Medical Sciences Group/Inter-Institute Cooperative LaboratoriesMasai Laboratory
(Biomedical Sciences Group, TMiMS)

Precise duplication of genetic materials is central to the stable maintenance of genomes through generations. Defects in the genome copying processes would generate genomic instability which could ultimately result in various diseases including cancer. The goal of our studies is to understand the molecular basis of how the huge genomes are accurately replicated and the precise copies of the genetic materials are inherited to the next generation. Three billion base pairs of the human genome (2 meter long) are replicated with almost no errors during the 6-8 hr time span of the cell cycle. This requires an extreme level of coordination of temporal and spatial arrangements of chromatin organization and signaling events for initiation of DNA replication (13).  We recently discovered novel and crucial roles of non-standard DNA structures in regulation of DNA replication and transcription. Notably, we found that G-quadruplex structures (Fig. 1), which are widely present on genomes (estimated to be at more than 370,000 locations on the human genome), regulate organization of chromatin architecture and initiation of DNA replication (Fig. 2; 6). Recent reports indicate crucial roles of these non-canonical DNA/RNA structures in diverse biological reactions as well as in pathogenesis of diseases. One of our major goals is to establish a novel principle of the genome by elucidating the fundamental and universal functions of G-quadruplex and other non-B type DNA structures in regulation of various genome functions. Through these efforts, we will also explore the possibility that mutations found in various diseases including cancer are related to alteration of these non-B DNA structures, which are likely to be essential components of genomes but somehow have been disregarded in the past.  Our other major projects include 1) Maintenance of genome integrity and its failure as a cause of diseases: Molecular dissection of cellular responses to replication stress, a major trigger for oncogenesis, and elucidation of mechanisms by which stalled forks are processed and the genome is protected from various insults, and of how the failure of this process leads to diseases and senescence (4,5,8). 2) Chromosome dynamics that determines cell fate and regulates cell proliferation: Elucidation of mechanisms regulating temporal and spatial regulation of genome duplication as well as coordination of replication, repair, recombination and transcription (1,3,7,9,10). 3) Unraveling the universal mechanisms of origin firing and its regulation (genetic and enzymological studies using E.coli as a model). 4) DNA replication and development: Understanding the roles of replication factors or replication timing regulation during development/ differentiation processes or during the functioning of various tissues and organs. We have recently found potential novel and critical roles of Cdc7 kinase in development of brain. 5) DNA replication as target of anti-caner drugs: we have developed specific inhibitors of a replication factor as novel anti-cancer drug, and try to find a highly efficient and side-effect-free therapy for cancer patients by novel combination of cell cycle modulation.  To achieve these goals, we are using E.coli, fission yeast, various mammalian cell lines, embryonic stem cells and model animals. We would like ultimately to apply the basic knowledge on the mechanisms of stable genome maintenance to the diagnosis and therapy of the relevant diseases including cancer.  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, USA and Germany and have been excited to have many different cultures in our laboratory. Please feel free to contact us at any time through e-mail or by telephone.

DNA replication, genome stability, cell cycle, chromatin architecture, DNA replication stress checkpoint, embryonic stem cells, G-quadruplex, RNA-DNA hybrids, cancer cells
  • Fig. 1 G-quadruplex (G4) structure

  • Fig. 2 Rif1 regulates chromatin architecture near nuclear periphery
    by binding to G4 structures on the genome.

  • 1  Moriyama et al. (2018) J. Biol. Chem. In press
  • 2  You, Z. and Masai, H. (2017) Nucleic Acids Res. 45, 6495-6506.
  • 3  Toteva et al. (2017) Proc. Natl. Acad. Sci. USA. 114, 1093-1098.
  • 4  Matsumoto et al. (2017) Mol Cell. Biol. 37, pii: e00355-16.
  • 5  Yang et al. (2016) Nature Communications 7:12135
  • 6  Kanoh, Y. et al. (2015) Nature Struct. Mol. Biol. 22, 889-897.
  • 7  Yamazaki, S. et al. (2013) Trends in Genetics. 29, 449-460.
  • 8  Yamada, M. et al. (2013) Genes and Development 27:2459-72.
  • 9  Yamazaki, S. et al. (2012) EMBO J. 31, 3167-3177.
  • 10 Hayano, M. et al. (2012) Genes and Development, 26,137-150.
  • 11 Hayano, M. et al. (2011) Mol. Cell. Biol. 31, 2380-2389.
  • 12 Matsumoto, S. et al. (2011) J. Cell Biol. 195, 387-401.
  • 13 Masai, H. et al. (2010) Ann. Rev. Biochem. 79, 89-130.
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