Educational Activities

The University of Tokyo, Graduate School of Frontier Science
University of Tokyo Graduate School of Arts and Sciences (Summer semester, ?"Life Science?”)
University of Tokyo Faculty of Science, Department of Biophysics and Biochemistry
Tokyo University of Agriculture
Miyazaki University
Nippon University

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. We try to elucidate how chromosomes replicate and how the inheritance of the replicated chromosomes is regulated to enable stable maintenance of the genome through generations. Answers to these questions will shed 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.
Through these studies, we have come to realize the roles of non-B DNA, more specifically, G-quadruple (G4) structures. Recent numerous reports indicate the essential roles of various G4 structures in transcription, recombination, genome rearrangement, epigenome regulation and others. Through analyzing the roles of G4 structures in replication initiation and chromatin regulation, we would like to disclose more general biological functions of G4 structures.
DNA replication needs to continue until the entire genome is replicated, once it is initiated. The block to ongoing DNA replication is a threat to the genomic integrity, and needs to be removed swiftly. Claspin/Mrc1 is a key protein that transmits the replication stress signal to the downstream effectors. We have discovered a novel function of Mrc1/Claspin in regulation of initiation through interaction with Cdc7 kinase. Furthermore, we have shown that Claspin is required also for different forms of stress. We propose that Claspin may act as a general stress response mediator by linking stress-specific PIKK (PI3 kinase related kinase) and downstream effectors.



Fig. 1 Regulation of chromatin architecture for establishing replication timing domains. Rif1 facilitates chromatin loop formation through its binding to G4 structures present in the intergenic segments and its multimerization activitiy. This will generate chromatin architecture that may be related to the replication timing domain structures.

Fig. 2 Potential biological roles of G4. Increasing numbers of reports indicate the crucial roles of G4 in various chromosome transactions.


Fig. 3 Roles of Claspin and Cdc7 in regulation of replication initiation and replication stress responses. Cdc7 is recruited to the acidic patch segment of Claspin and facilitates Mcm phosphorylation. Cdc7 also facilitates DNA stress-induced Chk1 activation by promoting Chk1 binding to CKBD.

Literature

Original papers (after 2006)
1. 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.

2. Tanaka, T. and *Masai, H. (2006) "Stabilization of a stalled replication fork by concerted actions of two helicases."
J. Biol. Chem. 281, 3484-3493.

3. 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.

4. 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.

5. 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.

6. 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." (*cocommunicating authors)
J. Immunol. 176, 5446-5454.

7. *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. (This paper was selected as ?"JBC paper of the week?" and was featured in the cover of December 22 issue of JBC.)

8. 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
9. 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.

10. 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

11. 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.

12. 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.

13. 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 the cover of the issue; ?"Exceptional?" evaluation in F1000)

14. Kakusho, N., Taniyama, C. and *Masai, H. (2008) "Identification of stimulators and inhibitors of CDC7 kinase in vitro."
J. Biol. Chem. 283, 19211-19218.

15. You Z. and Masai H. (2008) "Cdt1 forms a complex with MCM and activates its helicase activity."
J. Biol. Chem. 283, 24469-24477.

16. 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 14, 669-682.

17. Tanaka, H., Kubota, Y., Tsujimura, T., Kumano, M., Masai, H. and *Takisawa, H. (2009) "Replisome progression complex links DNA replication to sister chromatid cohesion in Xenopus egg extracts."
Genes to Cells 14, 949-963.

18. Yoshizawa-Sugata, N. and *Masai, H. (2009) "Roles of human AND-1 in chromosome transactions in S phase."
J. Biol. Chem. 284, 20718-20728.

19. Tanaka, T., Yokoyama, M., Matsumoto, S., Fukatsu, R., You, Z. and *Masai, H. (2010) ?"Fission yeast Swi1-Swi3 complex facilitates DNA binding of Mrc1.?"
J. Biol. Chem. 285, 39609-39622.

20. Kundu,L.R., Kumata, Y, Kakusho, N., Watanabe, S., Furukohri, A., Waga, S., Sekia, M., Masai, H., Enomoto, T., and *Tada, S. (2010) "Deregulated Cdc6 inhibits DNA replication and suppresses Cdc7-mediated phosphorylation of Mcm2-7 complex."
Nucleic Acid Res. 38, 5409-5418.

21. Takeishi, Y., Ohashi, E., Ogawa, K, Masai, H., Obuse, C. and *Tsurimoto, T. (2010) "Casein kinase 2-dependent phosphorylation of human Rad9 mediates the interaction between human Rad9-Hus1-Rad1 complex and TopBP1."
Genes Cells 15, 761-771.

22. Furuya, K., Miyabe, I., Tsutsui, Y., Paderi, F., Kakusho, N., Masai, H., Niki, H. and *Carr, A. M. (2010) "DDK phosphorylates checkpoint clamp Rad9 and promotes its release from damaged Chromatin."
Mol. Cell 40, 606-618.

23. Day, T.A., Palle, K., Barkley, L.R., Kakusho, N., Zou, Y., Tateishi, S., Verreault, A., Masai, H. and *Vaziri, C. (2010) "Cdc7-Mediated Rad18 Phosphorylation Directs the Accumulation of DNA Polymerase η at Sites of Stalled Replication."
J. Cell Biol. 191, 953-966.

24. Matsumoto, S., Shimmoto, M., Kakusho, N., Yokoyama, M., Russell, P. and *Masai, H. (2010) "Hsk1 kinase and Cdc45 regulate replication stress-induced checkpoint responses in fission yeast."
Cell Cycle 9, 4627-4637.

25. Kitamura, R., Fukatsu, R., Kakusho, N., Cho, Y-S., Taniyama, C., Yamazaki, S., Toh, G-T., Yanagi, K., Arai, N., Chang, H-J. and *Masai, H. (2011) "Molecular mechanism of activation of human Cdc7 kinase: Bipartite interaction with Dbf4/ASK stimulates ATP binding and substrate recognition."
J. Biol. Chem. 286, 23031-23043.

26. Hayano, M., Kanoh, Y., Matsumoto, S., Kakusho, N. and *Masai, H. (2011) "Pre-firing binding of Mrc1 defines the early-firing origins which are selectively hyper-activated upon loss of fork stabilizing factors in fission yeast."
Mol. Cell. Biol. 31, 2380-2389. (?"Recommended?" evaluation in F1000)

27. Uno, S and *Masai, H. (2011) "Efficient expression and purification of human replication fork-stabilizing factor, Claspin, from mammalian cells: DNA binding activity and novel protein interactions."
Genes to Cells, 16, 842-856.

28. Matsumoto, S., Hayano, M., Kanoh. Y. and *Masai, H. (2011) "Multiple pathways can bypass the essential role of fission yeast Hsk1 kinase in DNA replication initiation."
J. Cell Biol. 195, 387-401. (?"Must Read?" evaluation in F1000)

29. Hayano, M., Kanoh, Y., Matsumoto, S., Shrahige, K. and *Masai, H. (2012) "Rif1 is a global regulator of timing of replication origin firing in fission yeast."
Genes and Development 26,137-150. (?"Exceptional?" evaluation in F1000; Highlighted in A-IMBN Research)

30. Yamazaki, S., Ishii, A., Kanoh, Y., Oda, M., Nishito, Y. and *Masai, H. (2012) "Rif1 protein is a key regulator of the genome-wide DNA replication timing in human cells."
EMBO J. 31, 3167-3177. (Highlighted in Commentary; highlighted in A-IMBN Research)

31. Barkley, L.R., Palle, K., Durando, M., Day, T.A., Gurkar, A., Kakusho, N., Li, J., Masai, H., *Vaziri, C. (2012) "c-Jun N-terminal Kinase (JNK)-Mediated Rad18 Phosphorylation Facilitates Polη Recruitment to Stalled Replication Forks."
Mol. Biol. Cell. 23, 1943-1954.

32. Moriyama, K., Yoshizawa-Sugata, N., Obuse, C., Tsurimoto, T. and *Masai, H. (2012) "EBNA1-dependent recruitment of Orc on OriP of Epstein-Barr virus with purified proteins: Stimulation by Cdc6 through Its direct interaction with EBNA1."
J. Biol. Chem. 287, 23977-23994.

33. Ito, S., Ishii, A., Kakusho, N., Taniyama, C., Yamazaki, S., Sakaue-Sawano, A., Miyawaki, A., and *Masai, H. (2012) "Mechanism of cancer cell death induced by depletion of an essential replication regulator."
PLoS One, 7, e36372. (Highlighted in A-IMBN Research)

34. Uno, S., You, Z., and *Masai, H. (2012) "Purification of replication factors using insect and mammalian cell expression systems."
Methods, 57, 214-221.

35. Oda, M., Kanoh, Y., Watanabe, Y., and *Masai, H. (2012) "Regulation of DNA replication timing on human chromosome by a cell-type specific DNA binding protein SATB1."
PLoS One 7, e42375.

36. Miyoshi, T., Kugou, K., Yamada, S., Ito, M., Furuichi, M., Oda, A., Hirota, K. and Masai, H. and *Ohta, K. (2012) "A central coupler for recombination initiation linking chromosome architecture to S-phase checkpoint."
Mol. Cell 47, 722-733.

37. Suzuki, T., Tsuzuku, J., Hayashi, A., Shiomi, Y., Iwanari, H., Mochizuki, Y., Hamakubo, T., Kodama, T., Nishitani, H., Masai, H. and *Yamamoto, T. (2012) "Inhibition of DNA damage-induced apoptosis through Cdc7-mediated stabilization of Tob."
J. Biol. Chem. 287, 40256-40265. (Highlighted in A-IMBN Research)

38. Yamada, M., Watanabe, K., Mistrik, M., Mailand, N., Lee, M-H., Masai, H., Lukas, J. and *Bartek, B. (2013) "ATR-Chk1-APC/CCdh1-dependent stabilization of Cdc7-ASK(Dbf4) kinase complex is required for DNA damage bypass under replication stress."
Genes and Development 27, 2459-2472.

39. You, Z., De Falco, S., Pisani, F.M. and *Masai, H. (2012) "MCM helicase interacts with primase and stimulates its priming activity."
PLoS One 8, e72408

40. Aria, V., De Felice, M., Di Perna, R., Uno, S., Masai, H., Syvaoja, J.E., van Loon, B., Hubscher, U., *Pisani, F.M. (2013) "The Human Tim/Tipin Complex Directly Interacts with DNA Polymerase {epsilon} and Stimulates its Synthetic Activity."
J. Biol. Chem. 288, 12742-12752.

41. Jeffery, D.C., Wyse, B.A., Rehman, M.A., Brown, G.W., You, Z., Oshidari, R., Masai, H., *Yankulov, K.Y. (2013) "Analysis of epigenetic stability and conversions in Saccharomyces cerevisiae reveals a novel role of CAF-I in position-effect variegation."
Nucleic Acids Res. 41, 8475-8488.

42. Tanikawa, M., Wada-Hiraike, O., Yoshizawa-Sugata, N., Shirane A, Hirano M, Hiraike H, Miyamoto, Y., Sone, K., Ikeda, Y., Kashiyama, T., Oda K, Kawana K, Katakura Y, Yano T, Masai, H., Roy AL, Osuga, Y., *Fujii, T. (2013) "Role of multifunctional transcription factor TFII-I and putative tumour suppressor DBC1 in cell cycle and DNA double strand damage repair."
Br. J. Cancer. 109, 3042-3048.

43. Bellelli, R., Castellone, M.D., Guida, T., Limongello, R., Dathan, N.A., Merolla, F., Cirafici, A.M., Affuso, A., Masai, H., Costanzo, V., Grieco, D., Fusco, A., Santoro, M., and *Carlomagno, F. (2014) "NCOA4 Transcriptional Coactivator Inhibits Activation of DNA Replication Origins."
Mol. Cell 55, 123-137.

44. D., Kakusho, N., You, Z., Gharib, M., Wyse, B., Drury, E., Weinreich, M., Thibault, P. Verreault, A., Masai, H. and *Yankulov, K. (2015) "CDC28 phosphorylates Cac1p and regulates the association of Chromatin Assembly Factor I with chromatin."
Cell Cycle 14, 74-85.

45. Kotaro Koiwai, Takashi Kubota, Nobuhisa Watanabe, Katsutoshi Hori, Osamu Koiwai and *Hisao Masai (2015) "Definition of the transcription factor TdIF1 consensus binding sequence through genome-wide mapping of its binding sites."
Genes to Cells 20, 242-254.

46. Zech, J., Godfrey, E.L., Masai, H., Hartsuiker, E. and *Dalgaard, J.Z. (2015) "The DNA-Binding Domain of S. pombe Mrc1 (Claspin) Acts to Enhance Stalling at Replication Barriers."
PLoS One 10, e0132595.

47. Iguchi, T., Aoki, K., Ikawa, T., Taoka, M., Taya, C., Yoshitani, H., Toma-Hirano, M., Koiwai, O., Isobe, T., Kawamoto, H., Masai, H. and *Miyatake, S. (2015) "BTB-ZF Protein Znf131 Regulates Cell Growth of Developing and Mature T Cells."
J. Immunol. 195:982-993.

48. Yutaka Kanoh, Seiji Matsumoto, Rino Fukatsu, Naoko Kakusho, Nobuaki Kono, Claire Renard-Guillet, Koji Masuda, Keisuke Iida, Kazuo Nagasawa, Katsuhiko Shirahige, and *Hisao Masai (2015) "Rif1 binds to G-quadruplexes and suppresses replication over long distances."
Nature Struct. Mol. Biol. 22, 889-897.

49. Zhiying You, Koji L. Ode, Haruhiko Takisawa, and *Hisao Masai (2016) "Characterization of conserved arginine residues on Cdt1 that affect licensing activity and interaction with Geminin or Mcm complex."
Cell Cycle 5, 1213-1226.

50. Tanaka T, Nishito Y, *Masai H. (2016) "Fork restart protein, PriA, binds around oriC after depletion of nucleotide precursors: Replication fork arrest near the replication origin."
Biochem. Biophys. Res. Commun. 470, 546-551.

51. Tanaka H, Muto A, Shima H, Katoh Y, Sax N, Tajima S, Brydun A, Ikura T, Yoshizawa N, Masai H, Hoshikawa Y, Noda T, Nio M, Ochiai K, *Igarashi K. (2016) "Epigenetic Regulation of the Blimp-1 Gene (Prdm1) in B Cells Involves Bach2 and Histone Deacetylase 3."
J. Biol. Chem. 291, 6316-6330.

52. *Nonaka T, Suzuki G, Tanaka Y, Kametani F, Hirai S, Okado H, Miyashita T, Saitoe M, Akiyama H, Masai H, Hasegawa M. (2016) "Phosphorylation of TAR DNA-binding Protein of 43 kDa (TDP-43) by Truncated Kinase 1delta Triggers Mislocalization and Accumulation of TDP-43."
J. Biol. Chem. 291, 5473-5483.

53. Chi-Chun Yang, Masahiro Suzuki, Shiori Yamakawa, Syuzi Uno, Ai Ishii, Satoshi Yamazaki, Rino Fukatsu, Ryo Fujisawa, Kenji Sakimura3, Toshiki Tsurimoto, *Hisao Masai (2016) "Claspin recruits Cdc7 kinase for initiation of DNA replication in human cells."
Nature Communications 7:12135 doi: 10.1038/ncomms12135.

54. Matsumoto, S., Kanoh, Y., Shimmoto, M., Hayano, M., Ueda, K., Fukatsu, R., Kakusho, N., *Masai, H. (2017) "Checkpoint-independent Regulation of Origin Firing by Mrc1 through Interaction with Hsk1 kinase."
Mol. Cell. Biol. In press

55. Toteva, T., Mason, B., Kanoh, Y. Brogger, P. Green, D., Verhein-Hansen, J. Masai, H. and *Thon, G. (2017) "Establishment of expression-state boundaries by Rif1 and Taz1 in fission yeast."
Proc. Natl. Acad. Sci. USA. In press

56. You, Z. and Masai, H. (2017) ”Potent DNA strand annealing activity associated with mouse Mcm2~7 heterohexamer complex.”
Nucleic Acids Res. Revised manuscript submitted

Reviews and book chapters (after 2008)

1 Fujii-Yamamoto, H., Yamada. M., and *Masai, H. (2008) "Regulation of DNA replication factors by E2F in cancer and embryonic stem cells." in "Control of Cellular Physiology by E2F Transcription Factors" Research Signpost 209-221.

2 Ito, S., Taniyama, C., Arai, N. and *Masai, H. (2008) "Cdc7 as a potential new target for cancer therapy." Drug News and Perspectives 21, 481-488. Featured on the cover of the issue

3 Sawa, M., and *Masai, H. (2009) "Drug Design with Cdc7 kinase, a potential novel cancer therapy target." Drug Design, Development and Therapy 2, 255-264.

4 Toh, G.K., and *Masai, H. (2009) "ASK" UCSD-Nature Molecule Pages, Published online: 25 Feb 2009 | doi:10.1038/mp.a000345.01 (Review)

5 *Masai, H., Matsumoto, S., You, Z., Yoshizawa-Sugata, N. and Oda, M. (2010) "Eukaryotic DNA replication; where, when and how?" Annual Rev. Biochem. 79, 89-130.

6 *Masai, H., Tanaka, T. and Kohda, D. (2010) "Stalled replication forks: Making ends meet for recognition and stabilization." Bioessays 32, 687-697. (Review)

7 Tanaka, T. and *Masai, H. (2010) "Bacterial primosome." In: Encyclopedia of Life Sciences (ELS). John Wiley & Sons, Ltd: Chichester. DOI: 10.1002/9780470015902.a0001048.pub2

8 Tanaka, T. and *Masai, H. (2010) "Bacterial replication fork: synthesis of lagging strand." In: Encyclopedia of Life Sciences (ELS). John Wiley & Sons, Ltd: Chichester. DOI: 10.1002/9780470015902.a0001049.pub2

9 *Masai, H. (2010) "FANCs regulate firing of DNA replication origins." Cell Cycle 9, 2494.

10 Vaziri, C. and *Masai H. (2010) "Integrating DNA replication with Trans-Lesion Synthesis via Cdc7." Cell Cycle 9, 4818-4823.

11 *Masai, H. (2011) "RecQL4: a helicase linking formation and maintenance of a replication fork." J. Biochem. 149, 629-631 (commentary)

12 Toh G-T. and *Masai, H. (2012) "Cdc7L1" UCSD-Nature Molecule Pages, Published online: 31 August 2012 | doi:10.6072/H0.MP.A003137.01 (Review)

13 *Masai, H. (2012) "Cdc7" The Encyclopedia of Signaling Molecules Springer Reference and Database Publishing

14 *Masai, H. (2012) "Dbf4" The Encyclopedia of Signaling Molecules Springer Reference and Database Publishing

15 Yamazaki, Hayano, M. and *Masai, H. (2013) "Replication timing regulation of eukaryotic replicons: Rif1 as a global regulator of replication timing." Trends in Genetics. 29, 449-460.

16 *Masai, H. (2013) "A personal reflection on the Replicon Theory: from R1 plasmid to replication timing regulation in human cells." J. Mol. Biol. 425, 4663-4672. (Review)

17 Matsumoto, S. and *Masai, H. (2013) "Regulation of chromosome dynamics by Hsk1 kinase."
Biochemical Society Transactions 41, 1712-1719. (Review)

18 Yoshizawa-Sugata, N. and *Masai, H. (2014) "Cell cycle synchronization and flow cytometry analysis of mammalian cell."
Methods in Molecular Biology, 1170, 279-293. (Review)

19 *Masai, H. (2014) "ATM in prevention of genomic instability."
Cell Cycle, 13, 882-883. (News and Views)

20 Renard-Guillet, C., Kanoh, Y., Shirahige, K., and *Masai, H. (2014) "Recent advances in temporal and spatial regulation of eukaryotic DNA replication: From regulated initiation to genome-scale timing program." Seminars in Cell & Developmental Biology, 30, 110-120. (Review)

21 Yamada, M., Masai, H., and *Bartek, J. (2014) "Regulation and roles of Cdc7 kinase under replication stress." Cell Cycle 13, 1859-1866.

22 *Masai, H. (2015) "Building up the machinery for DNA replication." Cell Cycle 14, 3011-3012. (News and Views)

23 Naoko Yoshizawa, Satoshi Yamazaki, and *Hisao Masai (2015) "Rif1, a conserved chromatin factor regulating DNA replication, DNA repair and transcription." In The Initiation of DNA Replication in Eukaryotes (Springer)

24 Hayano, M., Matsumoto, S. and *Masai, H. (2015) "DNA Replication Timing: Temporal and Spatial Regulation of Eukaryotic DNA Replication." in Fumio Hanaoka and Kaoru Sugasawa (Eds): DNA Replication, Recombination, and Repair (Springer)

Other Activities

Journal Editorial
Editorial Board Member, Journal of Biological Chemistry (2009~2013)
Associate Editor, Genes to Cells (2009~Present)
Advisory Board, Journal of Biochemistry (2010~2012)
Editorial Board Member, World Journal of Biological Chemistry (2010~Present)
Associate Editor, Journal of Biochemistry (Tokyo) (2006~Present)
Editorial Board Member, Journal of Biochemistry (Tokyo) (1998-2001)
Editor, Frontiers in Bioscience (1995-Present)
Faculty1000 member (2011~Present)
Editor, Biochemical and Biophysical Research Communications (2013~Present)
Other responsibilities
?Associate Member, Science Council of Japan (2010~Present)
?Advisory Board Member, The Molecular Biology Society of Japan (2008~2010)
Advisory Board Member, The Molecular Biology Society of Japan (2017~Present?)
Advisory Board Member, Japanese Biochemistry Society (2006~Present)
AdHoc Panel Member, Ministry of Education, Culture, Sports, Science and Technology
Program committee, Symposium organizer at the Annual Meetings of Japanese Molecular Biology Society etc. spacer

Future Plan

In each cell cycle, three billion base pairs of the human genome are replicated within 6-8 hrs with amazing accuracy, while initiation takes place at tens of thousands of so called ?"replication origins?”. Selection of replication origins for initiation is regulated by a number of factors, while a large fraction of origin selection may be determined stochastically. Yet, the initiation does take place at sequences that may be associated with some features. Our studies as well those from other groups suggest that G-quadruplex may be a candidate structure that may be associated with replication initiation. Our current goal is to reconstitute ?"human-like?" replication system in E.coli with purified proteins on G4 sequences.
We have already indicated the importance of G4 in establishment of replication timing domain structures by showing that Rif1, a factor crucial for replication timing regulation, binds specifically to G4 DNA. We would like to understand molecular basis on how Rif1 facilitates chromatin loop formation by binding to G4. G4 is associated with other chromosome transactions as well, and a number of proteins bind to G4. We would like to clarify the modes and nature of interaction between G4 and its binding partners, elucidate the mode of actions of these proteins and ultimately obtain global views on potential biological functions of G4.
Replication factors are involved not only in the process of DNA replication but also in other aspects of chromosome functions. In order to clarify the organismal roles of replication factors, we target Cdc7, Claspin and other replication factors and generate genetically modified mice. Tissue/ organ-specific knock-out will reveal their novel functions, and will lead to understanding the pathology of human genetic disorders caused by mutations in these factors.
?"Oncogenic stress?” is known to induce replication stress, which inhibits the progression of replication forks. Thus, replication stress triggers the tumorigenesis process. The maintenance of replication fork integrity is central to the stable inheritance of genetic information through generations and to its preservation during the lifespan of an individual. Using mouse model systems as stated above, 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.

Messages to Students

Science can unite the world through its universal language. The journey to new discoveries is long and hard, but is rewarding. With your new findings, you can communicate with the entire world. We would like to provide international and stimulating environment in which you can devote yourself to science.
We are recruiting highly motivated and interested individuals who are communicative and can share excitement with us in the laboratory. We have had students from many foreign countries including Korea, Malaysia, Taiwan, China, Canada, Italy, France and Germany and have been excited to have many different cultures in our laboratory.
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.

URL

https://www.igakuken.or.jp/genome/?lang=en