural basis of the 3'-end recognition of a leading strand in stalled DNA replication forks by PriA."
EMBO J. 26, 19917-19927.
Kim, J.-M., Kakusho, N., Yamada, M., Kanoh, Y., Takemoto, N., and Masai, H. (2008) "Cdc7 kinase is required for Claspin phosphorylation in DNA replication checkpoint."
Oncogene 27, 3475-3482.
Sakaue-Sawano, A., Kurokawa, H., Morimura, T., Hanyu, A., Hama, H., Kashiwagi, S., Fukami, K., Imamura, T., Ogawa, M., Masai, H., and Miyawaki, A. (2008) "Spatio-temporal dynamics of multicellular cell cycle progression."
Cell 132, 487-498. Featured on cover of issue.
Sasanuma, H., Hirota, K., Fukuda, T., Kakusho, N., Kugou, N., Kawasaki, Y., Shibata, T., Masai, H., and Ohta, K. (2008) "Cdc7-dependent phosphorylation of Mer2 facilitates initiation of yeast meiotic recombination."
Genes & Dev. 22, 398-410.
Kakusho, N., Taniyama, C., and Masai, H. (2008) "Identification of stimulators and inhibitors of CDC7 kinase in vitro."
J. Biol. Chem. 283, 19211-19218.
You, Z., and Masai, H. (2008) "Cdt1 forms a complex with MCM and activates its helicase activity."
J. Biol. Chem. 283, 24469-24477.
Shimmoto, S., Matsumoto, S., Hayano, M., Yokoyama, M., Noguchi, E., Russell, P. and Masai, H. (2009) "Interactions between Swi1-Swi3, Mrc1 and S phase kinase, Hsk1 may regulate cellular responses to stalled replication forks in fission yeast."
Genes to Cells Apr 29. [Epub ahead of print] PMID: 19422421
Tanaka, H., Kubota, Y., Tsujimura, T., Kumano, M., Masai, H., Takisawa, H. (2009) "Replisom progression complex links DNA replication to sister chromatid cohesion in Xenopus egg extracts."
Genes to Cells 14, 949-963.
Yoshizawa-Sugata, N., and Masai, H. (2009) "Roles of human AND-1 in chromosome transactions in S phase."
J. Biol. Chem. 284, 20718-20728.
Reviews and book chapters (after 2002)
Masai, H. and Arai, K. (2002) Review with cover photo: "Cdc7 kinase complex: A key regulator for initiation of DNA replication."
J. Cell. Physiol. 190, 287-296.
Kim, J.-M., Yamada, M., and Masai, H. (2003) Review: "Defect in Cdc7 kinase leads to checkpoint responses and p53-dependent cell death in mammalian cells."
Mut. Res. 532, 29-40.
Kim, J.-M. and Masai, H. (2004) Review: "Genetic dissection of mammalian Cdc7 kinase: Cell cycle and developmental roles."
Cell Cycle 3, 300-304.
Masai, H., Zhiying, Y., and Arai, K. (2005) Review: "Control of DMA replication: regulation and activation of the eukaryotic replicative helicase, MCM."
IUBMB Life 57, 323-335.
Fujii-Yamamoto, H., Yamada. M., and Masai, H. (2008) Review: "Regulation of DNA replication factors by E2F in cancer and embryonic stem cells."
"Control of Cellular Physiology by E2F Transcription Factors" Research Signpost pp209-221.
Sawa, M., and Masai, H. (2008) Review: "Drug Design with Cdc7 kinase, a potential novel cancer therapy target."
Drug Design, Development and Therapy, 2, 255-264 2008.
Ito, S., Taniyama, C., Arai, N. and Masai, H. (2008) Review: "Cdc7 as a potential new target for cancer therapy."
Drug News and Perspectives, 21 481-488 Featured on the cover of the issue
Toh, G.K., and Masai, H. (2009) "ASK" UCSD-Nature Molecule Pages, in press.
Toh, G.K., and Masai, H. (2009) "Cdc7" UCSD-Nature Molecule Pages, submitted.
Masai, H., Matsumoto, S., You, Z., Sugata-Yoshizawa, N. and Oda, M. (2010) Review: "Eukaryotic DNA replication; where, when and how?" Annual Rev. Biochem. To be published in 2010
Matsumoto, S., Hayano, M., Kanoh, Y., and Masai, H. (2010) Review: "Selection of replication origins in fission yeast." Chromosoma To be published in 2010.
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| Other Activities |
Editorial Board Member, The Journal of Biological Chemistry (2009~)
Editorial Board Member, World Journal of Biological Chemistry (2009~)
Frontiers in Bioscience, Editorial Member (1995~)
Journal of Biochemistry (Tokyo) Advisory Board (1998~2001)
Journal of Biochemistry (Tokyo), Associate Editor (2005~)
Ministry of Education, Culture, Sports, Science, and Technology of Japan, Grant-in-Aid for Scientific Research on Priority Area "Chromosome Cycle", Group Leader
BMB2007 etc., Program Committee Member
Ministry of Education, Culture, Sports, Science, and Technology of Japan, Japan Society for the Promotion of Science, Review Committee Member
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| Future Plan |
In each cell cycle, three billion base pairs of the human genome are replicated within 6-8 hrs with amazing accuracy. The genetic program for this process may be differentially regulated in different cell types and is likely to be under developmental regulation. The elucidation of this "replication program" will shed light on how genome dynamics during DNA replication may be connected not only to other cell cycle events but also to gene expression, epigenesis of the genome, and other modes of regulation of genome functions. Through genomic and molecular approaches, we would like to discover the molecular mechanisms of how this program is regulated. Another goal of our study is to clarify the extraordinary molecular machine involved in this process and eventually reconstitute the machine with purified proteins.
"Oncogenic stresses" are known to induce replication stresses, which inhibit the progression of replication forks. Thus, replication stresses trigger the tumorigenesis process. The maintenance of replication fork integrity is central to the stable inheritance of genetic information through generations and to the preservation of genetic information during the lifespan of an individual. Using mouse model systems, we will unravel the cellular and developmental roles of replication factors. Ultimately, we aim to apply our expertise on the molecular mechanisms of DNA replication and its physiology to the development of strategies for preventing and treating diseases caused by the loss of genetic integrity.
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| Messages to Students |
Science can unite the world through its universal language. The journey to new discoveries is long and hard, but it is rewarding. With your new findings, you can communicate with the entire world. We would like to provide an international and stimulating environment in which you can devote yourself to science. You are welcome to visit our laboratory or contact me by e-mail at any time to find out more about current activities. We have monthly progress report meetings (first Monday of the month) and weekly journal clubs (every Monday morning), which you are welcome to attend.
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