Kyushu University [Mizuki Ohno (Assistant Professor) Faculty of Medical Sciences, Department of Basic Medicine]

092-642-6143

092-642-6145

PhD

No

Molecular genetics, Cytogenetics, Molecular biology

01years00months

Research Interests

Development of STEAM education program to improve genetic literacy in elementary education
keyword : education program, genetic literacy, STEAM
2022.04～2025.03.
Establishment of human iPS cell-derived aging cardiomyocyte model for developing cardiac anti-aging drugs.
keyword : human iPS, cardiomyocyte, anti-aging drugs
2022.04～2024.06.
Effects of chronic low-dose internal exposure to cesium-137 on mutations in somatic and germ cells in mice
keyword : Cesium-137, internal exposure, mutation、NGS
2020.04～2025.03.
Analysis of biological effects and mutagenesis of low-dose long-term radiation exposure in mice
keyword : low-dose, radiation, mutagenesis
2021.04～2024.04.
Molecular mechanism of the oocyte's ability to repair sperm DNA damage
keyword : sperm DNA damage, oocyte, DNA repair
2020.04～2024.03.
Effects of cesium-137 internal exposure on somatic and germline mutations in mice
keyword : Cesium-137, internal exposure, mutation
2018.04～2021.03.
The biological effects of chronic low-dose internal exposure to Cesium-137 in Mice
keyword : Cesium-137, internal exposure,
2016.04～2019.03.
Mammalian genome integrity
keyword : DNA damages, DNA repiar, mutation, genome
2018.04.
Molecular mechanism for maintaining mammalian genome integrity
Oxidative DNA Damage and Its Repair Mechanisms.
keyword : DNA damage, genome instability, genome evolution, mutation, 8-oxoguanine, chromosome
2013.05～2018.03.
Oxidative stress-induced DNA damage and repair mechanism
keyword : DNA damage, DNA Repair, Mutation, Oxidative Stress, Genome Instability, Chromosome Instability, Genome structure, Genome evolution, Epigenetics
2008.11～2018.03.

Academic Activities

Books

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1.	Ohno, M., Oka, S., and Nakabeppu, Y., Quantitative analysis of oxidized guanine, 8-oxoguanine, in mitochondrial DNA by immunofluorescence method. In Mitochondrial DNA, Methods and Protocols, (J.A. Stuart, ed.), Humana Press, New York,Methods Mol Biol , 544: 199-212, 2009.07.
2.	Oka, S., Ohno, M., and Nakabeppu, Y., Construction and characterization of a cell line deficient in repair of mitochondrial, but not nuclear, oxidative DNA damage. In Mitochondrial DNA, Methods and Protocols, (J.A. Stuart, ed.), Humana Press, New York,Methods Mol Biol, 544: 251-264.,2009.07., 2009.10.

Reports

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1.	, [URL].
2.	Mizuki Ohno, Analysis of de novo germline genome mutations, Impact, https://doi.org/10.21820/23987073.2018.3.63, Impact, Volume 2018, Number 3, June 2018, pp. 63-65(3), 2018.11.
3.	Triplex DNA in human interphase nuclei and its function.
4.	Biological significance of human chromosome bands.

Papers

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1.	Yasunobu Aoki, Mizuki Ohno, Michiyo Matsumoto, Michi Matsumoto, Kenichi Masumura, Takehiko Nohmi, Teruhisa Tsuzuki , Characteristic mutations induced in the small intestine of Msh2-knockout gpt delta mice , Genes and Environment , 10.1186/s41021-021-00196-0. , 2021.07.
2.	Yasunobu Aoki, YosukeTaniguchi, MichiyoMatsumoto, Michi Matsumoto, Mizuki Ohno, Kenichi Masumura, Shigeki Sasaki, Teruhisa Tsuzuki, Masayuki Yamamoto, Takehiko Nohmi, Oxidative-stress-driven in vivo mutagenesis induced by oral administration of potassium bromate in the small intestines of gpt delta mice, Mutation Research/Genetic Toxicology and Environmental Mutagenesis, https://doi.org/10.1016/j.mrgentox.2020.503136, 2020.01.
3.	Mizuki Ohno, Spontaneous de novo germline mutations in humans and mice rates, spectra, causes and consequences, Genes and Genetic Systems, 10.1266/ggs.18-00015, 94, 1, 13-22, 2019.01, Germline mutations are the origin of genetic variation and are widely considered to be the driving force of genome evolution. The rates and spectra of de novo mutations (DNMs) directly affect evolutionary speed and direction and thereby establish species-specific genomic futures in the long term. This has resulted in a keen interest in understanding the origin of germline mutations in mammals. Accumulating evidence from next-generation sequencing and family-based analysis indicates that the frequency of human DNMs varies according to sex, age and local genomic context. Thus, it is likely that there are multiple causes and drivers of mutagenesis, including spontaneous DNA lesions, DNA repair status and DNA polymerase errors. In this review, recent studies of human and mouse germline DNMs are discussed, and the rates and spectra of spontaneous germline DNMs in the mouse mutator lines Pold1exo/exo and TOY-KO (Mth1−/−/Ogg1−/−/ Mutyh−/− triple knockout) are summarized in the context of endogenous causes and mechanisms..
4.	Arikuni Uchimura, Mayumi Higuchi, Yohei Minakuchi, Ohno Mizuki, Atsushi Toyoda, Asao Fujiyama, Ikuo Miura, Shigeharu Wakana, Jo Nishino, Takeshi Yagi, Germline mutation rates and the long-term phenotypic effects of mutation accumulation in wild-type laboratory mice and mutator mice, Genome Research, 10.1101/gr.186148.114, 25, 8, 1125-1134, 2015.08, The germline mutation rate is an important parameter that affects the amount of genetic variation and the rate of evolution. However, neither the rate of germline mutations in laboratory mice nor the biological significance of the mutation rate in mammalian populations is clear. Here we studied genome-wide mutation rates and the long-term effects of mutation accumulation on phenotype in more than 20 generations of wild-type C57BL/6 mice and mutator mice, which have high DNA replication error rates. We estimated the base-substitution mutation rate to be 5.4 × 10^-9 (95% confidence interval = 4.6 × 10^-9-6.5 × 10^-9) per nucleotide per generation in C57BL/6 laboratory mice, about half the rate reported in humans. The mutation rate in mutator mice was 17 times that in wild-type mice. Abnormal phenotypes were 4.1-fold more frequent in the mutator lines than in the wild-type lines. After several generations, the mutator mice reproduced at substantially lower rates than the controls, exhibiting low pregnancy rates, lower survival rates, and smaller litter sizes, and many of the breeding lines died out. These results provide fundamental information about mouse genetics and reveal the impact of germline mutation rates on phenotypes in a mammalian population..
5.	Ohno Mizuki, SAKUMI Kunihiko, Fukumura Ryutaro, Masato Furuichi, Iwasaki Yuki, Hokama Masaaki, Ikemura Toshimichi, Teruhisa Tsuzuki, Gondo Yoichi, Yusaku Nakabeppu, 8-oxoguanine causes spontaneous de novo germline mutations in mice , Scientific reports, 10.1038/srep04689, 4:4689, 2014.04.
6.	Ichikawa J, Tsuchimoto D, Oka S, Ohno M, Furuichi M, Sakumi K, Nakabeppu Y., Oxidation of mitochondrial deoxynucleotide pools by exposure to sodium nitroprusside induces cell death., DNA Repair, 7(3):418-430, 2008.03.
7.	Oka S, Ohno M, Tsuchimoto D, Sakumi K, Furuichi M, Nakabeppu Y., Two distinct pathways of cell death triggered by oxidative damage to nuclear and mitochondrial DNAs., EMBO Journal.,27(2):421-432., 2008.01.
8.	Ohno M, Miura T, Furuichi M, Tominaga Y, Tsuchimoto D, Sakumi K, Nakabeppu Y., A genome-wide distribution of 8-oxoguanine correlates with the preferred regions for recombination and single nucleotide polymorphism in the human genome., Genome Res.,6(5):567-575, 2006.05.
9.	Yamaguchi, H., Kajitani K., Dan Y., Furuichi M., Ohno M., Sakumi K., Kang D. and Nakabeppu Y., MTH1, an oxidized purine nucleoside triphosphatase, protects the dopamine neurons from oxidative damage in nucleic acids caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine., Cell Death Differ,13(4):551-563, 2006.04.
10.	Yoshimura, D., K. Sakumi, M. Ohno, Y. Sakai, M. Furuichi, S. Iwai, and Y. Nakabeppu.,, An oxidized purine nucleoside triphosphatase, MTH1 suppresses cell death caused by oxidative stress., J. Biol. Chem.,278:37965-37973, 2003.09.
11.	Ohno M, Fukagawa T, Lee JS, Ikemura T., Triplex-forming DNAs in the human interphase nucleus visualized in situ by polypurine/polypyrimidine DNA probes and antitriplex antibodies., Chromosoma. 2002 Sep;111(3):201-13. Epub 2002 Jul 16., 2002.09.
12.	Mizuki Ohno, Tenzen T., Watanabe Y., Yamagata T., Kanaya S., Ikemura T., Non-B DNA structures spatially and sequence-specifically associated with individual cetromeres in the human interphase nucleus, Chromosome Today. Vol.13, 2000.10.
13.	Ohno M, Aoki N, Sasaki H., Allele-specific detection of nascent transcripts by fluorescence in situ hybridization reveals temporal and culture-induced changes in Igf2 imprinting during pre-implantation mouse development., Genes Cells. 2001 Mar;6(3):249-59., 10.1046/j.1365-2443.2001.00417.x, 6, 3, 249-259, 2001.03.

Presentations

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1.	Mizuki Ohno, Analysis of De novo Germline Mutations in DNA Repair Deficient Mice Lines, 13th International Conference on Environmental Mutagens (ICEM2022), 2022.08.
2.	Mizuki Ohno, Kunihoko Sakumi, Noriko Takano, Yoshimichi Nakatsu, Teruhisa Tsuzuki, Toward understanding de novo germline mutations in mammals, 日本放射線影響学会第62回大会, 2019.11.
3.	Mizuki OHNO, Kunihiko SAKUMI, Noriko TAKANO,Kosuke TESHIMA, Kyoko HIDAKA, Yoshimichi NAKATSU, Teruhisa TSUZUKI , Detection of de novo germline mutations in DNA repair-deficient mice lines , The Joint Meeting of The 6th Asian Congress on Environmental Mutagens(ACEM) and the 48th Annual Meeting of the Japanese Environmental Mutagen Society(JEMS), 2019.11.
4.	Mizuki Ohno, Noriko Takano, Kyouko Hidaka, Kunihiko Sakumi, Yusaku Nakabeppu, Yoshimichi Nakatsu, Teruhisa Tsuzuki, Somatic mutation analysis of oxidative stress-induced colon cancer model 大腸癌モデルマウスを用いた酸化ストレス誘発発がんと体細胞突然変異の解析, 第76回日本癌学会学術総会, 2017.09, Colorectal cancer (CRC) is one of the most common cancers, and oxidative stress is predicted to play an important role in the pathogenesis of CRC. MUTYH is an adenine DNA glycosylase that suppresses oxidative stress-induced mutagenesis by removing adenine mispaired with 8-oxoguanine (8-oxoG), a major oxidative DNA damage. Biallelic mutations in MUTYH gene cause an inherited predisposition to CRC, known as MUTYH-associated polyposis (MAP). Since oxidative stress-induced mutations would be relevant to driving force for tumorigenesis, we studied the property of somatic mutations in the intestines of Mutyh-deficient mice. We found a clear correlation among the levels of oxidative stress, the induced mutation frequency in pre-cancerous tissues, and the tumor incidence. Moreover, whole-exome analysis of tumors developed in the mice revealed a specific mutational pattern; predominant G:C > T:A mutations in the specific sequence contexts, which is resulted from unrepaired 8-oxoG:A mispairings. This pattern was also observed in the somatic mutations detected in the tumors from MAP patients. Thus, avoiding excess oxidative stress can be helpful to reduce a lifetime risk of CRC for MAP patients..
5.	大野　みずき, 作見邦彦, 中別府　雄作, Regulation of base substitution mutagenesis and chromosome recombination induced by 8-oxoguanine accumulated in the genome, 日本分子生物学会, 2016.12.
6.	Mizuki Ohno, Noriko Takano, Kunihiko Sakumi, 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.
7.	Ohno Mizuki, Takano Noriko, SAKUMI Kunihiko, 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 germline mutation, 15th International Congress of Radiation Research, 2015.05.
8.	Mizuki Ohno, Oxidative DNA damage and its repair system: implications for de novo germline mutations , 第38回日本分子生物学会, 2014.11.
9.	大野みずき, 鷹野典子, 中津可道, 中別府雄作, 續輝久, Oxidative stress-induced tumorigenesis in the small intestine of Mutyh-deficient mouse, 第73回日本癌学会学術総会, 2014.09.
10.	Ohno Mizuki, SAKUMI Kunihiko, FUKUMURA　Ryutaro, IWASAKI Yuki, IKEMURA Toshimichi, Teruhisa Tsuzuki, GONDO Yoichi, Yusaku Nakabeppu, 8-Oxoguanine causes spontaneous de novo germline mutations : a study from the mutator mouse line, SMBE Satellite Meeting / NIG International Symposium: The Causes of Genome Evolution, 2014.03.
11.	8-Oxoguanine repair system contribute to maintain stable phenotype of inbred mouse strain .
12.	Deficiency of 8-oxoguanine repair mechanisms increases spontaneous mutation frequency in mouse germ line and consequently causes hereditary congenital abnormalities.
13.	A study of radiation-induced oxidative DNA damage and its repair in mouse intestine.
14.	8-oxoguanine increases the frequency of meiotic homologous recombination via DNA strand breaks.
15.	It is well known that reactive oxygen species are generated not only by environmental factors but also by normal cellular metabolisms. We have been focusing on the effect of oxidative DNA damage to genome integrity. Previously we suggested that 8-oxoguanine (8-oxoG) is one of the main causes of base substitution and homologous recombination in the mammalian genome. To elucidate the influence of 8-oxoG on germ-line mutations, we analyzed DNA damage, damage response and resulting homologous recombination using testes derived from Ogg1, Mth1 deficient mice or X-ray irradiated wild-type mice. An increased amount of DNA damage as well as an activation of damage response was observed in the spermatocytes derived from testis of these mice. Moreover, we found an increased frequency of meiotic homologous recombination in Ogg1 or Mth1 deficient mice. .
16.	Biological sensitivity to radiation differs among cell and organ types, as well as their state of cell cycle when irradiated. This difference in radiation sensitivity can be attributed to multiple factors, including the amount or kind of DNA damage and mechanisms of damage response and repair. The effect of DNA exposure to radiation is both direct and indirect. The direct effect is the physical break, single or double, in DNA following ionizing radiation exposure. Free radical species, a product of the interaction between radiation and cellular water, results in many chemical and biological changes, producing an indirect effect. Of the latter, prolonged oxidative stress caused by low LET radiation is a risk factor for the alteration of genetic information. Mutations in somatic cells can result in cancer and other diseases, while those occurred in germ cells could potentially be inherited to offspring, and lead to congenital disorders. To study the effects of radiation-induced oxidative DNA damage and its repair mechanism, we analyzed the DNA damage response in the testis and intestine of X-ray irradiated mice, including damage status, degree of cell death and cell proliferation. Radiation exposure for 2 days and 7 days at 0.5, 1, 2, and 4Gy revealed a pattern of increased immunoreactivity in gH2AX, 53BP1 and Rad51, as well as a decrease in the number of BrdU positive cells within the testis. The same result was not observed in intestinal samples at those time points. The nuclear content of 8-oxoguanine, an oxidized form of guanine, was also analyzed together with the expression of repair factors in different cell types. .
17.	Production and analysis of the Ogg1, Mth1, Mutyh triple knockout mouse strain.
18.	The influence of oxidative damaged base on germ-line mutation.

Membership in Academic Society

Japanese Cancer Association
Japan Radiation Research Society
Japanease environmental mutagen society
Society of evolutionary studies, Japan
The molecular biology society of Japan
The genetic society of Japan

Awards

Oxidized base, 8-oxoguanine causes genome diversity in mammals
The influence of oxidative DNA damage to germ cell genome

Educational Activities

Graduate School Course: Medical Biophysics
Undergraduate Course: Introduction to Medical Biology (Cell and Molecular Biology), Fundamentals of Radiology (including Radiation Biology), Genetics

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