Faculty Profiles - TSUCHIMOTO DAISUKE

Information

写真a

TSUCHIMOTO DAISUKE

Organization

Medical Institute of Bioregulation Research Promotion Unit Assistant Professor

Tel

0926426797

Profile

Research of DNA repair and nucleotide pool sanitizing systems of mammals using mice, mouse cells, human cells and recombinant proteins. Support for undergraduate and graduate students in these research fields.

Homepage

https://www.bioreg.kyushu-u.ac.jp/index_e.html

External link

Degree

PhD of Medical Science

Research History

1990年4月-1999年3月　大塚製薬株式会社　研究員 1999年４月-2003年６月　科学技術振興事業団　研究員

1990年4月-1999年3月　大塚製薬株式会社　研究員 1999年４月-2003年６月　科学技術振興事業団　研究員

Research Interests・Research Keywords

Research theme： DNA repair and nucleotide pool sanitizing system in mammalian cells

Keyword： DNA repair, Base Excision Repair, AP endonuclease, DNA glycosylase, damaged nucleotide

Research period： 1998.1 - 2020.3

Awards

優秀ポスター賞

2016.12 日本分子生物学会第３９回日本分子生物学会年会における優秀ポスター賞

Papers

APE2 Promotes AID-Dependent Somatic Hypermutation in Primary B Cell Cultures That Is Suppressed by APE1. Reviewed International journal

Carol E Schrader, Travis Williams, Klaus Pechhold, Erin K Linehan, Daisuke Tsuchimoto, Yusaku Nakabeppu

Journal of immunology (Baltimore, Md. : 1950) 210 ( 11 ) 1804 - 1814 2023.6

　More details

Language：English Publishing type：Research paper (scientific journal)

Somatic hypermutation (SHM) is necessary for Ab diversification and involves error-prone DNA repair of activation-induced cytidine deaminase-induced lesions in germinal center (GC) B cells but can also cause genomic instability. GC B cells express low levels of the DNA repair protein apurinic/apyrimidinic (AP) endonuclease (APE)1 and high levels of its homolog APE2. Reduced SHM in APE2-deficient mice suggests that APE2 promotes SHM, but these GC B cells also exhibit reduced proliferation that could impact mutation frequency. In this study, we test the hypothesis that APE2 promotes and APE1 suppresses SHM. We show how APE1/APE2 expression changes in primary murine spleen B cells during activation, impacting both SHM and class-switch recombination (CSR). High levels of both APE1 and APE2 early after activation promote CSR. However, after 2 d, APE1 levels decrease steadily with each cell division, even with repeated stimulation, whereas APE2 levels increase with each stimulation. When GC-level APE1/APE2 expression was engineered by reducing APE1 genetically (apex1+/-) and overexpressing APE2, bona fide activation-induced cytidine deaminase-dependent VDJH4 intron SHM became detectable in primary B cell cultures. The C terminus of APE2 that interacts with proliferating cell nuclear Ag promotes SHM and CSR, although its ATR-Chk1-interacting Zf-GRF domain is not required. However, APE2 does not increase mutations unless APE1 is reduced. Although APE1 promotes CSR, it suppresses SHM, suggesting that downregulation of APE1 in the GC is required for SHM. Genome-wide expression data compare GC and cultured B cells and new models depict how APE1 and APE2 expression and protein interactions change during B cell activation and affect the balance between accurate and error-prone repair during CSR and SHM.

DOI： 10.4049/jimmunol.2100946
APE2 Is a General Regulator of the ATR-Chk1 DNA Damage Response Pathway to Maintain Genome Integrity in Pancreatic Cancer Cells Reviewed International journal

Md Akram Hossain, Yunfeng Lin, Garrett Driscoll, Jia Li1, Anne McMahon, Joshua Matos, Haichao Zhao, @Daisuke Tsuchimoto, @Yusaku Nakabeppu, Jianjun Zhao and Shan Yan

Frontiers in cell and developmental biology 2021.11

　More details

Language：English Publishing type：Research paper (scientific journal)

The maintenance of genome integrity and fidelity is vital for the proper function and survival of all organisms. Recent studies have revealed that APE2 is required to activate an ATR-Chk1 DNA damage response (DDR) pathway in response to oxidative stress and a defined DNA single-strand break (SSB) in Xenopus laevis egg extracts. However, it remains unclear whether APE2 is a general regulator of the DDR pathway in mammalian cells. Here, we provide evidence using human pancreatic cancer cells that APE2 is essential for ATR DDR pathway activation in response to different stressful conditions including oxidative stress, DNA replication stress, and DNA double-strand breaks. Fluorescence microscopy analysis shows that APE2-knockdown (KD) leads to enhanced gH2AX foci and increased micronuclei formation. In addition, we identified a small molecule compound Celastrol as an APE2 inhibitor that specifically compromises the binding of APE2 but not RPA to ssDNA and 30-50 exonuclease activity of APE2 but not APE1. The impairment of ATR-Chk1 DDR pathway by Celastrol in Xenopus egg extracts and human pancreatic cancer cells highlights the physiological significance of Celastrol in the regulation of APE2 functionalities in genome integrity. Notably, cell viability assays demonstrate that APE2-KD or Celastrol sensitizes pancreatic cancer cells to chemotherapy drugs. Overall, we propose APE2 as a general regulator for the DDR pathway in genome integrity maintenance.

DOI： 10.3389/fcell.2021.738502
Serum Anti-oligodendrocyte Autoantibodies in Patients With Multiple Sclerosis Detected by a Tissue-Based Immunofluorescence Assay Invited Reviewed International journal

@Yukino Miyachi , @Takayuki Fujii, @Ryo Yamasaki, @Daisuke Tsuchimoto, @Kyoko Iinuma, @Ayako Sakoda, @Shoko Fukumoto, @Takuya Matsushita, @Katsuhisa Masaki, @Noriko Isobe, @Yusaku Nakabeppu, @Jun-Ichi Kira

FRONTIERS IN NEUROLOGY 12 2021.8

　More details

Language：English Publishing type：Research paper (scientific journal)

DOI： 10.3389/fneur.2021.681980
MTH1 and OGG1 maintain a low level of 8-oxoguanine in Alzheimer's brain, and prevent the progression of Alzheimer's pathogenesis. Reviewed International journal

Sugako Oka, Julio Leon, Kunihiko Sakumi, Nona Abolhassani, Zijing Sheng, Daisuke Tsuchimoto, Frank M LaFerla, Yusaku Nakabeppu

Scientific reports 11 ( 1 ) 5819 - 5819 2021.3

　More details

Language：English Publishing type：Research paper (scientific journal)

8-Oxoguanine (8-oxoG), a major oxidative base lesion, is highly accumulated in Alzheimer's disease (AD) brains during the pathogenic process. MTH1 hydrolyzes 8-oxo-dGTP to 8-oxo-dGMP, thereby avoiding 8-oxo-dG incorporation into DNA. 8-OxoG DNA glycosylase-1 (OGG1) excises 8-oxoG paired with cytosine in DNA, thereby minimizing 8-oxoG accumulation in DNA. Levels of MTH1 and OGG1 are significantly reduced in the brains of sporadic AD cases. To understand how 8-oxoG accumulation in the genome is involved in AD pathogenesis, we established an AD mouse model with knockout of Mth1 and Ogg1 genes in a 3xTg-AD background. MTH1 and OGG1 deficiency increased 8-oxoG accumulation in nuclear and, to a lesser extent, mitochondrial genomes, causing microglial activation and neuronal loss with impaired cognitive function at 4-5 months of age. Furthermore, minocycline, which inhibits microglial activation and reduces neuroinflammation, markedly decreased the nuclear accumulation of 8-oxoG in microglia, and inhibited microgliosis and neuronal loss. Gene expression profiling revealed that MTH1 and OGG1 efficiently suppress progression of AD by inducing various protective genes against AD pathogenesis initiated by Aß/Tau accumulation in 3xTg-AD brain. Our findings indicate that efficient suppression of 8-oxoG accumulation in brain genomes is a new approach for prevention and treatment of AD.

DOI： 10.1038/s41598-021-84640-9
Cisplatin-mediated upregulation of APE2 binding to MYH9 provokes mitochondrial fragmentation and acute kidney injury. Reviewed International journal

Yi Hu, Chun Yang, Tania Amorim, Mohsin Maqbool, Jenny Lin, Chen Li, Chuanfeng Fang, Li Xue , Ariel Kwart, Hua Fang, Mei Yin, Allison J Janocha, Daisuke Tsuchimoto, Yusaku Nakabeppu, Xiaofeng Jiang, Alex Mejia-Garcia, Faiz Anwer, Jack Khouri, Xin Qi, Qing Y Zheng, Jennifer S Yu, Shan Yan, Thomas LaFramboise, Kenneth C Anderson, Leal C Herlitz, Nikhil C Munshi, Jianhong Lin, Jianjun Zhao

Cancer Research 81 ( 3 ) 713 - 723 2021.2

　More details

Language：English Publishing type：Research paper (scientific journal)

Cisplatin chemotherapy is standard care for many cancers but is toxic to the kidneys. How this toxicity occurs is uncertain. In this study, we identified apurinic/apyrimidinic endonuclease 2 (APE2) as a critical molecule upregulated in the proximal tubule cells (PTC) following cisplatin-induced nuclear DNA and mitochondrial DNA damage in cisplatin-treated C57B6J mice. The APE2 transgenic mouse phenotype recapitulated the pathophysiological features of C-AKI in the absence of cisplatin treatment. APE2 pulldown-MS analysis revealed that APE2 binds myosin heavy-Chain 9 (MYH9) protein in mitochondria after cisplatin treatment. Human MYH9-related disorder is caused by mutations in MYH9 that eventually lead to nephritis, macrothrombocytopenia, and deafness, a constellation of symptoms similar to the toxicity profile of cisplatin. Moreover, cisplatin-induced C-AKI was attenuated in APE2-knockout mice. Taken together, these findings suggest that cisplatin promotes AKI development by upregulating APE2, which leads to subsequent MYH9 dysfunction in PTC mitochondria due to an unrelated role of APE2 in DNA damage repair. This postulated mechanism and the availability of an engineered transgenic mouse model based on the mechanism of C-AKI provides an opportunity to identify novel targets for prophylactic treatment of this serious disease.

DOI： 10.1158/0008-5472.CAN-20-1010
Neural stem cell-specific ITPA deficiency causes neural depolarization and epilepsy Reviewed International journal

Yuichiro Koga, Daisuke Tsuchimoto, Yoshinori Hayashi, Nona Abolhassani, Yasuto Yoneshima, Kunihiko Sakumi, Hiroshi Nakanishi, Shinya Toyokuni, Yusaku Nakabeppu

JCI Insight 5 ( 22 ) e140229 2020.11

　More details

Language：English Publishing type：Research paper (scientific journal)

Inosine triphosphate pyrophosphatase (ITPA) hydrolyzes inosine triphosphate (ITP) and other deaminated purine nucleotides to the corresponding nucleoside monophosphates. In humans, ITPA deficiency causes severe encephalopathy with epileptic seizure, microcephaly, and developmental retardation. In this study, we established neural stem cell-specific conditional Itpa-KO mice (Itpa-cKO mice) to clarify the effects of ITPA deficiency on the neural system. The Itpa-cKO mice showed growth retardation and died within three weeks of birth. We did not observe any microcephaly in the Itpa-cKO mice although the female Itpa-cKO mice did show adrenal hypoplasia. The Itpa-cKO mice showed limb clasping upon tail suspension and spontaneous and/or audiogenic seizure. Whole-cell patch-clamp recordings from entorhinal cortex neurons in brain slices revealed a depolarized resting membrane potential, increased firing, and frequent spontaneous miniature excitatory postsynaptic current (mEPSC) and miniature inhibitory postsynaptic current (mIPSC) in the Itpa-cKO mice compared to ITPA-proficient controls. Accumulated ITP or its metabolites, such as cyclic inosine monophosphates, or RNA containing inosines may cause membrane depolarization and hyperexcitability in neurons, and induce the phenotype of ITPA-deficient mice, including seizure.

DOI： 10.1172/jci.insight.140229.

Repository Public URL： https://hdl.handle.net/2324/7174338
8-Oxoguanine accumulation in aged female brain impairs neurogenesis in the dentate gyrus and major island of Calleja, causing sexually dimorphic phenotypes. Reviewed

Naoki Haruyama, Sakumi Kunihiko, Atsuhisa Katogi, Daisuke Tsuchimoto, Gabriele De Luca, Margherita Bignami, Yusaku Nakabeppu

Progress in Neurobiology 2019.4

　More details

Language：English Publishing type：Research paper (scientific journal)

DOI： 10.1016/j.pneurobio.2019.04.002
A Novel Autoantibody against Plexin D1 in Patients with Neuropathic Pain Reviewed

Takayuki Fujii, Ryo Yamasaki, Kyoko Iinuma, Daisuke Tsuchimoto, Yoshinori Hayashi, Ban yu Saitoh, Takuya Matsushita, Mizuho A. Kido, Shinichi Aishima, Hiroshi Nakanishi, Yusaku Nakabeppu, Jun ichi Kira

Annals of Neurology 84 ( 2 ) 208 - 224 2018.8

　More details

Language：English Publishing type：Research paper (scientific journal)

Objective: To identify novel autoantibodies for neuropathic pain (NeP). Methods: We screened autoantibodies that selectively bind to mouse unmyelinated C-fiber type dorsal root ganglion (DRG) neurons using tissue-based indirect immunofluorescence assays (IFA) with sera from 110 NeP patients with various inflammatory and allergic neurologic diseases or other neuropathies, and 50 controls without NeP including 20 healthy subjects and 30 patients with neurodegenerative diseases or systemic inflammatory diseases. IgG purified from IFA-positive patients' sera was subjected to Western blotting (WB) and immunoprecipitation (IP) using mouse DRG lysates. Immunoprecipitates were analyzed by liquid chromatography tandem mass spectrometry (LC-MS/MS) to identify target autoantigens. Results: Antiunmyelinated C-fiber type DRG neuron antibodies were more frequent in patients with NeP than non-NeP subjects (10% vs 0%; p < 0.05). These autoantibodies were all from the IgG2 subclass and colocalized mostly with isolectin B4- and P2X3-positive pain-conducting small neurons but not with S100β-positive myelinated neurons. WB revealed a common immunoreactive band (approximately 220kDa). IP and LC-MS/MS studies identified plexin D1 as a target autoantigen. Immunoadsorption tests with recombinant human plexin D1 in IFA revealed that all 11 anti–small DRG neuron antibody-positive patients had anti–plexin D1 antibodies. Application of anti–plexin D1 antibody-positive patient sera to cultured DRG neurons increased membrane permeability, leading to cellular swelling. NeP patients with anti–plexin D1 antibodies commonly developed burning pain and current perception threshold abnormalities for C-fibers. Main comorbidities were atopy and collagen-vascular disease. Immunotherapies ameliorated NeP in 7 treated cases. Interpretation: Anti–plexin D1 antibodies are a novel biomarker for immunotherapy-responsive NeP.

DOI： 10.1002/ana.25279
2-Oxoadenosine induces cytotoxicity through intracellular accumulation of 2-oxo-ATP and depletion of ATP but not via the p38 MAPK pathway Invited Reviewed International journal

Shinji Asada, Eiko Ohta, Yoriko Akimoto, ABOLHASSANI NONA, Daisuke Tsuchimoto, Yusaku Nakabeppu

SCIENTIFIC REPORTS 7 2017.7

　More details

Language：English Publishing type：Research paper (scientific journal)

DOI： 10.1038/s41598-017-06636-8
Deficiency of the base excision repair enzyme NEIL3 is associated with increased lymphocyte apoptosis, autoantibodies and predisposition to autoimmunity. Reviewed International journal

M Massaad, J Zhou, Daisuke Tsuchimoto, J Chou, H Jabara, E Janssen, S Glauzy, B Olson, H Morbach, T Ohsumi, K Schmitz-Abe, M Kyriacos, J Kane, Kumiko Torisu, Yusaku Nakabeppu, LD Notarangelo, E Chouery, A Megarbane, PB Kang

The Journal of Clinical Investigation in press 2016.10

　More details

Language：English Publishing type：Research paper (scientific journal)
PKCη deficiency improves lipid metabolism and atherosclerosis in apolipoprotein E-deficient mice Reviewed International journal

Kumiko Torisu, Xueli Zhang, Mari Nonaka, Takahide Kaji, Daisuke Tsuchimoto, Kosuke Kajitani, SAKUMI Kunihiko, Torisu Takehiro, Kazuhiro Chida, Katsuo Sueishi, Michiaki Kubo, Jun Hata, Kitazono T, Yutaka Kiyohara, Yusaku Nakabeppu

Genes to cells 2016.10

　More details

Language：English Publishing type：Research paper (scientific journal)

Genome-wide association studies have shown that a non-synonymous single nucleotide polymorphism in PRKCH is associated with cerebral infarction and atherosclerosis-related complications. We examined the role of PKCη in lipid metabolism and atherosclerosis using apolipoprotein E-deficient (Apoe−/−) mice. PKCη expression was augmented in the aortas of mice with atherosclerosis and exclusively detected in MOMA2-positive macrophages within atherosclerotic lesions. Prkch+/+Apoe−/− and Prkch−/−Apoe−/− mice were fed a high-fat diet (HFD), and the dyslipidemia observed in Prkch+/+Apoe−/− mice was reduced in Prkch−/−Apoe−/− mice, with a particular reduction of serum LDL cholesterol and phospholipids. Liver steatosis, which developed in Prkch+/+Apoe−/− mice, was improved in Prkch−/−Apoe−/− mice, but glucose tolerance, adipose tissue and body weight, and blood pressure were unchanged. Consistent with improvements in LDL cholesterol, atherosclerotic lesions were decreased in HFD-fed Prkch−/−Apoe−/− mice. Immunoreactivity against 3-nitrotyrosine in atherosclerotic lesions was dramatically decreased in Prkch−/−Apoe−/− mice, accompanied by decreased necrosis and apoptosis in the lesions. ARG2 mRNA and protein levels were significantly increased in Prkch−/−Apoe−/− macrophages. These data demonstrate that PKCη deficiency improves dyslipidemia and reduces susceptibility to atherosclerosis in Apoe−/− mice, revealing that PKCη plays a role in atherosclerosis development.

DOI： 10.1111/gtc.12402.
Deoxyinosine triphosphate induces MLH1/PMS2- and p53-dependent cell growth arrest and DNA instability in mammalian cells. Reviewed International journal

Yasuto Yoneshima, Nona Abolhassani, Teruaki Iyama, Kunihiko Sakumi, Naoko Shiomi, Masahiko Mori, Tadahiro Shiomi, Tetsuo Noda, Daisuke Tsuchimoto, Yusaku Nakabeppu

Scientific Reports 6 32849 2016.9

　More details

Language：English Publishing type：Research paper (scientific journal)

Deoxyinosine (dI) occurs in DNA either by oxidative deamination of a previously incorporated deoxyadenosine residue or by misincorporation of deoxyinosine triphosphate (dITP) from the nucleotide pool during replication. To exclude dITP from the pool, mammals possess specific hydrolysing enzymes, such as inosine triphosphatase (ITPA). Previous studies have shown that deficiency in ITPA results in cell growth suppression and DNA instability. To explore the mechanisms of these phenotypes, we analysed ITPA-deficient human and mouse cells. We found that both growth suppression and accumulation of single-strand breaks in nuclear DNA of ITPA-deficient cells depended on MLH1/PMS2. The cell growth suppression of ITPA-deficient cells also depended on p53, but not on MPG, ENDOV or MSH2. ITPA deficiency significantly increased the levels of p53 protein and p21 mRNA/ protein, a well-known target of p53, in an MLH1-dependent manner. Furthermore, MLH1 may also contribute to cell growth arrest by increasing the basal level of p53 activity.

DOI： 10.1038/srep32849
MUTYH, an adenine DNA glycosylase, mediates p53 tumor suppression via PARP-dependent cell death Reviewed International journal

岡素雅子, Julio Jisus Leon Incio, 土本大介, 作見邦彦, 中別府雄作

Oncogenesis 2014.8

　More details

Language：Japanese Publishing type：Research paper (scientific journal)
Fosb gene products contribute to excitotoxic microglial activation by regulating the expression of complement C5a receptors in microglia. Reviewed International journal

Hiroko Nomaru, SAKUMI Kunihiko, Atsuhisa Katogi, Yoshinori N. Ohnishi, Kosuke Kajitani, Daisuke Tsuchimoto, Eric J. Nestler, Yusaku Nakabeppu

Glia 62 ( 8 ) 1284 - 1298 2014.8

　More details

Language：English Publishing type：Research paper (scientific journal)

The Fosb gene encodes subunits of the activator protein-1 transcription factor complex. Two mature mRNAs, Fosb and ΔFosb, encoding full-length FOSB and ΔFOSB proteins respectively, are formed by alternative splicing of Fosb mRNA. Fosb products are expressed in several brain regions. Moreover, Fosb-null mice exhibit depressive-like behaviors and adult-onset spontaneous epilepsy, demonstrating important roles in neurological and psychiatric disorders. Study of Fosb products has focused almost exclusively on neurons; their function in glial cells remains to be explored. In this study, we found that microglia express equivalent levels of Fosb and ΔFosb mRNAs to hippocampal neurons and, using microarray analysis, we identified six microglial genes whose expression is dependent on Fosb products. Of these genes, we focused on C5ar1 and C5ar2, which encode receptors for complement C5a. In isolated Fosb-null microglia, chemotactic responsiveness toward the truncated form of C5a was significantly lower than that in wild-type cells. Fosb-null mice were significantly resistant to kainate-induced seizures compared with wild-type mice. C5ar1 mRNA levels and C5aR1 immunoreactivity were increased in wild-type hippocampus 24 hours after kainate administration; however, such induction was significantly reduced in Fosb-null hippocampus. Furthermore, microglial activation after kainate administration was significantly diminished in Fosb-null hippocampus, as shown by significant reductions in CD68 immunoreactivity, morphological change and reduced levels of Il6 and Tnf mRNAs, although no change in the number of Iba-1-positive cells was observed. These findings demonstrate that, under excitotoxicity, Fosb products contribute to a neuroinflammatory response in the hippocampus through regulation of microglial C5ar1 and C5ar2 expression.

DOI： 10.1002/glia.22680.
Apurinic/Apyrimidinic Endonuclease 2 Regulates the Expansion of Germinal Centers by Protecting against Activation-Induced Cytidine Deaminase-Independent DNA Damage in B Cells. Reviewed International journal

Jeroen E. J. Guikema, Erin K. Linehan, Nada Esa, Daisuke Tsuchimoto, Yusaku Nakabeppu, Robert T. Woodland, Carol E. Schrader

The Journal of Immunology 2014.6

　More details

Language：English Publishing type：Research paper (scientific journal)

Activation-induced cytidine deaminase (AID) initiates a process generating DNA mutations and breaks in germinal center (GC) B cells that are necessary for somatic hypermutation and class-switch recombination. GC B cells can "tolerate" DNA damage while rapidly proliferating because of partial suppression of the DNA damage response by BCL6. In this study, we develop a model to study the response of mouse GC B cells to endogenous DNA damage. We show that the base excision repair protein apurinic/apyrimidinic endonuclease (APE) 2 protects activated B cells from oxidative damage in vitro. APE2-deficient mice have smaller GCs and reduced Ab responses compared with wild-type mice. DNA double-strand breaks are increased in the rapidly dividing GC centroblasts of APE2-deficient mice, which activate a p53-independent cell cycle checkpoint and a p53-dependent apoptotic response. Proliferative and/or oxidative damage and AID-dependent damage are additive stresses that correlate inversely with GC size in wild-type, AID-, and APE2-deficient mice. Excessive double-strand breaks lead to decreased expression of BCL6, which would enable DNA repair pathways but limit GC cell numbers. These results describe a nonredundant role for APE2 in the protection of GC cells from AID-independent damage, and although GC cells uniquely tolerate DNA damage, we find that the DNA damage response can still regulate GC size through pathways that involve p53 and BCL6.
Differential expression of APE1 and APE2 in germinal centers promotes error-prone repair and A:T mutations during somatic hypermutation Reviewed International journal

Janet Stavnezer, Erin K. Linehan, Mikayla R. Thompson, Ghaith Habboub, Anna J. Ucher, Tatenda Kadungure, Daisuke Tsuchimoto, Yusaku Nakabeppu, Carol E. Schrader

Proceedings of the National Academy of Sciences of the United States of America 2014.6

　More details

Language：English Publishing type：Research paper (scientific journal)

Somatic hypermutation (SHM) of antibody variable region genes is
initiated in germinal center B cells during an immune response by
activation-induced cytidine deaminase (AID), which converts cytosines
to uracils. During accurate repair in nonmutating cells, uracil
is excised by uracil DNA glycosylase (UNG), leaving abasic sites
that are incised by AP endonuclease (APE) to create single-strand
breaks, and the correct nucleotide is reinserted by DNA polymerase
β. During SHM, for unknown reasons, repair is error prone. There
are two APE homologs in mammals and, surprisingly, APE1, in contrast
to its high expression in both resting and in vitro-activated
splenic B cells, is expressed at very low levels in mouse germinal
center B cells where SHM occurs, and APE1 haploinsufficiency has
very little effect on SHM. In contrast, the less efficient homolog,
APE2, is highly expressed and contributes not only to the frequency
of mutations, but also to the generation of mutations at A:T base
pair (bp), insertions, and deletions. In the absence of both UNG and
APE2, mutations at A:T bp are dramatically reduced. Single-strand
breaks generated by APE2 could provide entry points for exonuclease
recruited by the mismatch repair proteins Msh2–Msh6, and the
known association of APE2 with proliferating cell nuclear antigen
could recruit translesion polymerases to create mutations at AIDinduced
lesions and also at A:T bp. Our data provide new insight
into error-prone repair of AID-induced lesions, which we propose is
facilitated by down-regulation of APE1 and up-regulation of APE2
expression in germinal center B cells.
8-Oxoguanine causes neurodegeneration during MUTYH-mediated DNA base excision repair Reviewed

Zijing Sheng, Sugako Oka, Daisuke Tsuchimoto, Nona Abolhassani, Hiroko Nomaru, SAKUMI Kunihiko, Hideaki Yamada, Yusaku Nakabeppu

The Journal of Clinical Investigation 122 ( 12 ) 4344 - 4361 2012.12

　More details

Language：English

DOI： 10.1172/JCI65053
AP-Endonuclease 2 is necessary for normal B cell development and recovery of lymphoid progenitors after chemotherapeutic challenge. Reviewed International journal

Jeroen E.J. Guikema, Rachel M. Gerstein, Erin K. Linehan, Erin K. Clohert, Eric Evan-Browning, Daisuke Tsuchimoto, Yusaku Nakabeppu, and Carol E. Schrader

Journal of Immunology 186(4) 2011.2

　More details

Language：English Publishing type：Research paper (scientific journal)
Cancer-related PRUNE2 protein is associated with nucleotides and is highly expressed in mature nerve tissues. Reviewed International journal

Iwama E., Tsuchimoto D., Iyama T., Sakumi K., Nakagawara A., Takayama K., Nakanishi Y., and Nakabeppu Y.

Journal of Molecular Neuroscience 2011.1

　More details

Language：English Publishing type：Research paper (scientific journal)
NUDT16 is a (deoxy)inosine diphosphatase, and its deficiency induces accumulation of single-strand breaks in nuclear DNA and growth arrest. Reviewed International journal

Iyama T, Abolhassani N, Tsuchimoto D, Nonaka M, Nakabeppu Y.

Nucleic Acids Research 38(14) 2010.8

　More details

Language：English Publishing type：Research paper (scientific journal)

DOI： doi:10.1093/nar/gkq249
NUDT16 and ITPA play a dual protective role in maintaining chromosome stability and cell growth by eliminating dIDP/IDP and dITP/ITP from nucleotide pools in mammals. Reviewed International journal

Abolhassani N, Iyama T, Tsuchimoto D, Sakumi K, Ohno M, Behmanesh M, Nakabeppu Y.

Nucleic Acids Res. 2010.5

　More details

Language：English Publishing type：Research paper (scientific journal)
Apex2 is required for efficient somatic hypermutation but not for class switch recombination of immunoglobulin genes Reviewed International journal

Sabouri Z, Okazaki IM, Shinkura R, Begum N, Nagaoka H, Tsuchimoto D, Nakabeppu Y, Honjo T

Int. Immunol. 2009.8

　More details

Publishing type：Research paper (scientific journal)
ITPase-deficient mice show growth retardation and die before weaning Reviewed International journal

Behmanesh M, Sakumi K, Abolhassani N, Toyokuni S, Oka S, Ohnishi YN, Tsuchimoto D, Nakabeppu Y

Cell Death and Differentiation 2009.6

　More details

Language：English Publishing type：Research paper (scientific journal)
Mouse RS21-C6 is a mammalian 2'-deoxycytidine 5'-triphosphate pyrophosphohydrolase that prefers 5-iodocytosine. Reviewed International journal

Nonaka M, Tsuchimoto D, Sakumi K, Nakabeppu Y.

FEBS J. 2009.3

　More details

Language：English Publishing type：Research paper (scientific journal)
Galectin-1 promotes basal and kainate-induced proliferation of neural progenitors in the dentate gyrus of adult mouse hippocampus. Reviewed International journal

Kajitani K, Nomaru H, Ifuku M, Yutsudo N, Dan Y, Miura T, Tsuchimoto D, Sakumi K, Kadoya T, Horie H, Poirier F, Noda M, Nakabeppu Y.

Cell Death Differ. 2009.3

　More details

Language：English Publishing type：Research paper (scientific journal)
Altered gene expression profiles and higher frequency of spontaneous DNA strand breaks in APEX2-null thymus. Reviewed International journal

Dan Y, Ohta Y, Tsuchimoto D, Ohno M, Ide Y, Sami M, Kanda T, Sakumi K, Nakabeppu Y.

DNA Repair (Amst) 2008.9

　More details

Language：English Publishing type：Research paper (scientific journal)
Oxidation of mitochondrial deoxynucleotide pools by exposure to sodium nitroprusside induces cell death Reviewed International journal

Ichikawa J, Tsuchimoto D, Oka S, Ohno M, Furuichi M, Sakumi K, Nakabeppu Y

DNA Repair 2008.3

　More details

Publishing type：Research paper (scientific journal)
Two distinct pathways of cell death triggered by oxidative damage to nuclear and mitochondrial DNAs. Reviewed International journal

Oka S, Ohno M, Tsuchimoto D, Sakumi K, Furuichi M, Nakabeppu Y

The EMBO Journal 2008.1

　More details

Language：English Publishing type：Research paper (scientific journal)
APE1- and APE2-dependent DNA breaks in immunoglobulin class switch recombination Reviewed International journal

Guikema JEJ, Kinehan EK, Tsuchimoto D, Nakabeppu Y, Strauss PR, Stavnezer J, and Schrader CE

The Journal of Experimental Medicine 2007.11

　More details

Language：English Publishing type：Research paper (scientific journal)
A genome-wide distribution of 8-oxoguanine correlates with the preferred regions for recombination and single-nucleotide polymorphism in the human genome. Reviewed International journal

Ohno M., Miura T., Furuichi M., Tominaga Y., Tsuchimoto D., Sakumi K. and Nakabeppu Y.

Genome Research 2006.5

　More details

Language：English Publishing type：Research paper (scientific journal)
Hematopoietic tissue-specific expression of mouse Neil3 for Endonuclease VIII-like protein. Reviewed International journal

Torisu K., Tsuchimoto D., Ohnishi Y. and Nakabeppu Y.

The Journal of Biochemistry 138 ( 6 ) 763 - 772 2005.12

　More details

Language：English Publishing type：Research paper (scientific journal)

DOI： 10.1093/jb/mvi168
Characterization of the structure and expression of mouse Itpa gene and its related sequences in the mouse genome. Reviewed International journal

Behmanesh B., Sakumi K., Tsuchimoto D., Torisu K., Ohnishi-Honda Y., Rancourt D.E. and Nakabeppu Y.

DNA Research 12 ( 1 ) 39 - 51 2005.2

　More details

Language：English Publishing type：Research paper (scientific journal)

DOI： 10.1093/dnares/12.1.39
A functional analysis of the DNA glycosylase activity of mouse MUTYH protein excising 2-hydroxyadenine opposite guanine in DNA. Reviewed International journal

Ushijima Y., Tominaga Y, Miura T, Tsuchimoto D, Sakumi K and Nakabeppu Y.

Nucleic Acids Research 33 ( 2 ) 672 - 682 2005.1

　More details

Language：English Publishing type：Research paper (scientific journal)

DOI： 10.1093/nar/gki214
Growth retardation and dyslymphopoiesis accompanied by G2/M arrest in APEX2-null mice. Reviewed International journal

Ide Y, Tsuchimoto D, Tominaga Y, Nakashima M, Watanabe T, Sakumi K, Ohno M, Nakabeppu Y.

Blood 104 ( 13 ) 4097 - 4103 2004.12

　More details

Language：English Publishing type：Research paper (scientific journal)

DOI： 10.1182/blood-2004-04-1476
A Mechanism of Transcriptional Regulation of the CSF-1 Gene by Interferon-gamma. Reviewed International journal

Tsuchimoto D, Tojo A, Asano S

Immunological Investigations 33 ( 4 ) 397 - 405 2004.12

　More details

Language：English Publishing type：Research paper (scientific journal)

DOI： 10.1081/IMM-200038662
Galectin-1beta, a natural monomeric form of galectin-1 lacking its six amino-terminal residues promotes axonal regeneration but not cell death Reviewed International journal

Miura T, Takahashi M, Horie H, Kurushima H, Tsuchimoto D, Sakumi K, Nakabeppu Y.

Cell Death and Differentiation 11 ( 10 ) 1076 - 1083 2004.10

　More details

Language：English Publishing type：Research paper (scientific journal)

DOI： 10.1038/sj.cdd.4401462
MUTYH prevents OGG1 or APEX1 from inappropriately processing its substrate or reaction product with its C-terminal domain Reviewed International journal

Tominaga Y, Ushijima Y, Tsuchimoto D, Mishima M, Shirakawa M, Hirano S, Sakumi K, Nakabeppu Y.

Nucleic Acids Research 32 ( 10 ) 3198 - 3211 2004.6

　More details

Language：English Publishing type：Research paper (scientific journal)

DOI： 10.1093/nar/gkh642
Biological significance of the defense mechanisms against oxidative damage in nucleic acids caused by reactive oxygen species: from mitochondria to nuclei International journal

Nakabeppu Y, Tsuchimoto D, Ichinoe A, Ohno M, Ide Y, Hirano S, Yoshimura D, Tominaga Y, Furuichi M, Sakumi K.

Ann N Y Acad Sci. 1011 101 - 111 2004.4

　More details

Language：English Publishing type：Research paper (international conference proceedings)

DOI： 10.1196/annals.1293.011
Identification and characterization of two forms of mouse MUTYH proteins encoded by alternatively spliced transcripts Reviewed International journal

Ichinoe A, Behmanesh M, Tominaga Y, Ushijima Y, Hirano S, Sakai Y, Tsuchimoto D, Sakumi K, Wake N, Nakabeppu Y.

Nucleic Acids Research 32 ( 2 ) 477 - 487 2004.1

　More details

Language：English Publishing type：Research paper (scientific journal)

DOI： 10.1093/nar/gkh214
Mutator phenotype of MUTYH-null mouse embryonic stem cells. Reviewed International journal

Hirano S, Tominaga Y, Ichinoe A, Ushijima Y, Tsuchimoto D, Honda-Ohnishi Y,

J Biol Chem. 278 ( 40 ) 38121 - 38124 2003.10

　More details

Language：English Publishing type：Research paper (scientific journal)

DOI： 10.1074/jbc.C300316200
DeltaFosB, but not FosB, induces delayed apoptosis independent of cell proliferation in the Rat1a embryo cell line. Reviewed International journal

Tahara K, Tsuchimoto D, Tominaga Y, Asoh S, Ohta S, Kitagawa M, Horie H, Nakabeppu Y

Cell Death Differ. 10 ( 5 ) 496 - 507 2003.5

　More details

Language：English Publishing type：Research paper (scientific journal)

DOI： 10.1038/sj.cdd.4401173
Characterization of the genomic structure and expression of the mouse Apex2 gene. Reviewed International journal

Ide Y, Tsuchimoto D, Tominaga Y, Iwamoto Y, Nakabeppu Y.

Genomics 81 ( 1 ) 47 - 57 2003.1

　More details

Language：English Publishing type：Research paper (scientific journal)

DOI： 10.1016/S0888-7543(02)00009-5
Human APE2 protein is mostly localized in the nuclei and to some extent in the mitochondria, while nuclear APE2 is partly associated with proliferating cell nuclear antigen. Reviewed International journal

Tsuchimoto D, Sakai Y, Sakumi K, Nishioka K, Sasaki M, Fujiwara T, Nakabeppu Y

Nucleic Acids Res. 29 ( 11 ) 2349 - 2360 2001.6

　More details

Language：English Publishing type：Research paper (scientific journal)

DOI： 10.1093/nar/29.11.2349

▼display all

Presentations

マウスモデルを用いた早期乳児てんかん性脳症（EIEE）35の発症メカニズムの解明 Invited

土本大介

第64回日本小児神経学会 2022.6

　More details

Event date： 2022.6

Language：Japanese Presentation type：Symposium, workshop panel (public)

Venue：群馬県高崎市Gメッセ群馬 Country：Japan
神経幹細胞特異的イノシン三リン酸分解酵素ノックアウトマウスは脳神経細胞脱分極とてんかん発作を示す Invited

土本大介

2020年度先端モデル動物支援プラットフォーム成果発表会 2021.2

　More details

Event date： 2021.2

Language：Japanese Presentation type：Symposium, workshop panel (public)

Venue：東京国際フォーラムハイブリッド開催 Country：Japan
Neural stem cell-specific Itpa knockout causes depolarization, epileptic seizure and early death in mice

土本大介、古賀祐一郎、林良憲、アボルハッサニノナ、米嶋康臣、作見邦彦、中西博、豊國伸哉、中別府雄作

第43回日本神経科学大会 2020.9

　More details

Event date： 2020.9

Language：English

Venue：Web開催 Country：Japan
Neural stem cell specific ITPA deficiency causes depolarization of neurons, resulting in epileptic seizure and early death in mice

Daisuke Tsuchimoto, Yuichiro Koga, @Yoshinori Hayashi, Nona Abolhassani, Yasuto Yoneshima, Kunihiko Sakumi, @Hiroshi Nakanishi, @Shinya Toyokuni, Yusaku Nakabeppu

日本分子生物学会年会 2019.12

　More details

Event date： 2019.12

Language：Japanese

Venue：福岡市、マリンメッセ Country：Japan
ITPA欠損によるヒトてんかん性脳症のモデルとしての神経幹細胞特異的Itpaノックアウトマウス

土本　大介、古賀　祐一郎、林　良憲、アボルハッサニ　ノナ、米嶋　康臣、@中西　博、@豊國　伸哉、中別府　雄作

平成３０年度「先端モデル動物支援プラットフォーム成果発表会」 2019.1

　More details

Event date： 2019.1

Language：Japanese

Venue：琵琶湖ホテル（滋賀県大津市浜町2−40） Country：Japan
ITPA欠損によるヒトてんかん性脳症のモデルとしての神経幹細胞特異的Itpaノックアウトマウス

土本　大介、古賀　祐一郎、林　良憲、アボルハッサニ　ノナ、米嶋　康臣、@中西　博、中別府　雄作

第４１回日本日本分子生物学会年会 2018.11

　More details

Event date： 2018.11

Language：Japanese

Venue：パシフィコ横浜（神奈川県横浜市西区みなとみらい１−１−１） Country：Japan
Neural stem cell-specific Itpa knockout mouse as a model of human epileptic encephalopathy caused by ITPA deficiency International conference

Daisuke Tsuchimoto, Yuichiro Koga, Yoshinori Hayashi, Nona Abolhassani,Yasuto Yoneshima, @Hiroshi Nakanishi, Yusaku Nakabeppu

The Joint Symposium of the 13th International Symposium of the Institute Network for Biomedical Sciences and the 28th Hot Spring Harbor International Symposium 2018 2018.10

　More details

Event date： 2018.10

Language：English

Venue：福岡県福岡市東区馬出九州大学百年記念講堂 Country：Japan
Neural stem cell-specific Itpa knockout mouse as a model of human ITPA deficiency

Daisuke Tsuchimoto, #Yuichiro Koga, Yoshinori Hayashi, Nona Abolhassani, Yasuto Yoneshima, @Hiroshi Nakanishi, Yusaku Nakabeppu

第４１回日本神経科学大会 2018.7

　More details

Event date： 2018.7 - 2018.8

Language：English

Venue：兵庫県神戸市神戸コンベンションセンター Country：Japan

Inosine triphosphate pyrophosphatase (ITPA), which is encoded by ITPA gene, hydrolyzes ITP and other deaminated purine nucleoside triphosphates to the corresponding nucleoside monophosphates and pyrophosphates, thus sanitizing intracellular nucleotide pools. In human, it was recently reported that patients with ITPA homozygous mutations show severe encephalopathy with epileptic seizure and microcephaly. All patients show developmental retardation and most of them die before 3 years old.
We previously reported that ITPA deficiency in mice causes partial embryonic lethality and survived litters also die within 2 weeks after birth with features of growth retardation. Echocardiography and ultrastructural analysis of hearts of Itpa knockout mice revealed unsynchronized movement and disorganized sarcomere structure.
In the present study, we established and analyzed neural stem cell-specific Itpa knockout mice (Itpaflox/flox/Nestin-Cre+/Tg). Knockout in the neural stem cells results in ITPA deficiency in neurons and glial cells except microglia. Itpaflox/flox/Nestin-Cre+/Tg mice did not exhibit embryonic lethality, but showed growth retardation and died within 3 weeks after birth. Some of them showed spontaneous and generalized seizure. Artificial audiogenic stress induced similar seizure in all analyzed knockout mice but not in ITPA-proficient control mice. In contrast to human patients, the ITPA deficient mice did not show microcephaly.
To analyze molecular mechanism of the seizure caused by ITPA deficiency in brain, we performed electrophysiological analysis of brain slices. Whole-cell patch-clamp recordings from entorhinal cortex neurons in Itpaflox/flox/Nestin-Cre+/Tg brain slices showed depolarized resting membrane potential and more frequent firing rates both under spontaneous and stimulated conditions, in comparison to those in wild-type brain slices. The membrane potential in neuron is generated by ion channels and sodium/potassium-transporting ATPase (Na+/K+-ATPase), which contains ATP1A1 or ATP1A3 as its  subunit ATPase. Biochemical analysis of recombinant ATP1A1 or ATP1A3 showed that ITP is not good substrate for them and does not inhibit their ATPase activities, suggesting that ITPA deficiency may cause depolarization of resting membrane potential via other mechanisms such as alteration of ion channel function.
イノシン三リン酸分解酵素ITPA欠損症のモデルマウス作製と解析

土本大介, 古賀祐一郎, 米嶋　康臣, 浅田　真司, 作見邦彦, 中別府　雄作

平成28年度先端モデル動物支援プラットフォーム成果発表会 2017.2

　More details

Event date： 2017.2

Language：Japanese

Venue：大津市琵琶湖ホテル Country：Japan

（デオキシ）イノシン三リン酸（[d]ITP）は，(d)ATPの酸化的脱アミノ化やイノシン一リン酸（IMP）のリン酸化によって生じると考えられているが，正常な哺乳動物細胞においてはイノシン三リン酸分解酵素（ITPA）により(d)IMPへと分解されるため検出されない．最近ヒトのITPA欠損が，発育遅延や小頭症，てんかん様けいれん発作を伴い生後２，３年以内に死亡する幼児脳症の原因となる事が報告された（Kevelam SH et al., Ann Neurol. 2015 Oct;78(4):649-58）．またその後，ITPAの活性低下につながる遺伝子多型と若年発症型の結核症との相関が報告された（Nakauchi A et al., Hum Genome Var. 2016 Feb 4;3:15067）．
　我々は，ITPA欠損が哺乳動物中枢神経系に及ぼす影響を調べる目的で，神経幹細胞特異的にItpa遺伝子を破壊したItpa(flox/flox)/NestinCre(Tg/+)マウスを樹立した．このマウスは正常ITPAを発現する同腹仔コントロールマウスと比較して発育遅延を示し，ほぼ全てが生後約３週間で死亡した．短期間の観察中に一部のマウスで自発性てんかん様けいれん発作を認めたことから，１６日齢のマウスに対して音刺激によるけいれん発作誘発を試みたところ，音刺激を与えた８匹のITPA欠損マウスは全てにおいてけいれん発作が誘発されたが，正常ITPAを発現する同腹仔コントロールマウス１９匹では全く発作を認めなかった．これらのことから，ITPA欠損マウスはヒトITPA欠損脳症のよいモデルであると考えられる．
　現在，このモデルマウスを用いてITPA欠損が脳症を引き起こすメカニズムの解析を行っている．
イノシン三リン酸分解酵素ITPA欠損の哺乳動物細胞およびマウス中枢神経系への影響の解析

土本大介, 米嶋康臣, 古賀祐一郎, ABOLHASSANI NONA, 猪山輝昭, 浅田真司, 作見邦彦, 塩見尚子, 森雅彦, 塩見忠博, 野田哲生, 中別府　雄作

日本分子生物学会 2016.12

　More details

Event date： 2016.11 - 2016.12

Language：Japanese

Venue：神奈川県横浜市パシフィコ横浜 Country：Japan

（デオキシ）イノシン三リン酸（[d]ITP）は，(d)ATPの酸化的脱アミノ化やイノシン一リン酸（IMP）のリン酸化によって生じると考えられているが，正常な哺乳動物細胞においてはイノシン三リン酸分解酵素（ITPA）により(d)IMPへと分解されるため検出されない．昨年，ヒトのITPA欠損が発育遅延や，小頭症，けいれん,を伴う幼児脳症の原因となる事が報告された（doi: 10.1002/ana.24496）．またその後，ITPAの活性低下につながる遺伝子多型と若年発症型の結核症との相関が報告された（doi: 10.1038/hgv.2015.67）．　我々は，ITPA欠損が哺乳動物細胞へ与える影響を調べる目的でItpaノックアウトマウス胎仔由来線維芽細胞やITPAノックダウンヒト培養細胞の解析を行った．その結果ITPA欠損はゲノムDNA中のデオキシイノシンの蓄積をもたらすと同時に，DNAミスマッチ修復関連タンパク質複合体MLH1/PMS2に依存したDNA一本鎖切断と細胞増殖抑制を引き起こした．この時ミスマッチ塩基対認識に必須のMSH2が関与しなかったことから，ミスマッチに依存しないMLH1/PMS2の機能であることが示された．更に細胞増殖抑制はp53依存性の細胞周期G1期停止を伴っていた．　次に我々はITPA欠損がマウス中枢神経系へ与える影響を調べる目的で，神経幹細胞特異的にItpa遺伝子のエクソン５が切除されるItpa^(flox/flox)/NestinCre^(Tg/+)マウスを作成した．このマウスは同腹仔コントロールマウスと比較して発育遅延を示し，ほぼ全てが生後約３週間で死亡した．更に短時間の観察中に一部のマウスで自発性てんかん様けいれん発作を認めたことから，ヒトITPA欠損脳症のよいモデルであると考えられる．　これらのITPA欠損細胞およびマウスの結果から，ヒトのITPA欠損が脳症や結核症を引き起こすメカニズムを考察したい．
イノシン三リン酸分解酵素ITPAの組織特異的欠損マウス作成と解析

土本大介, 古賀祐一郎, 米嶋康臣, 浅田真司, 中別府雄作

日本分子生物学会／日本生化学会合同年会 2015.12

　More details

Event date： 2015.12

Language：Japanese

Venue：兵庫県神戸市ポートピアホテル Country：Japan
デオキシイノシン三リン酸の蓄積はミスマッチ修復タンパク質MLH1に依存した細胞周期の遅延をもたらす

土本大介, 米嶋康臣, ABOLHASSANI NONA, 猪山輝昭, 作見邦彦, 塩見尚子, 森雅彦, 塩見忠博, 野田哲生, 中別府雄作

日本分子生物学会総会 2014.11

　More details

Event date： 2014.11

Language：Japanese

Venue：神奈川県横浜市 Country：Japan

DNA中に蓄積した損傷塩基は突然変異や細胞死を引き起こすため、様々な疾患の原因となる。我々は、DNA中の損傷塩基の起源としてヌクレオチドプール中に生じたの損傷ヌクレオチドに注目している。損傷ヌクレオチドはDNAに取り込まれることによりDNA損傷応答を引起こすと考えられる。このような損傷ヌクレオチドの多くは特異的加水分解酵素によって分解されることで、DNAへの取込みが抑制されている。
　デオキシイノシン三リン酸（dITP）はdATPの酸化的脱アミノ化によって生じる損傷ヌクレオチドである。これまでに我々は、ほ乳動物細胞にはdITPを加水分解するinosine triphosphatase（ITPA）や、nudix (nucleoside diphosphate linked moiety X)-type motif 16（NUDT16）が存在し、dITPの蓄積を抑えていることを明らかにしてきた。HeLa MR細胞ではNUDT16のノックダウンにより細胞増殖の抑制および核DNAに一本鎖切断の蓄積を認めたが、ミスマッチ修復（MMR）に必須の遺伝子MLH1の発現抑制によりこれらの現象は解除された。また、MLH1のナンセンス変異を両アリルに持つHCT116細胞はITPAノックダウンの影響を受けなかったが、この細胞に正常なMLH1配列をノックインしたH414細胞ではITPAノックダウンによる細胞増殖の抑制を認めた。
　今回、ITPAノックダウンにより細胞増殖が抑制されたH414細胞をフローサイトメトリーにより解析したところ、S期の細胞の減少と同時にG1期とG2期のそれぞれの細胞集団の増加を認めた。次に、ITPAをノックダウンしたH414細胞の培地にデオキシイノシンを添加したところさらなる細胞増殖の抑制を認めたが、イノシンでは何ら効果を認めなかった。この結果は、dITPの蓄積が細胞増殖抑制の原因になっていることを示している。現在、ミスマッチ修復において損傷部位の認識に関わるMSH2の欠損の影響や細胞周期チェックポイント機構に対する阻害剤の影響を解析しており、それらの結果も合わせて報告する。
デオキシイノシン三リン酸の蓄積はミスマッチ修復機構に依存した細胞増殖抑制とゲノム不安定性を引き起こす

米嶋康臣, 土本大介, アボルハッサニ　ノナ, 猪山輝昭, 作見邦彦, 塩見尚子, 森雅彦, 塩見忠博, 中別府雄作

第36回日本分子生物学会年会、ポスター発表（2013年12月4日2P-0150） 2013.12

　More details

Event date： 2013.12

Language：Japanese

Venue：兵庫県神戸市神戸ポートアイランド（神戸国際会議場、神戸国際展示場、神戸ポートピアホテル） Country：Japan

DNAの損傷は遺伝子変異や細胞死を引き起こすとともに、様々な疾患の原因となる。また、細胞内の遊離ヌクレオチドの損傷体は、DNAに取り込まれることによりDNA損傷の一因となる。このような損傷ヌクレオチドの多くは特異的加水分解酵素によって分解除去される。
　デオキシイノシン三リン酸（dITP）はdATPの酸化的脱アミノ化によって生じる損傷ヌクレオチドである。これまでに我々は、哺乳動物細胞にはdITPを加水分解するinosine triphosphatase（ITPA）や、nudix (nucleoside diphosphate linked moiety X)-type motif 16（NUDT16）が存在し、dITPの蓄積を抑えていることを明らかにしてきた。
　今回我々は、dITP分解酵素欠損による細胞増殖抑制とDNA中のデオキシイノシン（dI）の認識排除機構との関連性を調べた。HeLa MR細胞において、NUDT16のノックダウンを行うと細胞増殖抑制および核DNA一本鎖切断の蓄積を認めたが、DNAミスマッチ修復（MMR）に必須の遺伝子MLH1の発現抑制によりこれらの現象は解除された。また、MLH1のナンセンス変異を両アリルに持つHCT116細胞、およびこの細胞に正常なMLH1配列をノックインしたH414細胞を用いて、ITPAノックダウンの影響を解析したところ、MLH1に依存した細胞増殖抑制の誘導を認めた。次に、dIを含むオリゴ二本鎖DNAとHeLa MR細胞の核抽出物を用いたゲルシフトアッセイを行ったところ、dI:デオキシグアノシン（dG）ペアを含むDNAとMMRタンパク質との特異的結合が確認された。さらに抗MSH6抗体を加えるとこの結合は消失した。
　以上の結果から、細胞中に蓄積した遊離dITPが複製時にDNAに取り込まれ、dIがdGと塩基対を形成した場合に、MMRによる認識とそれに続く修復機構に依存して細胞増殖抑制が誘導されると考えられた。
2-OH-ATPによる細胞増殖抑制と細胞死に関与する遺伝子の網羅的解析

瀧口友香, 太田詠子, 土本大介, 作見邦彦, 中別府雄作

日本遺伝学会第84回大会（演題番号2C-05) 2012.9

　More details

Event date： 2012.9

Language：Japanese Presentation type：Oral presentation (general)

Venue：福岡市九州大学医学部百年講堂・同窓会館 Country：Japan

これまでに我々は、ATPの酸化体である2-OH-ATPおよびその脱リン酸化体である2-OH-adenosineが酸化プリンヌクレオチド分解酵素MTH1の欠損マウス細胞においてp38 MAPK経路を介した細胞増殖抑制と細胞死を誘導し, ヒトMTH1の発現がこれを抑制することを見出してきた。今回これらの細胞障害に関わる因子を明らかにするためMth1-/-マウス細胞およびヒトMTH1発現マウス細胞を用いて，2-OH-adenosine処理による転写プロファイルの変化をGeneChip Arrayを用いて解析した。変化を認めた遺伝子のうち，細胞増殖抑制や細胞死に関わる遺伝子に関してReal-time PCRで発現の確認を行った。
イノシン三リン酸によるゲノム不安定化機構と細胞内イノシン三リン酸生成経路の解明

米嶋康臣, 土本大介, 作見邦彦, 野田哲生, 中別府雄作

日本遺伝学会第84回大会（演題番号2E-02) 2012.9

　More details

Event date： 2012.9

Language：Japanese Presentation type：Oral presentation (general)

Venue：福岡 Country：Japan

イノシンヌクレオチドは、一部はプリンヌクレオチド合成経路の前駆体として生合成されている一方で、アデノシンヌクレオチドのC6位の脱アミノ化反応によっても生じる。（デオキシ）イノシン三リン酸（(d)ITP）はゲノムDNA不安定化やATP依存性タンパク質の機能阻害など、さまざまな生体障害を引き起こすと考えられる。我々は哺乳動物細胞の(d)ITPおよび（デオキシ）イノシン二リン酸の分解酵素としてITPAとNUDT16をそれぞれ同定して来た。今回、ITPA欠損マウス由来初代線維芽細胞を用いて(d)ITPによるゲノムDNA不安定化分子機構と細胞内(d)ITP生成経路の検討を行った。
ほ乳動物細胞におけるデオキシイノシンヌクレオチドによるゲノム不安定化機構とその防御システム

土本大介、猪山輝昭、アボルハッサニ・ノナ、米嶋康臣、作見邦彦、塩見尚子、森雅彦、塩見忠博、中別府雄作

第34回日本分子生物学会年会 2011.12

　More details

Event date： 2011.12

Language：Japanese

Venue：神奈川県横浜市、パシフィコ横浜 Country：Japan

Mechanism of genome instability triggered by deoxyinosine nucleotides and defense systems in mammalian cells
ほ乳動物細胞におけるデオキシイノシンヌクレオチドによるゲノム不安定化とその防御機構

土本大介、猪山輝昭、アボルハッサニ・ノナ、米嶋康臣、作見邦彦、中別府雄作

日本遺伝学会 2011.9

　More details

Event date： 2011.9

Language：Japanese Presentation type：Symposium, workshop panel (public)

Venue：京都府京都市、京都大学農学部 Country：Japan

Genome instability triggered by deoxyinosine nucleotides and defense mechanisms in mammalian cells
NUDT16 is a (deoxy)inosine diphosphatase, and its deficiency induces accumulation of single-strand breaks in nuclear DNA and growth arrest International conference

Teruaki Iyama, Nona Abolhassani, Daisuke Tsuchimoto, Yusaku Nakabeppu

The 7th Global COE International Symposium and 6th Young Investigators Forum 2011.2

　More details

Event date： 2011.2

Venue：Angsana Resort & Spa Bintan, Bintan Island, Indonesia Country：Indonesia
NUDT16 is a (deoxy)inosine diphosphatase, and its deficiency induces accumulation of single-strand breaks in nuclear DNA and growth arrest International conference

Teruaki Iyama, Nona Abolhassani, Daisuke Tsuchimoto, Yusaku Nakabeppu

Keystone Symposia on Molecular and Cellular Biology, Genomic Instability and DNA Repair 2011.2

　More details

Event date： 2011.2

Venue：Keystone Resort, Keystone, CO, USA Country：United States
NUDT16は（デオキシ）イノシン二リン酸分解酵素であり、その欠損は核DNAの一本鎖切断の蓄積と増殖抑制をもたらす

土本大介、猪山輝昭、アボルハッサニ　ノナ、野中麻里、中別府雄作

BMB2010 2010.12

　More details

Event date： 2010.12

Venue：神戸ポートアイランド Country：Japan
An increased expression of NUDT16 with IDP/dIDP hydrolyzing activity in immortalized ITPA-null mouse embryonic fibroblasts suppressed ITPA-deficient phenotypes

Nona Abolhassani, Teruaki Iyama, Daisuke Tsuchimoto, Kunihiko Sakumi, Mizuki Ohno, Behmanesh Mehrdad, Yusaku Nakabeppu

第３２回日本分子生物学会年会 2009.12

　More details

Event date： 2009.12

Venue：神奈川県横浜市パシフィコ横浜 Country：Japan
Human NUDT16 is a novel nucleotide pool sanitizing enzyme hydrolyzing (deoxy)inosine diphosphate to (deoxy)inosine monophosphate

Daisuke Tsuchimoto, Teruaki Iyama, Nona Abolhassani, Yusaku Nakabeppu

第３２回日本分子生物学会年会 2009.12

　More details

Event date： 2009.12

Language：English

Venue：神奈川県横浜市パシフィコ横浜 Country：Japan
Human NUDT16 Is a Novel Nucleotide Pool Sanitizing Enzyme Hydrolyzing (Deoxy)Inosine Diphosphate to (Deoxy)Inosine Monophosphate.

Teruaki Iyama, Daisuke Tsuchimoto, Nona Abolhassani, Yusaku Nakabeppu

The 49th annual meeting of the American Society for Cell Biology 2009.12

　More details

Event date： 2009.12

Venue：San Diego Convention Center, San Diego, CA, USA Country：Japan
ヒトＮＵＤＴ１６は（デオキシ）イノシン二リン酸を（デオキシ）イノシン一リン酸に加水分解する新規ヌクレオチドプール浄化酵素である

土本大介、猪山輝昭、アボルハッサニ・ノナ、中別府雄作

第２０回DNA複製・組換え・修復ワークショップ 2009.11

　More details

Event date： 2009.11

Language：Japanese Presentation type：Symposium, workshop panel (public)

Venue：滋賀県彦根市琵琶湖コンファレンスセンター Country：Japan
神経芽腫予後関連タンパク質Prune2の全長フォームの同定

土本大介、岩間映二、野中麻里、作見邦彦、中別府雄作

第32回日本神経科学大会 2009.9

　More details

Event date： 2009.9

Language：Japanese

Venue：名古屋国際会議場 Country：Japan
新規損傷ヌクレオチド浄化酵素ITPBP2の同定と機能解析

土本大介、猪山輝昭、吉田奈桜子、中別府雄作

BMB2008 2008.12

　More details

Event date： 2008.12

Language：Japanese

Venue：神戸ポートアイランド Country：Japan
新規cAMP phosphodiesteraseの同定と癌転移に関与する可能性の検討

岩間映二、土本大介、中別府雄作

BMB2008 2008.12

　More details

Event date： 2008.12

Venue：神戸ポートアイランド Country：Japan
Neil3遺伝子改変マウスにおける末梢白血球減少

土本大介，鳥巣久美子，中別府雄作

第２８回日本分子生物学会年会 2005.12

　More details

Presentation type：Oral presentation (general)

Venue：福岡市 Country：Japan

Decrease of peripheral white blood cells in Neil3 KO mice
ITP結合タンパク質ITPBP1の生化学的特性

野中麻里、土本大介、太田詠子、作見邦彦、中別府雄作

日本分子生物学会２００６フォーラム 2006.12

　More details

Presentation type：Oral presentation (general)

Venue：名古屋 Country：Japan

Biochemical charateristics of ITP binding protein, ITPBP1
ATP固定化樹脂を用いた損傷ヌクレオチド結合タンパク質の探索

土本大介、野中麻里、太田詠子、作見邦彦、中別府雄作

日本分子生物学会２００６フォーラム 2006.12

　More details

Presentation type：Oral presentation (general)

Venue：名古屋 Country：Japan

Screening of damaged nucleotide binding proteins by using ATP immobilized resin
ITP結合タンパク質ITPBP1の生物学的特性の解析

野中麻里、土本大介、太田詠子、作見邦彦、中別府雄作

日本分子生物学会 2007.12

　More details

Venue：パシフィコ横浜 Country：Japan
NUDT16 is a (deoxy)inosine diphosphatase, and its deficiency induces accumulation of single-strand breaks in nuclear DNA and growth arrest. International conference

Teruaki Iyama, Nona Abolhassani, Daisuke Tsuchimoto, Mari Nonaka, Yusaku Nakabeppu

The 7th 3R Symposium 2010.10

　More details

Language：English

Venue：富山 Country：Japan
Role of 8-oxoguanine accumulated in nuclear or mitochindrial DNA in the development of Alzheimer's disease

岡素雅子, 盛子敬, Julio Leon, 土本大介, 作見邦彦, 中別府　雄作

日本分子生物学会 2016.12

　More details

Event date： 2016.11 - 2016.12

Language：Japanese

Venue：神奈川県横浜市パシフィコ横浜 Country：Japan
AP-1転写因子を構成するFosb遺伝子産物による補体受容体遺伝子C5ar1発現制御機構の解析

森岡紀子, 能丸寛子, Julio Leon, 加藤木敦央, 土本大介, 作見邦彦, 中別府雄作

日本分子生物学会／日本生化学会合同年会 2015.12

　More details

Event date： 2015.12

Language：Japanese

Venue：兵庫県神戸市ポートピアホテル Country：Japan
X線照射によるプリンヌクレオシド修飾の包括的解析

秋本頼子, ABOLHASSANI NONA, Erika Castillo, 土本大介, 中別府雄作

日本分子生物学会／日本生化学会合同年会 2015.12

　More details

Event date： 2015.12

Language：Japanese

Venue：兵庫県神戸市ポートピアホテル Country：Japan
ヒトミトコンドリア型AP endonuclease 候補のcDNAクローニング

土本大介、中別府雄作

１９９８年第２１回日本分子生物学会年会 1998.12

　More details

Language：Japanese Presentation type：Oral presentation (general)

Venue：横浜 Country：Japan
マウス新規AP endonuclease候補遺伝子APE2のクローニングと遺伝子欠損ES細胞株の樹立

井手康人，冨永洋平，土本大介，酒井康成，今磯泰幸，中別府雄作

２０００年第２３回日本分子生物学会年会 2000.12

　More details

Presentation type：Oral presentation (general)

Venue：神戸 Country：Japan
Human APE2 protein is mostly localized in the nuclei and to some extent in the mitochondria, while nuclear APE2 is partly associated with proliferating cell nuclear antigen.

Daisuke Tsuchimoto, Yusaku Nakabeppu

２００１年第２４回日本分子生物学会年会 2001.12

　More details

Presentation type：Oral presentation (general)

Venue：横浜 Country：Japan
大腸菌Endonuclease VIII (Nei) 類似タンパク質NEIL3をコードするヒトおよびマウス遺伝子のゲノム構造と発現解析

土本　大介、○鳥巣（中原）久美子、中別府　雄作

２００２年第２５回日本分子生物学会年会 2002.12

　More details

Presentation type：Oral presentation (general)

Venue：横浜 Country：Japan
MUTYH protects an intermediate of base excision repair by itself in DNA from a double-strand break caused by OGG1 and APEX1

Yohei Tominaga, ◯Daisuke Tsuchimoto, Seiki Hirano, Akimasa Ichinoe, Kunihiko Sakumi, Masaki Mishima, Masahiro Shirakawa, Yusaku Nakabeppu

２００２年第２５回日本分子生物学会年会 2002.12

　More details

Presentation type：Oral presentation (general)

Venue：横浜 Country：Japan
Repair mechanism of misincorporated adenine opposite 8-oxoG by mammalian MutY homolog, MUTYH: its relevance to mutagenesis and carcinogenesis Invited

Daisuke Tsuchimoto, Yasuhiro Ushijima, Yohei Tominaga, Seiki Hirano, Akimasa Ichinoe, Kunihiko Sakumi, and Yusaku Nakabeppu

２００３年第７６回日本生化学会大会 2003.10

　More details

Presentation type：Symposium, workshop panel (public)

Venue：横浜 Country：Japan
Establishment and characterization of APEX2 null mice International conference

Daisuke Tsuchimoto, Yasuhito Ide, Manabu Nakashima, Takeshi Watanabe and Yusaku Nakabeppu

３Ｒ SYMPOSIUM, 2003.10

　More details

Presentation type：Oral presentation (general)

Venue：Awaji Yumebutai, Hyogo Country：Japan
APEX2欠損マウスの樹立とその解析

土本大介，井手康人，中島学，渡邊武，中別府雄作

２００３年第２６回日本分子生物学会年会 2003.12

　More details

Presentation type：Oral presentation (general)

Venue：神戸 Country：Japan
APEX2欠損マウスにおける抗オブアルブミン抗体産生の遅延

土本大介，井手康人，中島学，渡邊武，中別府雄作

第２７回日本分子生物学会年会 2004.12

　More details

Venue：神戸 Country：Japan

Retardation of production of anti-ovalubmin antibody in APEX2-null mice
NUDT16 and ITPA play a dual protective role in maintaining chromosome stability and cell growth by eliminating dIDP/IDP and dITP/ITP from nucleotide pools in mammals. International conference

Nona Abolhassani, Teruaki Iyama, Daisuke Tsuchimoto, SAKUMI Kunihiko, Ohno Mizuki, Mehrdad Behmanesh, Yusaku Nakabeppu

The 7th 3R Symposium 2010.10

　More details

Language：English

Venue：Toyama Country：Japan

▼display all

MISC

酸化的DNA 損傷と防御機構

土本大介, 中別府雄作

別冊・医学のあゆみ「レドックスUPDATE」 2015.7

　More details

Language：Japanese Publishing type：Article, review, commentary, editorial, etc. (scientific journal)

生物にとって，ゲノムDNA に保持された遺伝情報を細胞から細胞へ，親から子へと正確に伝え維持する
ことはもっとも基本的な生物学的機能であるが，ゲノムDNA やその前駆体のヌクレオチドは，酸素呼吸や
免疫応答などの過程で生じる活性酸素によって酸化される危険につねにさらされている．ゲノムDNA に酸
化損傷が蓄積すると，突然変異や細胞死を引き起こすことで癌や変性疾患の原因となる．これに対抗する防
御機構として，生物は酸化損傷DNA 修復や酸化ヌクレオチド排除のためのシステムを備えている．
A comprehensive screening system for damaged nucleotide-binding proteins.

Tsuchimoto D, Iyama T, Nonaka M, Abolhassani N, Ohta E, Sakumi K, and Nakabeppu Y.

Mutation Research 2010.6

　More details

Language：English Publishing type：Article, review, commentary, editorial, etc. (scientific journal)
酸化的ＤＮＡ損傷と防御機構

土本大介，中別府雄作

別冊・医学のあゆみ　『レドックス-ストレス防御の医学』 2005.7

　More details

Language：Japanese Publishing type：Article, review, commentary, editorial, etc. (scientific journal)
ミトコンドリアＤＮＡの酸化損傷に対する防御機構の生物学的重要性

土本大介，中別府雄作

実験医学 2003.9

　More details

Language：Japanese Publishing type：Article, review, commentary, editorial, etc. (scientific journal)
Biological Significance of the Defense Mechanisms against Oxidative Damage in Nucleic Acids Caused by Reactive Oxygen Species: from Mitochondria to Nuclei,

Nakabeppu, Y., D. Tsuchimoto, A. Ichinoe, M. Ohno, Y. Ide, S. Hirano, D. Yoshimura, Y. Tominaga, M. Furuichi, and K. Sakumi,

Ann NY Acad Sci, (in press) 2003.1

　More details

Language：English Publishing type：Article, review, commentary, editorial, etc. (scientific journal)

Industrial property rights

Patent	Number of applications: 0	Number of registrations: 1
Utility model	Number of applications: 0	Number of registrations: 0
Design	Number of applications: 0	Number of registrations: 0
Trademark	Number of applications: 0	Number of registrations: 0

Professional Memberships

The molecular biology society of Japan
Japan Neuroscience Society

Academic Activities

Screening of academic papers

Role(s)： Peer review

2020

　More details

Type：Peer review

Number of peer-reviewed articles in foreign language journals：1
Screening of academic papers

Role(s)： Peer review

2019

　More details

Type：Peer review

Number of peer-reviewed articles in foreign language journals：1
Screening of academic papers

Role(s)： Peer review

2018

　More details

Type：Peer review

Number of peer-reviewed articles in foreign language journals：1

Number of peer-reviewed articles in Japanese journals：1

Research Projects

イノシン三リン酸分解酵素欠損の分子病態解明

Grant number：21K06869 2021.4 - 2024.3

日本学術振興会科学研究費助成事業基盤研究（C）

Daisuke Tsuchimoto

　 More details

Authorship：Principal investigator Grant type：Scientific research funding
イノシン三リン酸分解酵素欠損症の分子病態解明とそれを利用した治療法開発

Grant number：18K06960 2018 - 2020

Japan Society for the Promotion of Science Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)

　 More details

Authorship：Principal investigator Grant type：Scientific research funding
活性酸素による脳機能障害とその防御機構の解明

Grant number：17H01391 2017 - 2019

Japan Society for the Promotion of Science Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (A)

　 More details

Authorship：Coinvestigator(s) Grant type：Scientific research funding
ＡＴＰの酸化体によるシグナル伝達

Grant number：23117713 2011 - 2012

Japan Society for the Promotion of Science・Ministry of Education, Culture, Sports, Science and Technology Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research on Innovative Areas

　 More details

Authorship：Principal investigator Grant type：Scientific research funding
環境ストレスによるヌクレオチドプールの恒常性破綻の分子病態と制御機構の解明

Grant number：22221004 2010 - 2014

Japan Society for the Promotion of Science Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (S)

　 More details

Authorship：Coinvestigator(s) Grant type：Scientific research funding
ATPおよびGTPの酸化体による細胞内シグナル伝達機構の解明

Grant number：21117512 2009 - 2010

Japan Society for the Promotion of Science・Ministry of Education, Culture, Sports, Science and Technology Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research on Innovative Areas

　 More details

Authorship：Principal investigator Grant type：Scientific research funding
マウスを用いたＤＮＡおよび遊離ヌクレオチドの品質管理機構欠損の分子病態解析

Grant number：19390114 2007 - 2009

Japan Society for the Promotion of Science Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)

　 More details

Authorship：Principal investigator Grant type：Scientific research funding
遺伝子改変マウスをモデルとしたＤＮＡ塩基除去修復欠損の分子病態解明

Grant number：16390119 2004 - 2006

Japan Society for the Promotion of Science Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)

　 More details

Authorship：Principal investigator Grant type：Scientific research funding

▼display all

Educational Activities

研究室所属の学部学生や博士課程および修士課程の大学院生、研究生の研究指導を通年行っている。また，研究室配属入門，基礎配属あるいは体験実習プログラムにおいて医学部医学科ならびに生命科学科の学生の研究指導を行っている。
2017年度より基幹教育の総合科目講義（講義名「核酸と生命」）も担当している。

Class subject

核酸と生命

2024.6 - 2024.7
核酸と生命

2023.6 - 2023.8 Summer quarter
核酸と生命

2022.6 - 2022.8 Summer quarter
核酸と生命

2021.6 - 2021.8 Summer quarter
遺伝子生化学

2021.4 - 2022.3 Full year
医科学ゼミナール

2021.4 - 2022.3 Full year
博士論文応用演習

2021.4 - 2022.3 Full year
細胞病理学

2021.4 - 2022.3 Full year
核酸と生命

2020.6 - 2020.8 Summer quarter
専攻コア統合科目「基礎医学研究者養成コース入門(1)-(4)」

2020.4 - 2021.3 Full year
神経化学

2020.4 - 2021.3 Full year
行動生理

2020.4 - 2021.3 Full year
総合医学 II ／総合生命科学 II （研究室配属）.

2020.4 - 2020.9 First semester
核酸と生命

2019.6 - 2019.8 Summer quarter
専攻コア統合科目「基礎医学研究者養成コース入門(1)-(4)」

2019.4 - 2020.3 Full year
細胞病理学

2019.4 - 2020.3 Full year
遺伝子生化学

2019.4 - 2020.3 Full year
脳機能制御学研究法

2019.4 - 2020.3 Full year
分子神経科学

2019.4 - 2020.3 Full year
神経化学

2019.4 - 2020.3 Full year
行動生理

2019.4 - 2020.3 Full year
総合医学 II ／総合生命科学 II （研究室配属）.

2019.4 - 2019.9 First semester
核酸と生命

2018.6 - 2018.8 Summer quarter
遺伝子生化学

2018.4 - 2019.3 Full year
医科学ゼミナール

2018.4 - 2019.3 Full year
博士論文応用演習

2018.4 - 2019.3 Full year
細胞病理学

2018.4 - 2019.3 Full year
博士論文応用演習

2017.4 - 2018.3 Full year
遺伝子生化学

2017.4 - 2018.3 Full year
細胞病理学

2017.4 - 2018.3 Full year
医科学ゼミナール

2017.4 - 2018.3 Full year
医科学ゼミナール（修士）

2016.4 - 2017.3 Full year
博士論文演習

2016.4 - 2017.3 Full year
専攻コア選択科目「細胞病理学」

2016.4 - 2017.3 Full year
専攻コア選択科目「遺伝子生化学」

2016.4 - 2017.3 Full year
基礎医学実習「基礎医学研究者養成コース入門（１）〜（４）」

2016.4 - 2017.3 Full year
遺伝子生化学

2015.4 - 2016.3 Full year
細胞病理学

2015.4 - 2016.3 Full year
医科学ゼミナール

2015.4 - 2016.3 Full year
博士論文応用演習

2015.4 - 2016.3 Full year

▼display all

FD Participation

2022.9 Role：Participation Title：全学FD「M2Bシステムの使い方　～新機能を中心に紹介～」

Organizer：University-wide
2019.10 Role：Participation Title：令和元年度馬出地区４部局合同男女共同参画FD

Organizer：[Undergraduate school/graduate school/graduate faculty]
2019.9 Role：Participation Title：M2B学習支援システム講習会☆入門編☆(馬出地区)09:30～11:30

Organizer：University-wide
2019.9 Role：Participation Title：2019年度第４回全学FD M2B学習支援システム講習会

Organizer：University-wide
2019.2 Role：Participation Title：情報セキュリティ関連ＦＤ

Organizer：[Undergraduate school/graduate school/graduate faculty]
2018.10 Role：Panelist Title：平成３０年度馬出地区４部局合同男女共同参画FD

Organizer：[Undergraduate school/graduate school/graduate faculty]
2017.10 Role：Participation Title：平成２９年度部局男女共同参画FD(第一部：講演「無意識のバイアスからの開放：ダイバーシティのススメ」、第二部：公開討論会）

Organizer：[Undergraduate school/graduate school/graduate faculty]
2016.10 Role：Participation Title：馬出地区キャンパスFD 「なぜ今『女性活躍推進法』か？ —男女共同参画の必要性と九州大学における取組み—」

Organizer：[Undergraduate school/graduate school/graduate faculty]
2007.4 Role：Participation Title：平成19 年度第１回全学FD

Organizer：University-wide

▼display all

Media Coverage

医療面において、てんかん性脳症発症の仕組み解明の研究成果が紹介された。 Newspaper, magazine

西日本新聞 2020.12

　More details

医療面において、てんかん性脳症発症の仕組み解明の研究成果が紹介された。
早期乳児てんかん性脳症発症のメカニズム解明の研究成果が紹介された。 Newspaper, magazine

科学新聞 2020.11

　More details

早期乳児てんかん性脳症発症のメカニズム解明の研究成果が紹介された。