Kyushu University Academic Staff Educational and Research Activities Database
Researcher information (To researchers) Need Help? How to update
Yoshimichi Nakatsu Last modified date:2019.06.25

Associate Professor / Bioregulation
Department of Basic Medicine
Faculty of Medical Sciences


Graduate School
Undergraduate School


E-Mail
Homepage
http://www.biophys.med.kyushu-u.ac.jp/
Department of Medical Biophysics and Radiation Biology, Faculty of Medical Sciences .
Phone
092-642-6142
Fax
092-642-6145
Academic Degree
Doctor of Science
Country of degree conferring institution (Overseas)
No
Field of Specialization
Molecular Biology
Total Priod of education and research career in the foreign country
03years08months
Research
Research Interests
  • Genomic destabilization under hypoxic culture condition
    keyword : Oxidative stress, Mutation, MSI, hiPSC, MEF
    2018.04~2020.03.
  • Search for environmental and genetic factors that enhance microsatellite instability in mismatch repair deficient human cells
    keyword : Genomic destabilization, mismatch repair, colorectal cancer
    2016.04.
  • Effects of plasma on mammalian genome
    keyword : Non-thermal plasma, rpsL-transgenic mice, ROS, NOS, mutation, cell death
    2015.04~2017.03.
  • Analysis of MUTYH/MutS alpha complex induced by oxidative stress
    keyword : oxidative DNA damage, mismatch repair, cell death, mutagenesis
    2014.04~2017.03.
  • Mutagenesis and carcinogenesis caused by the failure of the mechanisms for DNA damage response
    keyword : oxidative stress DNA repair mismatch repair cell-death
    2013.04~2017.03.
  • Molecular mechanisms for DNA damage response
    keyword : mutation cell-death adaptive response mismatch repair
    2009.04~2013.03.
  • Molecular mechanisms for prevention and elimination of oxidative DNA damages
    keyword : oxidative DNA damages, nucleotide, mutagenesis, cell death, carcinogenesis, gene-knockout mice, transgenic mice
    2001.06.
Current and Past Project
  • The MUTYH gene is known to be associated with Familial adenomatous polyposis (MAP: MUTYH -associated polyposis), and encodes a DNA repair protein that suppresses mutations caused by oxidative stress in mammalian cells. MUTYH is involved not only in the suppression of mutations but also in the cell death induced by oxidative stress. In this study, I investigate the role of MUTYH associated with mismatch repair proteins in the induction of cell death caused by oxidative stress.
  • We developed an experimental system for oxidative stress-inducing mutagenesis and carcinogenesis in the intestine of mice. In oder to identify the common genes mutated in the adenomas/carcinomas induced by using this system, we analyze the genomes of adenomas/carcinomas induced in the same animals.
  • Mutagenesis caused by oxidized nucleotides and it preventing mechanisms.
    Analysis of cell death pathway evoked by oxidized nucleotides.
  • Oxygen-induced DNA damage and its repair mechanism
Academic Activities
Books
1. Yoshimichi Nakatsu, Mutso Sekiguchi, Oxidative Damage to Nucleotide: Consequences and Preventive Mechanism, Imperial College Press, "Oxidative Stress, Disease and Cancer" Singh, KK (Ed), pp221-252, 2006.01.
Reports
1. Tsuzuki T, Nakatsu Y, Nakabeppu Y, Significance of error-avoiding mechanisms for oxidative DNA damage in carcinogenesis, Cancer Science, 2007.08.
Papers
1. Genki Hayashida, Seijiro Shioi, Kyoko Hidaka, Ryosuke Fujikane, Masumi Hidaka, Toshiki Tsurimoto, Teruhisa Tsuzuki, Shinya Oda, Yoshimichi Nakatsu, Differential genomic destabilisation in human cells with pathogenic MSH2 mutations introduced by genome editing, Experimental Cell Research, 10.1016/j.yexcr.2019.02.020, 377, 1-2, 24-35, 2019.04, Repeat destabilisation is variously associated with human disease. In neoplastic diseases, microsatellite instability (MSI) has been regarded as simply reflecting DNA mismatch repair (MMR) deficiency. However, several discrepancies have been pointed out. Firstly, the MSI + phenotype is not uniform in human neoplasms. Established classification utilises the frequency of microsatellite changes, i.e. MSI-H (high) and -L (low), the former regarded as an authentic MMR-defective phenotype. In addition, we have observed the qualitatively distinct modes of MSI, i.e. Type A and Type B. One discrepancy we previously pointed out is that tumours occurring in MMR gene knockout mice exhibited not drastic microsatellite changes typical in MSI-H tumours (i.e. Type B mode) but minor and more subtle alterations (i.e. Type A mode). In the present study, MSH2 mutations reported in Lynch syndrome (LS) kindred have been introduced into HeLa cells using the CRISPR/Cas9 system. The established mutant clones clearly exhibited MMR-defective phenotypes with alkylating agent-tolerance and elevated mutation frequencies. Nevertheless, microsatellites were not markedly destabilised as in MSI-H tumours occurring in LS patients, and all the observed alterations were uniformly Type A, which confirms the results in mice. Our findings suggest added complexities to the molecular mechanisms underlying repeat destabilisation in human genome..
2. Takuro Isoda, Yoshimichi Nakatsu, Kazumi Yamauchi, Takashi Yao, Jingshu Piao, Hiroshi Honda, Yusaku Nakabeppu, Teruhisa Tsuzuki, Abnormality in Wnt Signaling is Causatively Associated with Oxidative Stress-Induced Intestinal Tumorigenesis in MUTYH-Null Mice, Int. J. Biol. Sci., 10.7150/ijbs.9241, 10, 8, 940-947, 2014.08.
3. Jingshu Piao, Yoshimichi Nakatsu, Mizuki Ohno, Ken-ichi Taguchi, Teruhisa Tsuzuki, Mismatch repair deficient mice show susceptibility to oxidative stress-induced intestinal carcinogenesis, International Journal of Biological Sciences, 10.7150/ijbs.5750, 10, 1, 73-79, 2013.12.
4. Teik How Lim, Ryosuke Fujikane, Shiori Sano, Ryuji Sakagami, Yoshimichi Nakatsu, Teruhisa Tsuzuki, Mutsuo Sekiguchi, Masumi Hidaka, Activation of AMP-activated protein kinase by MAPO1 and FLCN induces apoptosis triggered by alkylated base mismatch in DNA, DNA Repair, doi:10.1016/j.dnarep.2011.11.006, 11, 259-266, 2011.12, O6-Methylguanine produced in DNA by the action of simple alkylating agents, such as N-methyl-N- nitrosourea (MNU), causes base-mispairing during DNA replication, thus leading to mutations and cancer. To prevent such outcomes, the cells carrying O6 -methylguanine undergo apoptosis in a mismatch repair protein-dependent manner. We previously identified MAPO1 as one of the components required for the induction of apoptosis triggered by O6-methylguanine. MAPO1, also known as FNIP2 and FNIPL, forms a complex with AMP-activated protein kinase (AMPK) and folliculin (FLCN), which is encoded by the BHD tumor suppressor gene. We describe here the involvement of the AMPK–MAPO1–FLCN complex in the signaling pathway of apoptosis induced by O6-methylguanine. By the introduction of siRNAs specific for these genes, the transition of cells to a population with sub-G1 DNA content following MNU treatment was significantly suppressed. After MNU exposure, phosphorylation of AMPK.
5. Teruhisa Tsuzuki, Jingshu Piao, Takuro Isoda, Kunihiko Sakumi, Yusaku Nakabeppu, Yoshimichi Nakatsu, Oxidative stress-induced tumorigenesis in the small intestine of various types of DNA repair-deficient mice, Health Physics, 100, 293-294, 2011.05.
6. Komori K, Takagi Y, Sanada M, Lim TH, Nakatsu Y, Tsuzuki T, Sekiguchi M, Hidaka M, A novel protein, MAPO1, that functions in apoptosis triggered by O6-methylguanine mispair in DNA, Oncogene, 28(8):1142-1150, 2009.02.
7. Kuraoka I, Ito S, Wada T, Hayashida M, Lee L, Saijo M, Nakatsu Y, Matsumoto M, Matsunaga T, Handa H, Qin J, Nakatani Y, Tanaka K, Isolation of XAB2 complex involved in pre-mRNA splicing, transcription, and transcription-coupled repair, J Biol Chem, 283(2):940-950, 2008.01.
8. Sakamoto K, Tominaga Y, Yamauchi K, Nakatsu Y, Sakumi K, Yoshiyama K, Egashira A, Kura S, Yao T, Tsuneyoshi M, Maki H, Nakabeppu Y, Tsuzuki T, MUTYH-null mice are susceptible to spontaneous and oxidative stress induced intestinal tumorigenesis, Cancer Research, 67(14):6599-6604, 2007.07.
Presentations
1. Yoshimichi Nakatsu, Noriko Takano, Mizuki Ohno, Satoshi Kitazaki, Kazunori Koga, Akiyo Tanaka, Masaharu Shiratani, Application of transgenic mice to analyze genotoxic effects induced by non-thermal atmospheric air plasma
, 10th Anniversary International Symposium on Advanced Plasma Science and its Applications for Nitrides and Nanomaterials /11th International Conference on Plasma-Nano Technology & Science. (ISPlasma2018 / IC-PLANTS2018), 2018.03, Non-thermal atmospheric plasma has been used for biomedical applications such as blood coagulation, wound healing, and decontamination [1]. In addition, the plasma has been proposed as a potential tool for cancer therapy because of its ability to induce apoptosis in cancer cells.
Non-thermal atmospheric plasma as well as ionizing radiation generates reactive oxygen species (ROS) in the liquid phase [2]. ROS such as hydroxyl radical induce DNA double-strand break (DSB) and lead to cell death. The apoptotic induction of cancer cells by plasma treatment could be mediated by ROS. The cytotoxic activity was also observed in plasma-treated medium, so called plasma-activated medium (PAM) [3]. PAM has been shown to have a selective cytotoxicity in several cancer cell lines, even chemotherapeutic agent resistant cell lines, providing a potential treatment for novel anti-cancer therapies [4]. The cytotoxic effect of PAM is suggested to be mediated by ROS such as H2O2.
DSBs can be repaired by two different pathways: homologous recombination (HR) and non-homologous end joining (NHEJ) [5]. HR is an error-free repair pathway, but it can be operated only in S and G2 phase of cell cycle because HR needs the sister chromatid as a repair template that is synthesized by DNA replication during the S phase. NHEJ is the predominant repair pathway during the G1 phase, and this is especially important for the cells in tissues/organs that is resting in G0/G1 phase or non-dividing status. NHEJ is characterized by rejoining of broken ends without the use of extensive homology, and is frequently associated with the presence of small insertions/deletions at DSB site. In addition to DSB, ROS induced various modified bases, and more than 20 different types of oxidatively altered purines and pyrimidines have been detected [6]. These DNA damages also induce mutations and cell death, if not repaired.
Biomedical applications of plasma in either direct or indirect way are always associated with the generation of ROS that cause oxidation of cellular DNA in the treated tissues. If the plasma-induced DNA damages are not correctly repaired in the surviving cells, the accumulation of mutations occurs in the surviving cells, leading to the increase of a risk for carcinogenesis in the treated tissues. Therefore, biomedical applications of plasma need to be strictly evaluated in terms of safety implications. Here, we performed mutation analysis using transgenic mice exposed by non-thermal atmospheric air plasma. Direct exposure of air plasma jet induced the mutations, mainly deletions, in the in vitro cultured splenocytes from rpsL-transgenic mice in a dose-dependent manner. Direct exposures of air plasma jet induced DNA damages in the epidermis of mouse skin. These results suggested that further investigations are needed to establish safety protocols for the long-term applications of plasma such as wound-healing and cancer treatment.
References
[1] G. Fridman, G. Friedman, A. Gutsol, A. B. Shekhter, V. N. Vasilets and A. Fridman: Plasma Processes and Polymers. 5, 503 (2008).
[2] M. U. Rehman, P. Jawaid, H. Uchiyama and TKondo: Arch Biochem Biophys. 605,19 (2016).
[3] H. Tanaka, M. Mizuno, K. Ishikawa, K. Nakamura, H. Kajiyama, H. Kano, F. Kikkawa and M. Hori: Plasma Medicine. 1, 265 (2011).
[4] F. Utsumi, H. Kajiyama, K. Nakamura, H. Tanaka, M. Mizuno, K. Ishikawa, H. Kondo H. Kano, M. Hori and F. Kikkawa: PLoS One. 8, e81576 (2013).
[5] K. Rodgers and M. McVey: J Cell Physiol. 231, 15 (2016).
[6] E. Gajewski, G. Rao, Z. Nackerdien and M. Dizdaroglu: Biochemistry. 29, 7876 (1990)..
2. Tsuzuki Teruhisa, Ohno Mizuki, Takano Noriko, Taguchi Ken-ichi, Nakabeppu Yusaku, Nakatsu Yoshimichi, DNA repair system as a constituent of mechanism underlying practical threshold of oxidative stress-induced tumorigenesis, The 12th International Conference and the 5th Asian Congress on Environmental Mutagens, 2017.11.
3. Tsuzuki Teruhisa, Ohno Mizuki, Takano Noriko, Taguchi Ken-ichi, Nakabeppu Yusaku, Nakatsu Yoshimichi, Oxidative stress-induced tumorigenesis: Lesson from the experiments with DNA repair-deficient mice, 4th Transgenic Technology Meeting, 2017.10.
4. Tsuzuki Teruhisa, Ohno Mizuki, Takano Noriko, Taguchi Ken-ichi, Nakabeppu Yusaku, Aoki Yasunobu, Nohmi Takehiko, Nakatsu Yoshimichi, Oxidative stress-induced intestinal tumors in Mutyh-deficient mice treated with low doses of potassium bromate, 6th US-Japan DNA Repair Meeting, 2017.05.
5. Yoshimichi Nakatsu, Noriko Takano, Mizuki Ohno, Satoshi Kitazaki, Kazunori Koga, Akiyo Tanaka, Masaharu Shiratani, Teruhisa Tsuzuki, Analyses of oxidative mutagenesis and carcinogenesis using genetically modified mice: application to plasma medicine, The 4th International Workshop on Plasma for Cancer Treatment (IWPCT-2017), 2017.03, Oxygen radicals attack DNA, and induce various lesions into the DNA. Among such lesions, 8-oxo-7, 8-dihydroguanine (8-oxoG) is highly mutagenic because of its ambiguous pairing property. Three enzymes, MTH1, OGG1, and MUTYH, play important roles in avoiding the 8-oxoG-related mutagenesis in mammalian cells. We have established an experimental system for oxidative DNA damage-induced mutagenesis and tumorigenesis in the intestine of mice. Oral administration of oxidizing reagent, potassium bromate (KBrO3), effectively induced G:C to T:A mutations and epithelial tumors in the small intestines of Mutyh-deficient mice, implying the significance of Mutyh in the suppression of mutagenesis and tumorigenesis induced by oxidative stress. To elucidate the roles of other DNA repair genes in the suppression of oxidative stress-induced tumorigenesis, we performed KBrO3-induced tumorigenesis experiments using various types of DNA repair-deficient mice. We observed an enhanced tumor-formation in the small intestines of Msh2-deficient mice, as compared with the wild type. No such enhancement was observed in Xpa-deficient mice. These results indicate that mismatch repair, but not nucleotide excision repair, is involved in the suppression of oxidative stress-induced intestinal tumorigenesis in mice. The number of tumors was marginally increased in Ogg1- and Mth1-deficient mice, in comparison to the wild-type mice, suggesting that in contrast to Mutyh, Ogg1 and Mth1 may play a limited role in the suppression of intestinal tumorigenesis caused by oxidative stress. Our data indicate that among the repair factors examined, only Mutyh and Msh2 play a significant role in the suppression of oxidative stress-induced intestinal tumorigenesis in mice.
To establish the application of plasma to humans, it is important to evaluate the potential risk of plasma to organisms. Plasma is a gas composed of electrons, various ions, and reactive oxygen/nitrogen species. The plasma exposure produced RONS not only in external environment but also in cells, thus anticipated the inductions of DNA damages and mutations. Therefore, we performed the mutation analyses using mouse cells exposed by non-thermal atmospheric air plasma. Direct exposure of air plasma jet induced the mutations, mainly deletions, in the in vitro cultured splenocytes from rpsL-transgenic mice in a dose-dependent manner. On the other hand, direct exposures of air plasma jet induced DNA damages in the epidermis of mouse skin. However, the increases of mutation frequencies were not detected in the air plasma-exposed mouse skins. These results suggest that genetically modified mice are useful tool for the risk assessment of plasma..
6. Yoshimichi Nakatsu, EFFECTS OF NON-THERMAL ATMOSPHERIC AIR PLASMA IRRADIATION ON MOUSE SKIN
, International Conference on Plasma Medical Science Innovation (ICPMSI) 2017, 2017.02.
7. Yoshimichi Nakatsu, Noriko Takano, Mizuki Ohno, Satoshi Kitazaki, Kazunori Koga, Akiyo Tanaka, Masaharu Shiratani, Teruhisa Tsuzuki, Analyses of oxidative mutagenesis and carcinogenesis using genetically modified mice: application to plasma medicine, 第26回日本MRS年次大会/Internatinal Symposium C-4, 2016.12.
8. Hayashida Genki, Nakatsu Yoshimichi, Hidaka Kyoko, Fujikane Ryosuke, Hidaka Masumi, Tsurimoto Toshiki, Tsuzuki Teruhisa, Development of assay systems to characterize the variants of mismatch repair factor MSH2 found in Lynch syndrome, The 10th International 3R (Replication, Recombination and Repair) Symposium, 2016.11.
9. Yoshimichi Nakatsu, Noriko Takano, Mizuki Ohno, Satoshi Kitazaki, Kazunori Koga, Takaaki Amano, Akiyo Tanaka, Miyuki Hirata, Masaharu Shiratani, Teruhisa Tsuzuki , Mutagenesis in Human and Mouse Cells Irradiated by Non-thermal Atmospheric Air Plasma
, 6th International Conference on Plasma Medicine (ICPM-6), 2016.09.
10. Mizuki Ohno, Noriko Takano, SAKUMI Kunihiko, Ryutaro Fukumura, Yuki Iwasaki, Toshimichi Ikemura, Yoichi Gondo, Yusaku Nakabeppu, Yoshimichi Nakatsu, Teruhisa Tsuzuki, Role of the oxidative DNA damage repair system in somatic and germline mutations in mice, Zing conference "Genome Integrity" , 2015.08.
11. Mizuki Ohno, Noriko Takano, Kunihiko Sakumi, Ryutaro Fukumura, Yuki Iwasaki, Toshimichi Ikemura, Yoichi Gondo, Yusaku Nakabeppu, Yoshimichi Nakatsu, Teruhisa Tsuzuki, Influence of Oxidative DNA Damage on the Rate of Somatic and Germiline Mutation, 15th International Congress of Radiation Research, 2015.05.
12. Teruhisa Tsuzuki, Mizuki Ohno, Noriko Takano, Kenichi Taguchi, Yusaku Nakabeppu, Yoshimichi Nakatsu, Oxidative Stress-induced Tumorigenesis: Lesson from the Experiments with DNA Repair-deficient Mice, Advances in Understanding the Biological Consequences by Environmental Stressors, 15th International Congress of Radiation Research, 2015.05.
13. Yoshimichi Nakatsu, Jingshu Piao, Takuya Hashizume, Mizuki Ohno, Kenichi Taguchi, Teruhisa Tsuzuki, Mismatch Repair Deficient Mice Show Susceptibility to Oxidative Stress-induced Intestinal Carcinogenesis, 15th International Congress of Radiation Research, 2015.05.
14. Teruhisa Tsuzuki, Mizuki Ohno, Noriko Takano, Kenichi Taguchi,, Yusaku Nakabeppu, Yasunobu Aoki, Takehiko Nohmi, Yoshimichi Nakatsu, Oxidative stress-induced intestinal tumors in Mutyh-deficient mice treated with low doses of potassium bromate, 4th Asian Conference on Environmental Mutagen, 2014.12.
15. Teruhisa Tsuzuki, Mizuki Ohno, Noriko Takano, Kenichi Taguchi, Yusaku Nakabeppu, Yasunobu Aoki, Takehiko Nohmi, Yoshimichi Nakatsu, Oxidative stress-induced intestinal tumors in Mutyh-deficient mice treated with low doses of potassium bromate, 5th US-Japan DNA Repair Meeting, 2014.10.
16. Teruhisa Tsuzuki, Jing Shu Piao, Noritaka Matsumoto, Yoshimichi Nakatsu, The roles of mismatch repair system and p53 in the suppression of oxidative stress-induced intestinal tumor-formation in mice., 4th US-Japan DNA Repair Meeting, 2012.04, In living cells, reactive oxygen species (ROS) is constantly generated by cellular metabolic reactions such as mitochondrial respiration, and also by external cause such as exposure to radiation and chemicals. DNA and its substrate, nucleotides, are continuously oxidized by ROS, and resulting oxidative DNA damages appear to cause mutagenesis and carcinogenesis in mammal. To counteract this hazardous effects of ROS, mammalian cells are equipped with several enzymatic systems. Following KBrO3 treatment in all mouse types, tumor-formation in the small intestines of Msh2-/- mice significantly increased as compared with Msh2+/+ and Msh2+/- mice. These results suggest that mismatch repair (MMR) is involved in the suppression of oxidative stress-induced intestinal tumorigenesis in mice. Following KBrO3-treatment, tumor-formation in the small intestine of Trp53-/- mice significantly increased as compared with Trp53+/+ and Trp53+/- mice and tumor-formation in the small intestine of Trp53+/- mice moderately increased as compared with Trp53+/+ mice. In addition to previous observation with Mutyh-deficient mice, our data suggest that MMR system as well as Trp53 is also involved in the suppression of oxidative stress-induced intestinal tumorigenesis in mice..
17. Oxidartive stress-induced intestinal tumorigensis in Trp53-deficient mice.
18. Oxidartive stress-induced intestinal tumorigensis in Trp53-deficient mice.
19. The roles of tumor-associated genes, Mutyh, Msh2 and Trp53, in the suppression of oxidative stress-induced tumorigenesis in mice.
20. A MAPO1 protein complex that involved in the induction of apoptosis triggered by O6-methylguanine.
21. Oxidative stress and intestinal carcinogenesis.
Membership in Academic Society
  • The Japanese Environmental Mutagen Society (JEMS)
  • Genetic Society of Japan
  • The Japan Radiation Research Society
  • Japanese Cancer Association
  • The Molecular Biology Society of Japan
Educational
Other Educational Activities
  • 2019.03.
  • 2018.09.
  • 2018.03.
  • 2017.09.
  • 2017.03.
  • 2017.01.
  • 2016.03.
  • 2015.09.
  • 2015.03.
  • 2014.08.
  • 2014.03.
  • 2013.08.
  • 2012.08.
  • 2013.03.
  • 2011.03.
  • 2012.03.
  • 2010.03.
  • 2010.03.
  • 2010.09.
  • 2009.09.