Details of the Researcher

PHOTO

Shinichiro Kanno
Section
Graduate School of Medicine
Job title
Specially Appointed Research Fellow
Degree
e-Rad No.
10400417

Professional Memberships 1

  • THE MOLECULAR BIOLOGY SOCIETY OF JAPAN

Research Interests 3

  • プロテオーム解析

  • タンパク質機能解析

  • DNA repair

Research Areas 1

  • Life sciences / Genomics / DNA repair

Papers 83

  1. A Novel Dysferlin-Binding Kinase CK2α Promotes Plasma Membrane Repair in Dysferlinopathy. International-journal

    Naoko Nakamura, Naoki Suzuki, Shin-Ichiro Kanno, Rei Yamanaka, Hiroya Ono, Rumiko Izumi, Rui Muliang, Christian Borgo, Akiyuki Ohno, Ryuhei Harada, Saki Saito, Yukino Funayama, Kensuke Ikeda, Shio Mitsuzawa, Yasuaki Watanabe, Tomomi Shijo, Tetsuya Akiyama, Toshiaki Takahashi, Makoto Kanzaki, Shion Osana, Hitoshi Warita, Yoshitsugu Aoki, Satoru Ebihara, Mauro Salvi, Ryoichi Nagatomi, Akira Yasui, Katsuya Miyake, Masashi Aoki

    FASEB journal : official publication of the Federation of American Societies for Experimental Biology　40　(6)　e71677　2026/03/31

    DOI： 10.1096/fj.202500773RRR 　

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    Dysferlinopathy is an adult-onset form of muscular dystrophy caused by mutations in the dysferlin gene and is inherited in an autosomal recessive manner. Dysferlin is primarily known for its role in plasma membrane repair. Although several proteins associated with dysferlin have been identified, many aspects of its signaling pathways and protein-protein interactions remain unclear. Here, we focused on the region between the third and fourth C2 domains, where frequent genetic mutations occur and functional domains are concentrated, and identified the protein kinase CK2α (formerly known as casein kinase 2) as a novel dysferlin-binding protein. CK2α was found to accumulate at membrane injury sites along with dysferlin in mouse skeletal muscle, and membrane repair was delayed in CK2α knockout cells. Furthermore, overexpression of CK2α in dysferlin-deficient mouse muscle led to improved membrane repair. Additionally, we revealed that CK2α plays a role in phosphorylating annexin A1, which is known to bind to dysferlin and is involved in plasma membrane repair. Our results indicated that CK2α controls membrane repair by participating in the phosphorylation of annexin A1. The molecular interplay among dysferlin, CK2α, and phosphorylated annexin A1 represents a novel therapeutic target for promoting membrane repair.

  2. The Role of Myoferlin in Vesicle Trafficking and the Effects of Its Overexpression in Prostate Cancer.

    Yuki Katsumata, Shuichi Shimada, Hiromichi Katayama, Tomonori Sato, Takuma Sato, Yoshihide Kawasaki, Naoki Kawamorita, Shinichi Yamashita, Mai Mochizuki, Keiichi Tamai, Shin-Ichiro Kanno, Akihiro Ito

    The Tohoku journal of experimental medicine　2026/02/12

    DOI： 10.1620/tjem.2025.J161 　

  3. BET family BRD3 initiates DSB-induced chromatin remodeling with TIP60 to promote R-loop-mediated HR. International-journal

    Jianghao Qian, Tomoko Watanabe, Reiko Watanabe, Shin-Ichiro Kanno, Akiko Takahashi, Shinji Kohsaka, Yuki Yoshino, Natsuko Chiba, Kozo Tanaka, Takashi Kohno, Akira Yasui, Ayako Ui

    Cell reports　44　(11)　116461-116461　2025/11/25

    DOI： 10.1016/j.celrep.2025.116461 　

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    Mechanisms for genome stability in actively transcribed regions are essential for cellular homeostasis; however, these mechanisms are poorly understood. Herein, we identify the bromodomain and extraterminal domain (BET) family BRD3 as the genome caretaker in actively transcribed chromatin. We identify the protein network between BRD3 and chromatin remodeler TIP60. During transcription, BRD3 localizes to actively transcribed chromatin through its N-terminal bromodomains. Following DNA double-strand breaks (DSBs) at the actively transcribed chromatin, the C-terminal extraterminal (ET) domain of BRD3 recruits CHD4 via its KIKL-like motifs to replace HP1 with the TIP60 (Tat-interactive protein, 60 kDa) complex, promoting H4K16 acetylation and MBTD1 recruitment, which creates chromatin barriers to 53BP1. This process recruits BRCA1 and R-loop-processing factors to promote R-loop-mediated homologous recombination (HR) and suppress 53BP1 and mutagenic non-homologous end-joining. Our study elucidates the mechanism by which BRD3 initiates DSB-induced chromatin remodeling by CHD4 and TIP60 to promote R-loop-mediated HR on actively transcribed chromatin to maintain genome stability.

  4. Responses of Regulator of G Protein Signaling Proteins and Circadian Clock Components to Sustained Depolarization-Induced Dedifferentiation in MIN6 β-Cells

    Satoshi Okano, Yu Sasaki, Akira Yasui, Shin-ichiro Kanno, Kennichi Satoh, Masahiko Igarashi, Osamu Nakajima

    Experimental and Clinical Endocrinology & Diabetes　2025/11/07

    Publisher: Georg Thieme Verlag KG

    DOI： 10.1055/a-2741-4294 　

    ISSN： 0947-7349

    eISSN： 1439-3646

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    Background:Regulators of G protein signaling (RGSs) are key modulators of β-cell function and stress adaptation. Similarly, circadian clock components are intricately implicated in the regulation of insulin secretion and β-cell physiology. However, their responses to sustained cellular stimulation under depolarizing conditions remain incompletely understood.Methods:We used MIN6 cells subjected to prolonged potassium chloride (KCl) exposure to induce sustained membrane depolarization, mimicking conditions of chronic β-cell stimulation. We analyzed the expression levels of Rgs and core clock genes, and assessed associated changes in cellular stress and differentiation markers.Results:KCl treatment led to the upregulation of endoplasmic reticulum (ER) stress markers, including Chop and Atf4, without inducing oxidative stress. Expression of Rgs2, Rgs4, and Rgs16 was elevated. RGS2 partially co-localized with eIF2α, suggesting a role in translational control during stress. Furthermore, KCl-induced depolarization was associated with characteristic changes in β-cell differentiation markers and disallowed genes, indicative of a dedifferentiation-like state. Transcript levels of several circadian genes were altered, including significant downregulation of Dbp and upregulation of its repressor E4bp4. Notably, Dec1, a clock gene known to be inducible by various external stimuli, was also upregulated, suggesting broader circadian disruption under depolarizing conditions.Conclusion:Sustained membrane depolarization induces ER stress and transcriptional remodeling in MIN6 β-cells, including the modulation of RGS proteins and key circadian regulators such as DBP, E4BP4, and DEC1. These alterations may contribute to functional impairment and a dedifferentiation-like state of β-cells under chronic stimulatory conditions.

  5. FAXC depletion contributes to tumor progression via the c-MET pathway in renal cell carcinoma. International-journal

    Masato Konno, Haruna Fujimori, Shin-Ichiro Kanno, Rie Shibuya-Takahashi, Mai Mochizuki, Kazunori Yamaguchi, Jun Yasuda, Shigekazu Murakami, Kennichi Satoh, Hisanobu Adachi, Akihiro Ito, Keiichi Tamai, Naoki Asano

    Biochemical and biophysical research communications　778　152388-152388　2025/07/18

    DOI： 10.1016/j.bbrc.2025.152388 　

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    Renal cell carcinoma (RCC), the most common types of kidney cancer, still requires novel therapeutic targets to improve patients' outcome. In this study, we focus on Failed Axon Connections Homolog (FAXC) gene, a newly identified and potentially important cancer target, and investigated its detailed role in RCC. In RCC cells, FAXC knockdown resulted in increased cell proliferation, and elevated c-MET expression and phosphorylation. Blockade of c-MET phosphorylation inhibited cell proliferation promoted by FAXC knockdown. In contrast, FAXC overexpression reduced cell proliferation and downregulated c-MET expression in RCC cells. We also found that FAXC is localized to the mitochondria in RCC cells. Additionally, an investigation of RCC patient specimens revealed that FAXC expression was negatively correlated with c-MET phosphorylation and was downregulated in tumor region compared with adjacent normal tissues. Taken together, our findings indicate that FAXC depletion promotes cell proliferation through the activation of c-MET in RCC cells.

  6. Cover Image

    Yoshiyasu Tongu, Tomoko Kasahara, Tetsuro Matsuhashi, Yoshitsugu Oikawa, Ryota Akimoto, Yuhan Luo, Sayaka Sekine, Momoka Suzuki, Hitomi Kashiwagi, Shinichiro Kanno, Yoshikazu Tanaka, Kyohei Sato, Yusuke Okubo, Akihiko Muto, Hidetaka Tokuno, Chitose Suzuki, Chiharu Kawabe, Takamasa Ishikawa, Shun Watanabe, Koichi Kikuchi, Shun Itai, Takeya Sato, Takehiro Suzuki, Kazuhiro Igarashi, Shinji Fukuda, Tomoyoshi Soga, Kei Murayama, Erina Kuranaga, Takafumi Toyohara, Takaaki Abe

    The FASEB Journal　39　(12)　2025/06/30

    Publisher: Wiley

    DOI： 10.1096/fsb2.70816 　

    ISSN： 0892-6638

    eISSN： 1530-6860

  7. Mitochondria-Homing Drug Mitochonic Acid 5 Improves Barth Syndrome Myopathy in a Human-Induced Pluripotent Stem Cell Model and Barth Syndrome Drosophila Model. International-journal

    Yoshiyasu Tongu, Tomoko Kasahara, Tetsuro Matsuhashi, Yoshitsugu Oikawa, Ryota Akimoto, Yuhan Luo, Sayaka Sekine, Momoka Suzuki, Hitomi Kashiwagi, Shinichiro Kanno, Yoshikazu Tanaka, Kyohei Sato, Yusuke Okubo, Akihiko Muto, Hidetaka Tokuno, Chitose Suzuki, Chiharu Kawabe, Takamasa Ishikawa, Shun Watanabe, Koichi Kikuchi, Shun Itai, Takeya Sato, Takehiro Suzuki, Kazuhiro Igarashi, Shinji Fukuda, Tomoyoshi Soga, Kei Murayama, Erina Kuranaga, Takafumi Toyohara, Takaaki Abe

    FASEB journal : official publication of the Federation of American Societies for Experimental Biology　39　(12)　e70739　2025/06/30

    DOI： 10.1096/fj.202401856RRR 　

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    Barth syndrome (BTHS) is a rare disease caused by mutations in the tafazzin gene that affects the heart and muscles; however, to date, no clinically effective drugs are available. In BTHS, mitochondrial function is reduced owing to changes in cardiolipin metabolism. We developed mitochonic acid 5 (MA-5), a small-molecule compound that increases ATP levels, improves mitochondrial dynamics, and is effective in treating mitochondrial and muscle diseases. Therefore, this study examined the effectiveness of MA-5 in treating BTHS. The mitochondrial functions of four isolated BTHS skin fibroblasts were examined. Human BTHS induced pluripotent stem cell (iPSC) were differentiated into myoblasts and cardiolipin metabolism and mitochondrial functions were analyzed. RNA-seq was performed to clarify the metabolic changes. Using a Drosophila melanogaster model of BTHS, the effects of MA-5 on motor performance and cardiac phenotype were examined. MA-5 improved mitochondrial function and reduced cell death due to oxidative stress in skin fibroblasts of patients with BTHS. MA-5 promoted ATP production and reduced oxidative stress in human BTHS iPS cell-derived myoblasts. RNA-seq analysis revealed that MA-5 alleviated endoplasmic reticulum stress in BTHS cells. Administration of MA-5 to BTHS Drosophila improved locomotor ability and tachycardia observed in patients with BTHS. Protein interaction analyses suggested colocalization of ATPase and the MA-5-binding protein mitofilin. These data suggested that MA-5 improves BTHS dysfunction and may serve as a novel therapeutic agent for BTHS.

  8. Non-DNA-damaging DNA-PK activation improving hearing and prolonging life due to NAD+and SIRT upregulation

    Yohei Honkura, Takehiro Suzuki, Ryota Kujirai, Shinichiro Kanno, Yotaro Matsumoto, Yoshikazu Tanaka, Hengphasatporn Kowit, Satoru Nagatoishi, Alexander Tyshkovskiy, Tomoko Kasahara, Yoshiyasu Tongu, Zhang Bohan, Hitomi Kashiwagi, Chika Saegusa, Msato Fujioka, Reina Usami, Shunsuke Chikuma, Yukiko Tokifuji, Tetsuro Matsuhashi, Yoshitsugu Oikawa, Hiroka Komatsu, Kei Murayama, Takehito Sugasawa, Fumika Nanto-Hara, Kensei Taguchi, Daisuke Saigusa, Chitose Suzuki, Takeya Sato, Jun Suzuki, Yuji Owada, Kuniyasu Niizuma, Hidenori Endo, Ko Hashimoto, Takafumi Toyohara, Kohei Tsumoto, Paul Anderson, Vadim N. Gladyshev, Ken-ichiro Hayashi, Yukio Katori, Yoshihisa Tomioka, Takaaki Abe

    2025/04/23

    Publisher: Cold Spring Harbor Laboratory

    DOI： 10.1101/2025.04.18.649305 　

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    SUMMARY Emerging evidence strongly supports a close relationship between age-related hearing loss and frailty, highlighting the importance of early detection and intervention. Recently, we invented a mitochondria-homing drug named mitochonic acid 5 (MA-5), that increases the adenosine triphosphate (ATP) levels, rescue mitochondrial function, and protect tissue damages. Currently, the phase I clinical trial has been finished in Japan (jRCT2031210495) and the phase 2 clinical trial has already been approved by PMDA. Here we show that MA-5 improved various types of hearing loss in mouse models. Structural chemical bioanalysis revealed that MA-5 is a mixture of equal amount of S- and R- enantiomer and both S- and R- enantiomer increase ATP by binding mitochondrial protein, mitofilin. However, S-enantiomer significantly increased the NAD+levels by binding to the NAD+-producing key enzyme nicotinamide phosphoribosyltransferase (NAMPT). Moreover, the S-enantiomer increased the sirtuin 1 protein by suppressing polyubiquitination induced by tripartite motif containing 28 (TRIM28) phosphorylation which was triggered by DNA-dependent protein kinase (DNA-PK) activation in the absence of DNA damage. Transcriptomic signatures showed that the signature of MA-5 shows an inverse correlation with aging and mortality and is oriented in the same direction as the OSKM-related iPSCs, suggesting the modification of aging pathways. Oral administration of MA-5 to mitochondrial disease model mouse showed increased survival. Our findings suggest that, in addition to enhancing ATP levels, the coordinated regulation of NAD+metabolism, SIRT protein expression, and DNA-PK activity-constituting a novel therapeutic triad may contribute to the amelioration of hearing impairment and mitochondrial dysfunction, thereby improving life prognosis.

  9. Armadillo domain of ARID1A directly interacts with DNA-PKcs to couple chromatin remodeling with nonhomologous end joining (NHEJ) pathway. International-journal

    Shin-Ichiro Kanno, Takayasu Kobayashi, Reiko Watanabe, Akihiro Kurimasa, Kozo Tanaka, Akira Yasui, Ayako Ui

    Nucleic acids research　53　(5)　2025/02/27

    DOI： 10.1093/nar/gkaf150 　

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    The SWI/SNF chromatin-remodeling complex that comprises multiple subunits orchestrates diverse cellular processes, including gene expression, DNA repair, and DNA replication, by sliding and releasing nucleosomes. AT-interacting domain-rich protein 1A (ARID1A) and ARID1B (ARID1A/B), a pivotal subunit, have significant relevance in cancer management because they are frequently mutated in a broad range of cancer types. To delineate the protein network involving ARID1A/B, we investigated the interactions of this with other proteins under physiological conditions. The ARID domain of ARID1A/B interacts with proteins involved in transcription and DNA/RNA metabolism. Several proteins are responsible for genome integrity maintenance, including DNA-dependent protein kinase catalytic subunit (DNA-PKcs), bound to the armadillo (ARM) domain of ARID1A/B. Introducing a knock-in mutation at the binding amino acid of DNA-PKcs in HCT116 cells reduced the autophosphorylation of DNA-PKcs and the recruitment of LIG4 in response to ionizing radiation. Our findings suggest that within the SWI/SNF complex, ARID1A couples DNA double-strand break repair processes with chromatin remodeling via the ARM domains to directly engage with DNA-PKcs to maintain genome stability.

  10. Zn結合不全型CRY1発現マウスの特異な膵管病変におけるTFF2の発現と膵α細胞の新生

    岡野 聡, 安井 明, 菅野 新一郎, 佐々木 悠, 佐藤 賢一, 五十嵐 雅彦, 中島 修

    膵臓　39　(3)　A519-A519　2024/07

    Publisher: (一社)日本膵臓学会

    ISSN： 0913-0071

    eISSN： 1881-2805

  11. CD271 mRNA/hnRNPA2B1 complex promotes proliferation and stemness in oral and head and neck squamous cell carcinoma. International-journal

    Mai Mochizuki, Rie Shibuya-Takahashi, Shin-Ichiro Kanno, Shungo Adachi, Haruna Fujimori, Akira Nakazato, Keitaro Fujii, Shinkichi Morita, Satoshi Saijoh, Tomoko Yamazaki, Takayuki Imai, Yukinori Asada, Kazunori Yamaguchi, Jun Yasuda, Norihisa Shindo, Kazuo Sugamura, Keiichi Tamai

    Cancer science　2024/05/06

    DOI： 10.1111/cas.16187 　

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    RNAs, such as noncoding RNA, microRNA, and recently mRNA, have been recognized as signal transduction molecules. CD271, also known as nerve growth factor receptor, has a critical role in cancer, although the precise mechanism is still unclear. Here, we show that CD271 mRNA, but not CD271 protein, facilitates spheroid cell proliferation. We established CD271-/- cells lacking both mRNA and protein of CD271, as well as CD271 protein knockout cells lacking only CD271 protein, from hypopharyngeal and oral squamous cell carcinoma lines. Sphere formation was reduced in CD271-/- cells but not in CD271 protein knockout cells. Mutated CD271 mRNA, which is not translated to a protein, promoted sphere formation. CD271 mRNA bound to hnRNPA2B1 protein at the 3'-UTR region, and the inhibition of this interaction reduced sphere formation. In surgical specimens, the CD271 mRNA/protein expression ratio was higher in the cancerous area than in the noncancerous area. These data suggest CD271 mRNA has dual functions, encompassing protein-coding and noncoding roles, with its noncoding RNA function being predominant in oral and head and neck squamous cell carcinoma.

  12. FAXC interacts with ANXA2 and SRC in mitochondria and promotes tumorigenesis in cholangiocarcinoma. International-journal

    Haruna Fujimori, Mao Shima-Nakamura, Shin-Ichiro Kanno, Rie Shibuya-Takahashi, Mai Mochizuki, Masamichi Mizuma, Michiaki Unno, Yuta Wakui, Makoto Abue, Wataru Iwai, Daisuke Fukushi, Kennich Satoh, Kazunori Yamaguchi, Norihisa Shindo, Jun Yasuda, Keiichi Tamai

    Cancer science　2024/03/13

    DOI： 10.1111/cas.16140 　

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    Cholangiocarcinoma (CCA) is one of the most difficult malignancies to treat as the therapeutic options are limited. Although several driver genes have been identified, most remain unknown. In this study, we identified a failed axon connection homolog (FAXC), whose function is unknown in mammals, by analyzing serially passaged CCA xenograft models. Knockdown of FAXC reduced subcutaneous tumorigenicity in mice. FAXC was bound to annexin A2 (ANXA2) and c-SRC, which are tumor-promoting genes. The FAXC/ANXA2/c-SRC complex forms in the mitochondria. FAXC enhances SRC-dependent ANXA2 phosphorylation at tyrosine-24, and the C-terminal amino acid residues (351-375) of FAXC are required for ANXA2 phosphorylation. Transcriptome data from a xenografted CCA cell line revealed that FAXC correlated with epithelial-mesenchymal transition, hypoxia, and KRAS signaling genes. Collectively, these findings advance our understanding of CCA tumorigenesis and provide candidate therapeutic targets.

  13. LZTR1欠損はEMT誘導とKLHL12依存的なコラーゲン分泌を制御することで腫瘍増殖と腫瘍転移を促進する

    阿部 太紀, 菅野 新一郎, 新堀 哲也, 寺尾 美穂, 高田 修治, 青木 洋子

    日本生化学会大会プログラム・講演要旨集　96回　[1P-666]　2023/10

    Publisher: (公社)日本生化学会

  14. LZTR1欠損はEMT誘導とKLHL12依存的なコラーゲン分泌を制御することで腫瘍増殖と腫瘍転移を促進する

    阿部 太紀, 菅野 新一郎, 新堀 哲也, 寺尾 美穂, 高田 修治, 青木 洋子

    日本生化学会大会プログラム・講演要旨集　96回　[1P-666]　2023/10

    Publisher: (公社)日本生化学会

  15. LZTR1 deficiency exerts high metastatic potential by enhancing sensitivity to EMT induction and controlling KLHL12-mediated collagen secretion. International-journal

    Taiki Abe, Shin-Ichiro Kanno, Tetsuya Niihori, Miho Terao, Shuji Takada, Yoko Aoki

    Cell death & disease　14　(8)　556-556　2023/08/25

    DOI： 10.1038/s41419-023-06072-9 　

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    Leucine zipper-like transcriptional regulator 1 (LZTR1), a substrate adaptor of Cullin 3 (CUL3)-based E3 ubiquitin ligase, regulates proteostasis of the RAS subfamily. Mutations in LZTR1 have been identified in patients with several types of cancer. However, the role of LZTR1 in tumor metastasis and the target molecules of LZTR1, excluding the RAS subfamily, are not clearly understood. Here, we show that LZTR1 deficiency increases tumor growth and metastasis. In lung adenocarcinoma cells, LZTR1 deficiency induced the accumulation of the RAS subfamily and enhanced cell proliferation, invasion, and xenograft tumor growth. Multi-omics analysis to clarify the pathways related to tumor progression showed that MAPK signaling, epithelial-mesenchymal transition (EMT), and extracellular matrix (ECM) remodeling-related gene ontology terms were enriched in LZTR1 knockout cells. Indeed, LZTR1 deficiency induced high expression of EMT markers under TGF-β1 treatment. Our search for novel substrates that interact with LZTR1 resulted in the discovery of a Kelch-like protein 12 (KLHL12), which is involved in collagen secretion. LZTR1 could inhibit KLHL12-mediated ubiquitination of SEC31A, a component of coat protein complex II (COPII), whereas LZTR1 deficiency promoted collagen secretion. LZTR1-RIT1 and LZTR1-KLHL12 worked independently regarding molecular interactions and did not directly interfere with each other. Further, we found that LZTR1 deficiency significantly increases lung metastasis and promotes ECM deposition around metastatic tumors. Since collagen-rich extracellular matrix act as pathways for migration and facilitate metastasis, increased expression of RAS and collagen deposition may exert synergistic or additive effects leading to tumor progression and metastasis. In conclusion, LZTR1 deficiency exerts high metastatic potential by enhancing sensitivity to EMT induction and promoting collagen secretion. The functional inhibition of KLHL12 by LZTR1 provides important evidence that LZTR1 may be a repressor of BTB-Kelch family members. These results provide clues to the mechanism of LZTR1-deficiency carcinogenesis.

  16. 亜鉛結合不全型の時計蛋白質CRY1発現マウスの膵島内膵管における膵α細胞の新生

    岡野 聡, 安井 明, 菅野 新一郎, 佐々木 悠, 佐藤 賢一, 五十嵐 雅彦, 中島 修

    膵臓　38　(3)　A475-A475　2023/07

    Publisher: (一社)日本膵臓学会

    ISSN： 0913-0071

    eISSN： 1881-2805

  17. Novel Calcium-Binding Ablating Mutations Induce Constitutive RET Activity and Drive Tumorigenesis. International-journal

    Junya Tabata, Takashi Nakaoku, Mitsugu Araki, Ryunosuke Yoshino, Shinji Kohsaka, Ayaka Otsuka, Masachika Ikegami, Ayako Ui, Shin-Ichiro Kanno, Keiko Miyoshi, Shigeyuki Matsumoto, Yukari Sagae, Akira Yasui, Masakazu Sekijima, Hiroyuki Mano, Yasushi Okuno, Aikou Okamoto, Takashi Kohno

    Cancer research　82　(20)　3751-3762　2022/10/17

    DOI： 10.1158/0008-5472.CAN-22-0834 　

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    Distinguishing oncogenic mutations from variants of unknown significance (VUS) is critical for precision cancer medicine. Here, computational modeling of 71,756 RET variants for positive selection together with functional assays of 110 representative variants identified a three-dimensional cluster of VUSs carried by multiple human cancers that cause amino acid substitutions in the calmodulin-like motif (CaLM) of RET. Molecular dynamics simulations indicated that CaLM mutations decrease interactions between Ca2+ and its surrounding residues and induce conformational distortion of the RET cysteine-rich domain containing the CaLM. RET-CaLM mutations caused ligand-independent constitutive activation of RET kinase by homodimerization mediated by illegitimate disulfide bond formation. RET-CaLM mutants possessed oncogenic and tumorigenic activities that could be suppressed by tyrosine kinase inhibitors targeting RET. This study identifies calcium-binding ablating mutations as a novel type of oncogenic mutation of RET and indicates that in silico-driven annotation of VUSs of druggable oncogenes is a promising strategy to identify targetable driver mutations. SIGNIFICANCE: Comprehensive proteogenomic and in silico analyses of a vast number of VUSs identify a novel set of oncogenic and druggable mutations in the well-characterized RET oncogene.

  18. CHAMP1-POGZ counteracts the inhibitory effect of 53BP1 on homologous recombination and affects PARP inhibitor resistance. International-journal

    Hiroki Fujita, Masanori Ikeda, Ayako Ui, Yunosuke Ouchi, Yoshiko Mikami, Shin-Ichiro Kanno, Akira Yasui, Kozo Tanaka

    Oncogene　41　(19)　2706-2718　2022/05

    DOI： 10.1038/s41388-022-02299-6 　

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    DNA double-strand break (DSB) repair-pathway choice regulated by 53BP1 and BRCA1 contributes to genome stability. 53BP1 cooperates with the REV7-Shieldin complex and inhibits DNA end resection to block homologous recombination (HR) and affects the sensitivity to inhibitors for poly (ADP-ribose) polymerases (PARPs) in BRCA1-deficient cells. Here, we show that a REV7 binding protein, CHAMP1 (chromosome alignment-maintaining phosphoprotein 1), has an opposite function of REV7 in DSB repair and promotes HR through DNA end resection together with POGZ (POGO transposable element with ZNF domain). CHAMP1 was recruited to laser-micro-irradiation-induced DSB sites and promotes HR, but not NHEJ. CHAMP1 depletion suppressed the recruitment of BRCA1, but not the recruitment of 53BP1, suggesting that CHAMP1 regulates DSB repair pathway in favor of HR. Depletion of either CHAMP1 or POGZ impaired the recruitment of phosphorylated RPA2 and CtIP (CtBP-interacting protein) at DSB sites, implying that CHAMP1, in complex with POGZ, promotes DNA end resection for HR. Furthermore, loss of CHAMP1 and POGZ restored the sensitivity to a PARP inhibitor in cells depleted of 53BP1 together with BRCA1. These data suggest that CHAMP1and POGZ counteract the inhibitory effect of 53BP1 on HR by promoting DNA end resection and affect the resistance to PARP inhibitors.

  19. USP39 is essential for mammalian epithelial morphogenesis through upregulation of planar cell polarity components. International-journal

    Chiharu Kimura-Yoshida, Kyoko Mochida, Shin-Ichiro Kanno, Isao Matsuo

    Communications biology　5　(1)　378-378　2022/04/19

    DOI： 10.1038/s42003-022-03254-7 　

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    Previously, we have shown that the translocation of Grainyhead-like 3 (GRHL3) transcription factor from the nucleus to the cytoplasm triggers the switch from canonical Wnt signaling for epidermal differentiation to non-canonical Wnt signaling for epithelial morphogenesis. However, the molecular mechanism that underlies the cytoplasmic localization of GRHL3 protein and that activates non-canonical Wnt signaling is not known. Here, we show that ubiquitin-specific protease 39 (USP39), a deubiquitinating enzyme, is involved in the subcellular localization of GRHL3 as a potential GRHL3-interacting protein and is necessary for epithelial morphogenesis to up-regulate expression of planar cell polarity (PCP) components. Notably, mouse Usp39-deficient embryos display early embryonic lethality due to a failure in primitive streak formation and apico-basal polarity in epiblast cells, resembling those of mutant embryos of the Prickle1 gene, a crucial PCP component. Current findings provide unique insights into how differentiation and morphogenesis are coordinated to construct three-dimensional complex structures via USP39.

  20. Responses of Regulator of G Protein Signaling Proteins and Circadian Clock Proteins to Induction of Dedifferentiation in Pancreatic β-cells

    Satoshi Okano, Akira Yasui, Shin-ichiro Kanno, Kennichi Satoh, Masahiko Igarashi, Osamu Nakajima

    2022/03/03

    Publisher: Research Square Platform LLC

    DOI： 10.21203/rs.3.rs-1395694/v1 　

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    Abstract Regulator of G protein signaling proteins (RGSs) are involved in regulating β-cell functions. This study was conducted to examine the cellular responses to the occurrence of β-cell dedifferentiation in terms of the changes of expression levels of Rgs and clock genes: We used MIN6 cells, for which the cellular contents of zinc were reduced by prolonged treatment of the cells by potassium chloride, in this way inducing the cells to a progenitor-like state. The results indicate that endoplasmic reticulum (ER)-stress markers were up-regulated in the treated cells. All examined RGS were up-regulated in treated cells compared with control cells. RGS2 partly co-localized eIF2 α in the treated cells, although no discernable co-localization was observed for RGS4 and 16, suggesting that RGS2 specifically participates in the translational control of protein in response to cellular stresses. Altered mRNA levels of a uniquely specific set of clock genes were observed, suggesting malfunction of the molecular clock in β-cells. Taken together, G protein signaling and translation process are probably fine-tuned by RGSs. Thereby β-cells can cope with stress attributable to the decrease of zinc. The attenuation of circadian rhythm, in addition to some G protein signaling, can be prerequisites for induction of β-cell dedifferentiation.

  21. Loss of Axdnd1 causes sterility due to impaired spermatid differentiation in mice.

    Yuki Hiradate, Ryua Harima, Rin Yanai, Kenshiro Hara, Kazue Nagasawa, Makoto Osada, Tomoe Kobayashi, Makoto Matsuyama, Shin-Ichiro Kanno, Akira Yasui, Kentaro Tanemura

    Reproductive medicine and biology　21　(1)　e12452　2022

    DOI： 10.1002/rmb2.12452 　

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    PURPOSE: Spermiogenesis, the process of deformation of sperm head morphology and flagella formation, is a phenomenon unique to sperm. Axonemal dynein light chain proteins are localized to sperm flagella and are known to be involved in sperm motility. Here, we focused on the gene axonemal dynein light chain domain containing 1 (Axdnd1) with the aim to determine the function of its protein product AXDND1. METHODS: To elucidate the role of AXDND1 in spermatogenesis, we generated Axdnd1 knockout (KO) mice using the CRISPR/Cas9 system. The generated mice were subjected to fertility tests and analyzed by immunohistochemistry. RESULT: The Axdnd1 KO mouse exhibited sterility caused by impaired spermiogenesis during the elongation step as well as abnormal nuclear shaping and manchette, which are essential for spermiogenesis. Moreover, AXDND1 showed enriched testicular expression and was localized from the mid-pachytene spermatocytes to the early spermatids. CONCLUSION: Axdnd1 is essential for spermatogenesis in the mouse testes. These findings improve our understanding of spermiogenesis and related defects. According to a recent report, deleterious heterozygous mutations in AXDND1 were found in non-obstructive azoospermia (NOA) patients. Therefore, Axdnd1 KO mice could be used as a model system for NOA, which will greatly contribute to future NOA treatment studies.

  22. Identification of Binding Proteins for TSC22D1 Family Proteins Using Mass Spectrometry. International-journal

    Ryouta Kamimura, Daisuke Uchida, Shin-Ichiro Kanno, Ryo Shiraishi, Toshiki Hyodo, Yuta Sawatani, Michiko Shimura, Tomonori Hasegawa, Maki Tsubura-Okubo, Erika Yaguchi, Yuske Komiyama, Chonji Fukumoto, Sayaka Izumi, Atsushi Fujita, Takahiro Wakui, Hitoshi Kawamata

    International journal of molecular sciences　22　(20)　2021/10/09

    DOI： 10.3390/ijms222010913 　

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    TSC-22 (TGF-β stimulated clone-22) has been reported to induce differentiation, growth inhibition, and apoptosis in various cells. TSC-22 is a member of a family in which many proteins are produced from four different family genes. TSC-22 (corresponding to TSC22D1-2) is composed of 144 amino acids translated from a short variant mRNA of the TSC22D1 gene. In this study, we attempted to determine the intracellular localizations of the TSC22D1 family proteins (TSC22D1-1, TSC-22 (TSC22D1-2), and TSC22(86) (TSC22D1-3)) and identify the binding proteins for TSC22D1 family proteins by mass spectrometry. We determined that TSC22D1-1 was mostly localized in the nucleus, TSC-22 (TSC22D1-2) was localized in the cytoplasm, mainly in the mitochondria and translocated from the cytoplasm to the nucleus after DNA damage, and TSC22(86) (TSC22D1-3) was localized in both the cytoplasm and nucleus. We identified multiple candidates of binding proteins for TSC22D1 family proteins in in vitro pull-down assays and in vivo binding assays. Histone H1 bound to TSC-22 (TSC22D1-2) or TSC22(86) (TSC22D1-3) in the nucleus. Guanine nucleotide-binding protein-like 3 (GNL3), which is also known as nucleostemin, bound to TSC-22 (TSC22D1-2) in the nucleus. Further investigation of the interaction of the candidate binding proteins with TSC22D1 family proteins would clarify the biological roles of TSC22D1 family proteins in several cell systems.

  23. BEX2 suppresses mitochondrial activity and is required for dormant cancer stem cell maintenance in intrahepatic cholangiocarcinoma. International-journal

    Keiichi Tamai, Mao Nakamura-Shima, Rie Shibuya-Takahashi, Shin-Ichiro Kanno, Akira Yasui, Mai Mochizuki, Wataru Iwai, Yuta Wakui, Makoto Abue, Kuniharu Yamamoto, Koh Miura, Masamichi Mizuma, Michiaki Unno, Sadafumi Kawamura, Ikuro Sato, Jun Yasuda, Kazunori Yamaguchi, Kazuo Sugamura, Kennichi Satoh

    Scientific reports　10　(1)　21592-21592　2020/12/09

    DOI： 10.1038/s41598-020-78539-0 　

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    Cancer stem cells (CSCs) define a subpopulation of cancer cells that are resistant to therapy. However, little is known of how CSC characteristics are regulated. We previously showed that dormant cancer stem cells are enriched with a CD274low fraction of cholangiocarcinoma cells. Here we found that BEX2 was highly expressed in CD274low cells, and that BEX2 knockdown decreased the tumorigenicity and G0 phase of cholangiocarcinoma cells. BEX2 was found to be expressed predominantly in G0 phase and starvation induced the USF2 transcriptional factor, which induced BEX2 transcription. Comprehensive screening of BEX2 binding proteins identified E3 ubiquitin ligase complex proteins, FEM1B and CUL2, and a mitochondrial protein TUFM, and further demonstrated that knockdown of BEX2 or TUFM increased mitochondria-related oxygen consumption and decreased tumorigenicity in cholangiocarcinoma cells. These results suggest that BEX2 is essential for maintaining dormant cancer stem cells through the suppression of mitochondrial activity in cholangiocarcinoma.

  24. FABP7 Regulates Acetyl-CoA Metabolism Through the Interaction with ACLY in the Nucleus of Astrocytes. International-journal

    Yoshiteru Kagawa, Banlanjo Abdulaziz Umaru, Hiroki Shima, Ryo Ito, Ryo Zama, Ariful Islam, Shin-Ichiro Kanno, Akira Yasui, Shun Sato, Kosuke Jozaki, Subrata Kumar Shil, Hirofumi Miyazaki, Shuhei Kobayashi, Yui Yamamoto, Hiroshi Kogo, Chie Shimamoto-Mitsuyama, Akira Sugawara, Norihiro Sugino, Masayuki Kanamori, Teiji Tominaga, Takeo Yoshikawa, Kohji Fukunaga, Kazuhiko Igarashi, Yuji Owada

    Molecular neurobiology　57　(12)　4891-4910　2020/12

    DOI： 10.1007/s12035-020-02057-3 　

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    Fatty acid binding protein 7 (FABP7) is an intracellular fatty acid chaperon that is highly expressed in astrocytes, oligodendrocyte-precursor cells, and malignant glioma. Previously, we reported that FABP7 regulates the response to extracellular stimuli by controlling the expression of caveolin-1, an important component of lipid raft. Here, we explored the detailed mechanisms underlying FABP7 regulation of caveolin-1 expression using primary cultured FABP7-KO astrocytes as a model of loss of function and NIH-3T3 cells as a model of gain of function. We discovered that FABP7 interacts with ATP-citrate lyase (ACLY) and is important for acetyl-CoA metabolism in the nucleus. This interaction leads to epigenetic regulation of several genes, including caveolin-1. Our novel findings suggest that FABP7-ACLY modulation of nuclear acetyl-CoA has more influence on histone acetylation than cytoplasmic acetyl-CoA. The changes to histone structure may modify caveolae-related cell activity in astrocytes and tumors, including malignant glioma.

  25. 骨格筋疾患の動物モデルの実験的治療 Dysferlinopathyに対する治療法の開発

    小野 洋也, 鈴木 直輝, 菅野 新一郎, 川原 玄理, 割田 仁, 林 由起子, 三宅 克也, 青木 正志

    神経治療学　37　(6)　S101-S101　2020/10

    Publisher: (一社)日本神経治療学会

    ISSN： 0916-8443

    eISSN： 2189-7824

  26. 骨格筋疾患の動物モデルの実験的治療 Dysferlinopathyに対する治療法の開発

    小野 洋也, 鈴木 直輝, 菅野 新一郎, 川原 玄理, 割田 仁, 林 由起子, 三宅 克也, 青木 正志

    神経治療学　37　(6)　S101-S101　2020/10

    Publisher: (一社)日本神経治療学会

    ISSN： 0916-8443

    eISSN： 2189-7824

  27. がん原遺伝子産物RASの恒常性維持機構の解明

    阿部 太紀, 梅木 郁美, 菅野 新一郎, 井上 晋一, 新堀 哲也, 青木 洋子

    日本生化学会大会プログラム・講演要旨集　93回　[P-190]　2020/09

    Publisher: (公社)日本生化学会

  28. AMPK Complex Activation Promotes Sarcolemmal Repair in Dysferlinopathy. International-journal Peer-reviewed

    Hiroya Ono, Naoki Suzuki, Shin-Ichiro Kanno, Genri Kawahara, Rumiko Izumi, Toshiaki Takahashi, Yasuo Kitajima, Shion Osana, Naoko Nakamura, Tetsuya Akiyama, Kensuke Ikeda, Tomomi Shijo, Shio Mitsuzawa, Ryoichi Nagatomi, Nobukazu Araki, Akira Yasui, Hitoshi Warita, Yukiko K Hayashi, Katsuya Miyake, Masashi Aoki

    Molecular therapy : the journal of the American Society of Gene Therapy　28　(4)　1133-1153　2020/04/08

    DOI： 10.1016/j.ymthe.2020.02.006 　

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    Mutations in dysferlin are responsible for a group of progressive, recessively inherited muscular dystrophies known as dysferlinopathies. Using recombinant proteins and affinity purification methods combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS), we found that AMP-activated protein kinase (AMPK)γ1 was bound to a region of dysferlin located between the third and fourth C2 domains. Using ex vivo laser injury experiments, we demonstrated that the AMPK complex was vital for the sarcolemmal damage repair of skeletal muscle fibers. Injury-induced AMPK complex accumulation was dependent on the presence of Ca2+, and the rate of accumulation was regulated by dysferlin. Furthermore, it was found that the phosphorylation of AMPKα was essential for plasma membrane repair, and treatment with an AMPK activator rescued the membrane-repair impairment observed in immortalized human myotubes with reduced expression of dysferlin and dysferlin-null mouse fibers. Finally, it was determined that treatment with the AMPK activator metformin improved the muscle phenotype in zebrafish and mouse models of dysferlin deficiency. These findings indicate that the AMPK complex is essential for plasma membrane repair and is a potential therapeutic target for dysferlinopathy.

  29. Oxidation resistance 1 prevents genome instability through maintenance of G2/M arrest in gamma-ray-irradiated cells. International-journal

    Ako Matsui, Junya Kobayashi, Shin-Ichiro Kanno, Kazunari Hashiguchi, Masahiro Miyaji, Yukihiro Yoshikawa, Akira Yasui, Qiu-Mei Zhang-Akiyama

    Journal of radiation research　61　(1)　1-13　2020/01/23

    DOI： 10.1093/jrr/rrz080 　

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    Human oxidation resistance 1 (OXR1) was identified as a protein that decreases genomic mutations in Escherichia coli caused by oxidative DNA damage. However, the mechanism by which OXR1 defends against genome instability has not been elucidated. To clarify how OXR1 maintains genome stability, the effects of OXR1-depletion on genome stability were investigated in OXR1-depleted HeLa cells using gamma-rays (γ-rays). The OXR1-depleted cells had higher levels of superoxide and micronucleus (MN) formation than control cells after irradiation. OXR1-overexpression alleviated the increases in reactive oxygen species (ROS) level and MN formation after irradiation. The increased MN formation in irradiated OXR1-depleted cells was partially attenuated by the ROS inhibitor N-acetyl-L-cysteine, suggesting that OXR1-depeletion increases ROS-dependent genome instability. We also found that OXR1-depletion shortened the duration of γ-ray-induced G2/M arrest. In the presence of the cell cycle checkpoint inhibitor caffeine, the level of MN formed after irradiation was similar between control and OXR1-depleted cells, demonstrating that OXR1-depletion accelerates MN formation through abrogation of G2/M arrest. In OXR1-depleted cells, the level of cyclin D1 protein expression was increased. Here we report that OXR1 prevents genome instability by cell cycle regulation as well as oxidative stress defense.

  30. LZTR1 facilitates polyubiquitination and degradation of RAS-GTPases. International-journal Peer-reviewed

    Taiki Abe, Ikumi Umeki, Shin-Ichiro Kanno, Shin-Ichi Inoue, Tetsuya Niihori, Yoko Aoki

    Cell death and differentiation　27　(3)　1023-1035　2019/07/23

    DOI： 10.1038/s41418-019-0395-5 　

    ISSN： 1350-9047

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    Leucine zipper-like transcriptional regulator 1 (LZTR1) encodes a member of the BTB-Kelch superfamily, which interacts with the Cullin3 (CUL3)-based E3 ubiquitin ligase complex. Mutations in LZTR1 have been identified in glioblastoma, schwannomatosis, and Noonan syndrome. However, the functional role of LZTR1 in carcinogenesis or human development is not fully understood. Here, we demonstrate that LZTR1 facilitates the polyubiquitination and degradation of RAS via the ubiquitin-proteasome pathway, leading to the inhibition of the RAS/MAPK signaling. The polyubiquitination and degradation of RAS was also observed in cells expressing MRAS, HRAS, NRAS, and KRAS as well as oncogenic RAS mutants and inhibited the activation of ERK1/2 and cell growth. In vivo ubiquitination assays showed that MRAS-K127 and HRAS-K170 were ubiquitinated by LZTR1 and that the polyubiquitinated-chains contained mainly Ub-K48, K63, and K33-linked chains, suggesting its possible involvement in autophagy. Immunoprecipitation analyses showed the interaction of LZTR1 and RAS-GTPases with autophagy-related proteins, including LC3B and SQSTM1/p62. Co-expression of LZTR1 and RAS increased the expression of lipidated form of LC3B. However, long-term treatment with chloroquine had little effect on RAS protein levels, suggesting that the contribution of autophagy to LZTR1-mediated RAS degradation is minimal. Taken together, these results show that LZTR1 functions as a "RAS killer protein" mainly via the ubiquitin-proteasome pathway regardless of the type of RAS GTPase, controlling downstream signal transduction. Our results also suggest a possible association of LZTR1 and RAS-GTPases with the autophagy. These findings provide clues for the elucidation of the mechanisms of RAS degradation and regulation of the RAS/MAPK signaling cascade.

  31. RACK1 regulates centriole duplication by controlling localization of BRCA1 to the centrosome in mammary tissue-derived cells. International-journal Peer-reviewed

    Yuki Yoshino, Huicheng Qi, Ryo Kanazawa, Mami Sugamata, Kenta Suzuki, Akihiro Kobayashi, Kazuha Shindo, Ayako Matsuzawa, Shun Shibata, Shino Endo, Yutaro Miyanishi, Tatsuro Shimaoka, Chikashi Ishioka, Shin-Ichiro Kanno, Akira Yasui, Natsuko Chiba

    Oncogene　38　(16)　3077-3092　2019/04

    DOI： 10.1038/s41388-018-0647-8 　

    ISSN： 0950-9232

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    Breast cancer gene 1 (BRCA1) is a tumor suppressor that is associated with hereditary breast and ovarian cancer. BRCA1 functions in DNA repair and centrosome regulation together with BRCA1-associated RING domain protein (BARD1), a heterodimer partner of BRCA1. Obg-like ATPase 1 (OLA1) was identified as a protein that interacts with BARD1. OLA1 regulates the centrosome by binding to and collaborating with BRCA1 and BARD1. We identified receptor for activated C kinase (RACK1) as a protein that interacts with OLA1. RACK1 directly bound to OLA1, the N-terminal region of BRCA1, and γ-tubulin, associated with BARD1, and localized the centrosomes throughout the cell cycle. Knockdown of RACK1 caused abnormal centrosomal localization of BRCA1 and abrogated centriole duplication. Overexpression of RACK1 increased the centrosomal localization of BRCA1 and caused centrosome amplification due to centriole overduplication. The number of centrioles in cells with two γ-tubulin spots was higher in cell lines derived from mammary tissue compared to those derived from other tissues. The effects of aberrant RACK1 expression level on centriole duplication were observed in cell lines derived from mammary tissue, but not in those derived from other tissues. Two BRCA1 variants, R133H and E143K, and a RACK1 variant, K280E, associated with cancer, which weakened the BRCA1-RACK1 interaction, interfered with the centrosomal localization of BRCA1 and reduced centrosome amplification induced by overexpression of RACK1. These results suggest that RACK1 regulates centriole duplication by controlling the centrosomal localization of BRCA1 in mammary tissue-derived cells and that this is dependent on the BRCA1-RACK1 interaction.

  32. Cep128 associates with Odf2 to form the subdistal appendage of the centriole. International-journal Peer-reviewed

    Hiroka Kashihara, Shuhei Chiba, Shin-Ichiro Kanno, Koya Suzuki, Tomoki Yano, Sachiko Tsukita

    Genes to cells : devoted to molecular & cellular mechanisms　24　(3)　231-243　2019/03

    DOI： 10.1111/gtc.12668 　

    ISSN： 1356-9597

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    The mother centriole in a cell has two appendages, the distal appendage (DA) and subdistal appendage (SDA), which have roles in generating cilia and organizing the cellular microtubular network, respectively. In the knockout (KO) cells of Odf2, the component of the DA and SDA, both appendages simultaneously disappear. However, the molecular mechanisms by which the DA and SDA form independently but close to each other downstream of Odf2 are unknown. Here, using super-resolution structured illumination microscopy (SR-SIM), we found that the signal for GFP-tagged Odf2 overlapped considerably with that of immunofluorescently labeled Cep128. We further found that Cep128 knockdown (KD) caused the dissociation of other SDA components from the centriole, including centriolin, Ndel1, ninein and Cep170, whereas Odf2 was still associated with the centriole. In contrast, the DA components remained associated with the centriole in Cep128 KD cells. Consistent with this observation, we identified Cep128 as an Odf2-interacting protein by immunoprecipitation. Taken with the finding that Cep128 deletion decreased the stability of centriolar microtubules, our results indicate that Cep128 associates with Odf2 in the hierarchical assembly of SDA components to elicit the microtubule-organizing function.

  33. Delineation of LZTR1 mutation-positive patients with Noonan syndrome and identification of LZTR1 binding to RAF1-PPP1CB complexes. International-journal Peer-reviewed

    Ikumi Umeki, Tetsuya Niihori, Taiki Abe, Shin-Ichiro Kanno, Nobuhiko Okamoto, Seiji Mizuno, Kenji Kurosawa, Keisuke Nagasaki, Makoto Yoshida, Hirofumi Ohashi, Shin-Ichi Inoue, Yoichi Matsubara, Ikuma Fujiwara, Shigeo Kure, Yoko Aoki

    Human genetics　138　(1)　21-35　2019/01

    DOI： 10.1007/s00439-018-1951-7 　

    ISSN： 0340-6717

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    RASopathies are a group of developmental disorders caused by mutations in genes that regulate the RAS/MAPK pathway and include Noonan syndrome (NS), Costello syndrome, cardiofaciocutaneous syndrome and other related disorders. Whole exome sequencing studies recently identified LZTR1, PPP1CB and MRAS as new causative genes in RASopathies. However, information on the phenotypes of LZTR1 mutation-positive patients and functional properties of the mutations are limited. To identify variants of LZTR1, PPP1CB, and MRAS, we performed a targeted next-generation sequencing and reexamined previously analyzed exome data in 166 patients with suspected RASopathies. We identified eight LZTR1 variants, including a de novo variant, in seven probands who were suspicious for NS and one known de novo PPP1CB variant in a patient with NS. One of the seven probands had two compound heterozygous LZTR1 variants, suggesting autosomal recessive inheritance. All probands with LZTR1 variants had cardiac defects, including hypertrophic cardiomyopathy and atrial septal defect. Five of the seven probands had short stature or intellectual disabilities. Immunoprecipitation of endogenous LZTR1 followed by western blotting showed that LZTR1 bound to the RAF1-PPP1CB complex. Cells transfected with a small interfering RNA against LZTR1 exhibited decreased levels of RAF1 phosphorylated at Ser259. These are the first results to demonstrate LZTR1 in association with the RAF1-PPP1CB complex as a component of the RAS/MAPK pathway.

  34. Karyopherin Alpha 2-Expressing Pancreatic Duct Glands and Intra-Islet Ducts in Aged Diabetic C414A-Mutant-CRY1 Transgenic Mice. International-journal Peer-reviewed

    Okano S, Yasui A, Kanno SI, Satoh K, Igarashi M, Nakajima O

    Journal of diabetes research　2019　7234549-7234549　2019

    DOI： 10.1155/2019/7234549 　

    ISSN： 2314-6745

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    Our earlier studies demonstrated that cysteine414- (zinc-binding site of mCRY1-) alanine mutant mCRY1 transgenic mice (Tg mice) exhibit diabetes characterized by the reduction of β-cell proliferation and by β-cell dysfunction, presumably caused by senescence-associated secretory phenotype- (SASP-) like characters of islets. Earlier studies also showed that atypical duct-like structures in the pancreas developed age-dependently in Tg mice. Numerous reports have described that karyopherin alpha 2 (KPNA2) is highly expressed in cancers of different kinds. However, details of the expression of KPNA2 in pancreatic ductal atypia and in normal pancreatic tissues remain unclear. To assess the feature of the expression of KPNA2 in the development of the ductal atypia and islet architectures, we scrutinized the pancreas of Tg mice histopathologically. Results showed that considerable expression of KPNA2 was observed in pancreatic β-cells, suggesting its importance in maintaining the functions of β-cells. In mature stages, the level of KPNA2 expression was lower in islets of Tg mice than in wild-type controls. At 4 weeks, the expression levels of KPNA2 in islets of Tg mice were the same as those in wild-type controls. These results suggest that the reduction of KPNA2 might contribute to β-cell dysfunction in mature Tg mice. Additionally, the formation of mucin-producing intra-islet ducts, islet fibrosis, and massive T cell recruitment to the islet occurred in aged Tg mice. In exocrine areas, primary pancreatic intraepithelial neoplasias (PanINs) with mucinous pancreatic duct glands (PDGs) emerged in aged Tg mice. High expression of KPNA2 was observed in the ductal atypia. By contrast, KPNA2 expression in normal ducts was quite low. Thus, upregulation of KPNA2 seemed to be correlated with progression of the degree of atypia in pancreatic ductal cells. The SASP-like microenvironment inside islets might play stimulatory roles in the formation of ductal metaplasia inside islets and in islet fibrosis in Tg mice.

  35. DNMTs and SETDB1 function as co-repressors in MAX-mediated repression of germ cell-related genes in mouse embryonic stem cells. International-journal Peer-reviewed

    Daiki Tatsumi, Yohei Hayashi, Mai Endo, Hisato Kobayashi, Takumi Yoshioka, Kohei Kiso, Shinichiro Kanno, Yuji Nakai, Ikuma Maeda, Kentaro Mochizuki, Makoto Tachibana, Haruhiko Koseki, Akihiko Okuda, Akira Yasui, Tomohiro Kono, Yasuhisa Matsui

    PloS one　13　(11)　e0205969　2018

    DOI： 10.1371/journal.pone.0205969 　

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    In embryonic stem cells (ESCs), the expression of development-related genes, including germ cell-related genes, is globally repressed. The transcription factor MAX represses germ cell-related gene expression in ESCs via PCGF6-polycomb repressive complex 1 (PRC1), which consists of several epigenetic factors. However, we predicted that MAX represses germ cell-related gene expression through several additional mechanisms because PCGF6-PRC1 regulates the expression of only a subset of genes repressed by MAX. Here, we report that MAX associated with DNA methyltransferases (DNMTs) and the histone methyltransferase SETDB1 cooperatively control germ cell-related gene expression in ESCs. Both DNA methylation and histone H3 lysine 9 tri-methylation of the promoter regions of several germ cell-related genes were not affected by knockout of the PRC1 components, indicating that the MAX-DNMT and MAX-SETDB1 pathways are independent of the PCGF6-PRC1 pathway. Our findings provide insights into our understanding of MAX-based repressive mechanisms of germ cell-related genes in ESCs.

  36. mCRY1-C414A変異体過剰発現マウスの膵臓におけるtubular complexからの膵β細胞の新生とKPNA2の発現

    岡野 聡, 安井 明, 菅野 新一郎, 佐藤 賢一, 早坂 清, 五十嵐 雅彦, 中島 修

    生命科学系学会合同年次大会　2017年度　[2P-0788]　2017/12

    Publisher: 生命科学系学会合同年次大会運営事務局

  37. Nucleosome remodelling, DNA repair and transcriptional regulation build negative feedback loops in cancer and cellular ageing Peer-reviewed

    Reiko Watanabe, Shin-ichiro Kanno, Amaneh Mohammadi Roushandeh, Ayako Ui, Akira Yasui

    PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES　372　(1731)　2017/10

    DOI： 10.1098/rstb.2016.0473 　

    ISSN： 0962-8436

    eISSN： 1471-2970

  38. Dynamic feature of mitotic arrest deficient 2-like protein 2 (MAD2L2) and structural basis for its interaction with chromosome alignment-maintaining phosphoprotein (CAMP) Peer-reviewed

    Kodai Hara, Shota Taharazako, Masanori Ikeda, Hiroki Fujita, Yoshiko Mikami, Sotaro Kikuchi, Asami Hishiki, Hideshi Yokoyama, Yoshinobu Ishikawa, Shin-ichiro Kanno, Kozo Tanaka, Hiroshi Hashimoto

    JOURNAL OF BIOLOGICAL CHEMISTRY　292　(43)　17658-17667　2017/10

    DOI： 10.1074/jbc.M117.804237 　

    ISSN： 0021-9258

    eISSN： 1083-351X

  39. DNA Polymerase Beta Participates in Mitochondrial DNA Repair Peer-reviewed

    P. Sykora, S. Kanno, M. Akbari, T. Kulikowicz, B. A. Baptiste, G. S. Leandro, H. Lu, J. Tian, A. May, K. A. Becker, D. L. Croteau, D. M. Wilson, R. W. Sobol, A. Yasui, V. A. Bohr

    MOLECULAR AND CELLULAR BIOLOGY　37　(16)　2017/08

    DOI： 10.1128/MCB.00237-17 　

    ISSN： 0270-7306

    eISSN： 1098-5549

  40. Mitochonic Acid 5 (MA-5) Facilitates ATP Synthase Oligomerization and Cell Survival in Various Mitochondrial Diseases Peer-reviewed

    Tetsuro Matsuhashi, Takeya Sato, Shin-ichiro Kanno, Takehiro Suzuki, Akihiro Matsuo, Yuki Oba, Motoi Kikusato, Emi Ogasawara, Tai Kudo, Kosuke Suzuki, Osamu Ohara, Hiroko Shimbo, Fumika Nanto, Hiroaki Yamaguchi, Daisuke Saigusa, Yasuno Mukaiyama, Akiko Watabe, Koichi Kikuchi, Hisato Shima, Eikan Mishima, Yasutoshi Akiyama, Yoshitsugu Oikawa, Hsin-Jung Ho, Yukako Akiyama, Chitose Suzuki, Mitsugu Uematsu, Masaki Ogata, Naonori Kumagai, Masaaki Toyomizu, Atsushi Hozawa, Nariyasu Mano, Yuji Owada, Setsuya Aiba, Teruyuki Yanagisawa, Yoshihisa Tomioka, Shigeo Kure, Sadayoshi Ito, Kazuto Nakada, Ken-ichiro Hayashi, Hitoshi Osaka, Takaaki Abe

    EBIOMEDICINE　20　27-38　2017/06

    DOI： 10.1016/j.ebiom.2017.05.016 　

    ISSN： 2352-3964

  41. 分子の集合・離脱がつかさどる動的な細胞機能 中心体機能制御インターフェースとしてのアペンデージ構造の分子基盤

    柏原 宏香, 千葉 秀平, 菅野 新一郎, 月田 早智子

    日本細胞生物学会大会講演要旨集　69回　11-11　2017/05

    Publisher: (一社)日本細胞生物学会

  42. A pleckstrin homology-like domain is critical for F-actin binding and cofilin-phosphatase activity of Slingshot-1 Peer-reviewed

    Katsunori Takahashi, Haruka Okabe, Shin-ichiro Kanno, Tomoaki Nagai, Kensaku Mizuno

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS　482　(4)　686-692　2017/01

    DOI： 10.1016/j.bbrc.2016.11.095 　

    ISSN： 0006-291X

    eISSN： 1090-2104

  43. Mitochonic Acid 5 Binds Mitochondria and Ameliorates Renal Tubular and Cardiac Myocyte Damage Peer-reviewed

    Takehiro Suzuki, Hiroaki Yamaguchi, Motoi Kikusato, Osamu Hashizume, Satoru Nagatoishi, Akihiro Matsuo, Takeya Sato, Tai Kudo, Tetsuro Matsuhashi, Kazutaka Murayanna, Yuki Ohba, Shun Watanabe, Shin-ichiro Kanno, Daichi Minaki, Daisuke Saigusa, Hiroko Shinbo, Nobuyoshi Mori, Akinori Yuri, Miyuki Yokoro, Eikan Mishima, Hisato Shima, Yasutoshi Akiyama, Yoichi Takeuchi, Koichi Kikuchi, Takafumi Toyohara, Chitose Suzuki, Takaharu Ichimura, Jun-ichi Anzai, Masahiro Kohzuki, Nariyasu Mario, Shigeo Kure, Teruyuki Yanagisawa, Yoshihisa Tomioka, Masaaki Toyomizu, Kohei Tsumoto, Kazuto Nakada, Joseph V. Bonventre, Sadayoshi Ito, Hitoshi Osaka, Ken-ichi Hayashi, Takaaki Abe

    JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY　27　(7)　1925-1932　2016/07

    DOI： 10.1681/ASN.2015060623 　

    ISSN： 1046-6673

    eISSN： 1533-3450

  44. Activation of cytosolic Slingshot-1 phosphatase by gelsolin-generated soluble actin filaments Peer-reviewed

    Katsunori Takahashi, Shin-ichiro Kanno, Kensaku Mizuno

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS　454　(3)　471-477　2014/11

    DOI： 10.1016/j.bbrc.2014.10.108 　

    ISSN： 0006-291X

    eISSN： 1090-2104

  45. Insulin receptor substrate-4 binds to Slingshot-1 phosphatase and promotes cofilin dephosphorylation. International-journal Peer-reviewed

    Yuta Homma, Shin-ichiro Kanno, Kazutaka Sasaki, Michiru Nishita, Akira Yasui, Tomoichiro Asano, Kazumasa Ohashi, Kensaku Mizuno

    The Journal of biological chemistry　289　(38)　26302-13　2014/09/19

    DOI： 10.1074/jbc.M114.565945 　

    ISSN： 0021-9258

    More details Close

    Cofilin plays an essential role in cell migration and morphogenesis by enhancing actin filament dynamics via its actin filament-severing activity. Slingshot-1 (SSH1) is a protein phosphatase that plays a crucial role in regulating actin dynamics by dephosphorylating and reactivating cofilin. In this study, we identified insulin receptor substrate (IRS)-4 as a novel SSH1-binding protein. Co-precipitation assays revealed the direct endogenous binding of IRS4 to SSH1. IRS4, but not IRS1 or IRS2, was bound to SSH1. IRS4 was bound to SSH1 mainly through the unique region (amino acids 335-400) adjacent to the C terminus of the phosphotyrosine-binding domain of IRS4. The N-terminal A, B, and phosphatase domains of SSH1 were bound to IRS4 independently. Whereas in vitro phosphatase assays revealed that IRS4 does not directly affect the cofilin phosphatase activity of SSH1, knockdown of IRS4 increased cofilin phosphorylation in cultured cells. Knockdown of IRS4 decreased phosphatidylinositol 3-kinase (PI3K) activity, and treatment with an inhibitor of PI3K increased cofilin phosphorylation. Akt preferentially phosphorylated SSH1 at Thr-826, but expression of a non-phosphorylatable T826A mutant of SSH1 did not affect insulin-induced cofilin dephosphorylation, and an inhibitor of Akt did not increase cofilin phosphorylation. These results suggest that IRS4 promotes cofilin dephosphorylation through sequential activation of PI3K and SSH1 but not through Akt. In addition, IRS4 co-localized with SSH1 in F-actin-rich membrane protrusions in insulin-stimulated cells, which suggests that the association of IRS4 with SSH1 contributes to localized activation of cofilin in membrane protrusions.

  46. SWI/SNF Factors Required for Cellular Resistance to DNA Damage Include ARID1A and ARID1B and Show Interdependent Protein Stability Peer-reviewed

    Reiko Watanabe, Ayako Ui, Shin-ichiro Kanno, Hideaki Ogiwara, Takahiro Nagase, Takashi Kohno, Akira Yasui

    CANCER RESEARCH　74　(9)　2465-2475　2014/05

    DOI： 10.1158/0008-5472.CAN-13-3608 　

    ISSN： 0008-5472

    eISSN： 1538-7445

  47. Possible involvement of LKB1-AMPK signaling in non-homologous end joining Peer-reviewed

    A. Ui, H. Ogiwara, S. Nakajima, S. Kanno, R. Watanabe, M. Harata, H. Okayama, C. C. Harris, J. Yokota, A. Yasui, T. Kohno

    ONCOGENE　33　(13)　1640-1648　2014/03

    DOI： 10.1038/onc.2013.125 　

    ISSN： 0950-9232

    eISSN： 1476-5594

  48. The Novel Zinc Finger Protein dASCIZ Regulates Mitosis in Drosophila via an Essential Role in Dynein Light-Chain Expression Peer-reviewed

    Olga Zaytseva, Nora Tenis, Naomi Mitchell, Shin-ichiro Kanno, Akira Yasui, Joerg Heierhorst, Leonie M. Quinn

    GENETICS　196　(2)　443-+　2014/02

    DOI： 10.1534/genetics.113.159541 　

    ISSN： 0016-6731

    eISSN： 1943-2631

  49. The BRCA1/BARD1-Interacting Protein OLA1 Functions in Centrosome Regulation Peer-reviewed

    Ayako Matsuzawa, Shin-ichiro Kanno, Masahiro Nakayama, Hironori Mochiduki, Leizhen Wei, Tatsuro Shimaoka, Yumiko Furukawa, Kei Kato, Shun Shibata, Akira Yasui, Chikashi Ishioka, Natsuko Chiba

    MOLECULAR CELL　53　(1)　101-114　2014/01

    DOI： 10.1016/j.molcel.2013.10.028 　

    ISSN： 1097-2765

  50. Damage response of XRCC1 at sites of DNA single strand breaks is regulated by phosphorylation and ubiquitylation after degradation of poly(ADP-ribose) Peer-reviewed

    Leizhen Wei, Satoshi Nakajima, Ching-Lung Hsieh, Shinichiro Kanno, Mitsuko Masutani, Arthur S. Levine, Akira Yasui, Li Lan

    JOURNAL OF CELL SCIENCE　126　(19)　4414-4423　2013/10

    DOI： 10.1242/jcs.128272 　

    ISSN： 0021-9533

  51. Furry promotes acetylation of microtubules in the mitotic spindle by inhibition of SIRT2 tubulin deacetylase Peer-reviewed

    Tomoaki Nagai, Masanori Ikeda, Shuhei Chiba, Shin-ichiro Kanno, Kensaku Mizuno

    JOURNAL OF CELL SCIENCE　126　(19)　4369-4380　2013/10

    DOI： 10.1242/jcs.127209 　

    ISSN： 0021-9533

  52. 核膜孔複合体の構成因子Nup188の分裂期における役割(Mitotic role of Nup188, a component of nuclear pore complex)

    伊藤 剛, 池田 真教, 菅野 新一郎, アミン・ムハマド, 家村 顕自, 安井 明, 広田 亨, 田中 耕三

    日本生化学会大会プログラム・講演要旨集　86回　1T14a-03　2013/09

    Publisher: (公社)日本生化学会

  53. Nucleoporin Nup188 is required for chromosome alignment in mitosis Peer-reviewed

    Go Itoh, Shiro Sugino, Masanori Ikeda, Mayumi Mizuguchi, Shin-ichiro Kanno, Mohammed A. Amin, Kenji Iemura, Akira Yasui, Toru Hirota, Kozo Tanaka

    CANCER SCIENCE　104　(7)　871-879　2013/07

    DOI： 10.1111/cas.12159 　

    ISSN： 1349-7006

  54. Nucleoporin Nup188 is required for chromosome alignment in mitosis Peer-reviewed

    Go Itoh, Shiro Sugino, Masanori Ikeda, Mayumi Mizuguchi, Shin-Ichiro Kanno, Mohammed A. Amin, Kenji Iemura, Akira Yasui, Toru Hirota, Kozo Tanaka

    Cancer Science　104　(7)　871-879　2013/07

    DOI： 10.1111/cas.12159 　

    ISSN： 1347-9032 1349-7006

    eISSN： 1349-7006

  55. Over-expression of ATR causes autophagic cell death Peer-reviewed

    Chihiro Mori, Yoshihiro Yamaguchi, Mika Teranishi, Takako Takanami, Takahiro Nagase, Shinichiro Kanno, Akira Yasui, Atsushi Higashitani

    Genes to Cells　18　(4)　278-287　2013/04

    DOI： 10.1111/gtc.12034 　

    ISSN： 1356-9597 1365-2443

  56. 微小管結合蛋白質Furryによる微小管アセチル化制御機構

    永井 友朗, 千葉 秀平, 池田 真教, 菅野 新一郎, 水野 健作

    生化学　84　(6)　507-507　2012/06

    Publisher: (公社)日本生化学会

    ISSN： 0037-1017

    eISSN： 2189-0544

  57. Mutations in UVSSA cause UV-sensitive syndrome and destabilize ERCC6 in transcription-coupled DNA repair Peer-reviewed

    Xue Zhang, Katsuyoshi Horibata, Masafumi Saijo, Chie Ishigami, Akiko Ukai, Shin-ichiro Kanno, Hidetoshi Tahara, Edward G. Neilan, Masamitsu Honma, Takehiko Nohmi, Akira Yasui, Kiyoji Tanaka

    NATURE GENETICS　44　(5)　593-+　2012/05

    DOI： 10.1038/ng.2228 　

    ISSN： 1061-4036

  58. WRNIP1 accumulates at laser light irradiated sites rapidly via its ubiquitin-binding zinc finger domain and independently from its ATPase domain Peer-reviewed

    Hironoshin Nomura, Akari Yoshimura, Takato Edo, Shin-ichiro Kanno, Syusuke Tada, Masayuki Seki, Akira Yasui, Takemi Enomoto

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS　417　(4)　1145-1150　2012/01

    DOI： 10.1016/j.bbrc.2011.12.080 　

    ISSN： 0006-291X

  59. Polynucleotide Kinase and Aprataxin-like Forkhead-associated Protein (PALF) Acts as Both a Single-stranded DNA Endonuclease and a Single-Stranded DNA 3 ' Exonuclease and Can Participate in DNA End Joining in a Biochemical System Peer-reviewed

    Sicong Li, Shin-ichiro Kanno, Reiko Watanabe, Hideaki Ogiwara, Takashi Kohno, Go WatanabeO, Akira Yasui, Michael R. Lieber

    JOURNAL OF BIOLOGICAL CHEMISTRY　286　(42)　36368-36377　2011/10

    DOI： 10.1074/jbc.M111.287797 　

    ISSN： 0021-9258

  60. CAMP (C13orf8, ZNF828) is a novel regulator of kinetochore-microtubule attachment Peer-reviewed

    Go Itoh, Shin-ichiro Kanno, Kazuhiko S. K. Uchida, Shuhei Chiba, Shiro Sugino, Kana Watanabe, Kensaku Mizuno, Akira Yasui, Toru Hirota, Kozo Tanaka

    EMBO JOURNAL　30　(1)　130-144　2011/01

    DOI： 10.1038/emboj.2010.276 　

    ISSN： 0261-4189

    eISSN： 1460-2075

  61. The ACF1 Complex Is Required for DNA Double-Strand Break Repair in Human Cells Peer-reviewed

    Li Lan, Ayako Ui, Satoshi Nakajima, Kotomi Hatakeyama, Mikiko Hoshi, Reiko Watanabe, Susan M. Janicki, Hideaki Ogiwara, Takashi Kohno, Shin-ichiro Kanno, Akira Yasui

    MOLECULAR CELL　40　(6)　976-987　2010/12

    DOI： 10.1016/j.molcel.2010.12.003 　

    ISSN： 1097-2765

  62. Solution structure of a zinc-finger domain that binds to poly-ADP-ribose Peer-reviewed

    Shin Isogai, Shin-Ichiro Kanno, Mariko Ariyoshi, Hidehito Tochio, Yutaka Ito, Akira Yasui, Masahiro Shirakawa

    Genes to Cells　15　(2)　101-110　2010/02

    DOI： 10.1111/j.1365-2443.2009.01369.x 　

    ISSN： 1356-9597 1365-2443

  63. Phosphorylation of protein phosphatase 2C zeta by c-Jun NH2-terminal kinase at Ser(92) attenuates its phosphatase activity Peer-reviewed

    Kenjiro Awano, Kazutaka Amano, Yuko Nagaura, Shin-ichiro Kanno, Seishi Echigo, Shinri Tamura, Takayasu Kobayashi

    BIOCHEMISTRY　47　(27)　7248-7255　2008/07

    DOI： 10.1021/bi800067p 　

    ISSN： 0006-2960

  64. A polycomb group protein, PHF1, is involved in the response to DNA double-strand breaks in human cell Peer-reviewed

    Zehui Hong, Jie Jiang, Li Lan, Satoshi Nakajima, Shin-ichiro Kanno, Haruhiko Koseki, Akira Yasui

    NUCLEIC ACIDS RESEARCH　36　(9)　2939-2947　2008/05

    DOI： 10.1093/nar/gkn146 　

    ISSN： 0305-1048

  65. HMGB1 is a cofactor in mammalian base excision repair Peer-reviewed

    Rajendra Prasad, Yuan Liu, Leesa J. Deterding, Vladimir P. Poltoratsky, Padmini S. Kedar, Julie K. Horton, Shin-Ichiro Kanno, Kenjiro Asagoshi, Esther W. Hou, Svetlana N. Khodyreva, Olga I. Lavrik, Kenneth B. Tomer, Akira Yasui, Samuel H. Wilson

    MOLECULAR CELL　27　(5)　829-841　2007/09

    DOI： 10.1016/j.molcel.2007.06.029 　

    ISSN： 1097-2765

  66. A novel human AP endonuclease with conserved zinc-finger-like motifs involved in DNA strand break responses Peer-reviewed

    Shin-ichiro Kanno, Hiroyuki Kuzuoka, Shigeru Sasao, Zehui Hong, Li Lan, Satoshi Nakajima, Akira Yasui

    EMBO JOURNAL　26　(8)　2094-2103　2007/04

    DOI： 10.1038/sj.emboj.7601663 　

    ISSN： 0261-4189

  67. Replication-dependent and -independent responses of RAD18 to DNA damage in human cells Peer-reviewed

    Satoshi Nakajima, Li Lan, Shin-ichiro Kanno, Noriko Usami, Katsumi Kobayashi, Masahiko Mori, Tadahiro Shiomi, Akira Yasui

    JOURNAL OF BIOLOGICAL CHEMISTRY　281　(45)　34687-34695　2006/11

    DOI： 10.1074/jbc.M605545200 　

    ISSN： 0021-9258

  68. Light-induced DNA damage and tolerance for the survival of nucleotide excision repair-deficient human cells Peer-reviewed

    S Nakajima, L Lan, S Kanno, M Takao, K Yamamoto, APM Eker, A Yasui

    JOURNAL OF BIOLOGICAL CHEMISTRY　279　(45)　46674-46677　2004/11

    DOI： 10.1074/jbc.M406070200 　

    ISSN： 0021-9258

  69. Functional and physical interactions between ERCC1 and MSH2 complexes for resistance to cis-diamminedichloroplatinum(II) in mammalian cells Peer-reviewed

    L Lan, T Hayashi, RM Rabeya, S Nakajima, S Kanno, M Takao, T Matsunaga, M Yoshino, M Ichikawa, HT Riele, S Tsuchiya, K Tanaka, A Yasui

    DNA REPAIR　3　(2)　135-143　2004/02

    DOI： 10.1016/j.dnarep.2003.10.005 　

    ISSN： 1568-7864

  70. Dna damage, repair and aging Peer-reviewed

    Akira Yasui, Shin-Ichiro Kanno, Masashi Takao

    Japanese Journal of Geriatrics　40　(6)　593-595　2003

    DOI： 10.3143/geriatrics.40.593 　

    ISSN： 0300-9173

  71. A back-up glycosylase in Nth1 knock-out mice is a functional Nei (endonuclease VIII) homologue Peer-reviewed

    M Takao, S Kanno, K Kobayashi, QM Zhang, S Yonei, GTJ van der Horst, A Yasui

    JOURNAL OF BIOLOGICAL CHEMISTRY　277　(44)　42205-42213　2002/11

    DOI： 10.1074/jbc.M206884200 　

    ISSN： 0021-9258

  72. Novel nuclear and mitochondrial glycosylases revealed by disruption of the mouse Nth1 gene encoding an endonuclease III homolog for repair of thymine glycols Peer-reviewed

    M Takao, S Kanno, T Shiromoto, R Hasegawa, H Ide, S Ikeda, AH Sarker, S Seki, JZ Xing, XC Le, M Weinfeld, K Kobayashi, J Miyazaki, M Muijtjens, JHJ Hoeijmakers, G van der Horst, A Yasui

    EMBO JOURNAL　21　(13)　3486-3493　2002/07

    DOI： 10.1093/emboj/cdf350 　

    ISSN： 0261-4189

  73. チミングリコールを切るマウスDNAグリコシラーゼ遺伝子のノックアウトの影響について

    高尾雅, 菅野新一郎, 安井明

    加齢医学研究所雑誌　53　(1〜2)　14-14　2002/02

  74. Activation of c-Jun amino-terminal kinase is required for retinoic acid-induced neural differentiation of P19 embryonal carcinoma cells Peer-reviewed

    H Wang, S Ikeda, S Kanno, LM Guang, M Ohnishi, M Sasaki, T Kobayashi, S Tamura

    FEBS LETTERS　503　(1)　91-96　2001/08

    DOI： 10.1016/S0014-5793(01)02699-0 　

    ISSN： 0014-5793

  75. Cellular responses and repair of single-strand breaks introduced by UV damage endonuclease in mammalian cells Peer-reviewed

    S Okano, S Kanno, S Nakajima, A Yasui

    JOURNAL OF BIOLOGICAL CHEMISTRY　275　(42)　32635-32641　2000/10

    DOI： 10.1074/jbc.M004085200 　

    ISSN： 0021-9258

  76. Repair of apurinic/apyrimidinic sites by UV damage endonuclease; a repair protein for UV and oxidative damage Peer-reviewed

    S Kanno, S Iwai, M Takao, A Yasui

    NUCLEIC ACIDS RESEARCH　27　(15)　3096-3103　1999/08

    DOI： 10.1093/nar/27.15.3096 　

    ISSN： 0305-1048

  77. Mammalian Cry1 and Cry2 are essential for maintenance of circadian rhythms Peer-reviewed

    GTJ van der Horst, M Muijtjens, K Kobayashi, R Takano, S Kanno, M Takao, J de Wit, A Verkerk, APM Eker, D van Leenen, R Buijs, D Bootsma, JHJ Hoeijmakers, A Yasui

    NATURE　398　(6728)　627-630　1999/04

    DOI： 10.1038/19323 　

    ISSN： 0028-0836

  78. マウス光回復酵素ホモローグの機能解析

    菅野新一郎, 岡野聡, 小林久美子, 高野りや, 高尾雅, 安井明, 大畠慶子, HorstBert van der

    加齢医学研究所雑誌　50　(3-4)　114-115　1999

  79. A putative blue-light receptor from Drosophila melanogaster Peer-reviewed

    S Okano, S Kanno, M Takao, APM Eker, K Isono, Y Tsukahara, A Yasui

    PHOTOCHEMISTRY AND PHOTOBIOLOGY　69　(1)　108-113　1999/01

    DOI： 10.1562/0031-8655(1999)069<0108:APBLRF>2.3.CO;2 　

    ISSN： 0031-8655

    eISSN： 1751-1097

  80. CPD及び64光回復酵素遺伝子のヒト細胞への導入と発現による紫外線細胞死への影響

    中嶋敏, 高野りや, 菅野新一郎, 高尾雅, 山本和生, 安井明

    日本放射線影響学会大会講演要旨集　41回　141-141　1998/11

  81. Characterization of photolyase/blue-light receptor homologs in mouse and human cells Peer-reviewed

    K Kobayashi, S Kanno, R Smit, GTJ van der Horst, M Takao, A Yasui

    NUCLEIC ACIDS RESEARCH　26　(22)　5086-5092　1998/11

    DOI： 10.1093/nar/26.22.5086 　

    ISSN： 0305-1048

  82. PHOSPHORYLATION OF MG2+-DEPENDENT PROTEIN PHOSPHATASE-ALPHA (TYPE-2C-ALPHA) BY CASEIN KINASE-II Peer-reviewed

    T KOBAYASHI, S KANNO, T TERASAWA, T MURAKAMI, M OHNISHI, K OHTSUKI, A HIRAGA, S TAMURA

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS　195　(1)　484-489　1993/08

    ISSN： 0006-291X

    eISSN： 1090-2104

  83. グリチルリチンによる水ほう性口内炎ウイルス結合性プロテインキナーゼ活性阻害 Peer-reviewed

    菅野新一郎

    医学の歩み　148　(2)　113-114　1989

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    中村 尚子, 鈴木 直輝, 小野 洋也, 菅野 新一郎, 山中 玲, 井泉 瑠美子, 高橋 俊明, 三宅 克也, 青木 正志

    日本筋学会学術集会プログラム・抄録集　11回　99-99　2025/08

    Publisher: (一社)日本筋学会

    ISSN： 2433-975X

  2. Spasmolytic Polypeptide-Expressing Metaplasia-Like Features of Intraislet Ducts in ZincBinding Site-Mutated CRY1-Expressing Diabetic Mice

    Satoshi Okano, Akira Yasui, Shin-Ichiro Kanno, Yu Sasaki, Kennichi Satoh, Masahiko Igarashi, Osamu Nakajima

    DIABETES　74　2025/06

    DOI： 10.2337/db25-1805-P 　

    ISSN： 0012-1797

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    NAKAMURA Naoko, SUZUKI Naoki, ONO Hiroya, KANNO Shin-ichiro, YAMANAKA Rei, IZUMI Rumiko, TAKAHASHI Toshiaki, FUNAYAMA Yukino, SAITOH Saki, HARADA Ryuhei, OHNO Akiyuki, MITSUZAWA Shio, SHIJO Tomomi, IKEDA Kensuke, WARITA Hitoshi, MIYAKE Katsuya, AOKI Masashi

    日本神経学会学術大会プログラム・抄録集　65th　2024

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    日本分子生物学会年会プログラム・要旨集(Web)　47th　2024

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    阿部太紀, 菅野新一郎, 新堀哲也, 寺尾美穂, 高田修治, 青木洋子

    日本薬学会年会要旨集(Web)　144th　2024

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    阿部太紀, 梅木郁美, 菅野新一郎, 井上晋一, 新堀哲也, 青木洋子

    日本分子生物学会年会プログラム・要旨集(Web)　42nd　2019

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    小野 洋也, 鈴木 直輝, 菅野 新一郎, 川原 玄理, 井泉 瑠美子, 高橋 俊明, 北嶋 康雄, 長名 シオン, 秋山 徹也, 池田 謙輔, 四條 友望, 光澤 志緒, 割田 仁, 永富 良一, 荒木 伸一, 安井 明, 林 由起子, 三宅 克也, 青木 正志

    日本筋学会学術集会プログラム・抄録集　4回　160-160　2018/08

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    ISSN： 2433-975X

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    ISSN： 2433-1708

  11. 細胞膜修復機構に着目したジスフェルリン異常症の病態解明と治療法開発

    小野洋也, 鈴木直輝, 菅野新一郎, 川原玄理, 井泉瑠美子, 高橋俊明, 北嶋康雄, 長名シオン, 秋山徹也, 池田謙輔, 四條友望, 光澤志緒, 割田仁, 永富良一, 荒木伸一, 安井明, 林由起子, 三宅克也, 三宅克也, 青木正志

    筋ジストロフィー医療研究　4　87-87　2017/10

    Publisher: 筋ジストロフィー医療研究会

    ISSN： 2433-1708

  12. 細胞膜修復機構に着目したDysferlinopathyの病態解明と治療法開発

    小野 洋也, 鈴木 直輝, 菅野 新一郎, 川原 玄理, 井泉 瑠美子, 高橋 俊明, 北嶋 康雄, 長名 シオン, 秋山 徹也, 池田 謙輔, 四條 友望, 光澤 志緒, 割田 仁, 永富 良一, 荒木 伸一, 安井 明, 林 由起子, 三宅 克也, 青木 正志

    日本筋学会学術集会プログラム・抄録集　3回　141-141　2017/07

    Publisher: 日本筋学会

    ISSN： 2433-975X

  13. 細胞膜修復機構に着目したDysferlinopathyの病態解明と治療法開発

    小野洋也, 鈴木直輝, 菅野新一郎, 川原玄理, 井泉瑠美子, 高橋俊明, 北嶋康雄, 長名シオン, 秋山徹也, 池田謙輔, 四條友望, 光澤志緒, 割田仁, 永富良一, 荒木伸一, 安井明, 林由起子, 三宅克也, 三宅克也, 青木正志

    日本筋学会学術集会プログラム・抄録集　3回　141-141　2017/07

    Publisher: 日本筋学会

    ISSN： 2433-975X

  14. Reduced Expression of KPAN2 and Dysfunction of beta-Cells in C414A-CRY1 Transgenic Mice

    Satoshi Okano, Akira Yasui, Shinichiro Kanno, Kiyoshi Hayasaka, Masahiko Igarashi, Osamu Nakajima

    DIABETES　66　A572-A572　2017/06

    ISSN： 0012-1797

    eISSN： 1939-327X

  15. 筋ジストロフィー関連疾患の基盤的診断・治療開発研究 Dysferlinopathyおよび類似疾患の次世代シークエンサーを用いた診断および結合蛋白に注目した病態研究

    青木正志, 小野洋也, 井泉瑠美子, 鈴木直輝, 菅野新一郎, 高橋俊明, 割田仁, 加藤昌昭, 西山亜由美, 島倉奈緒子, 舟山亮, 中山啓子, 新堀哲也, 青木洋子, 三宅克也, 三宅克也

    筋ジストロフィー関連疾患の基盤的診断・治療開発研究 平成26-28年度 総括研究報告書　18‐20　2017

  16. Research for the pathogenesis and therapy of dysferlinopathy using proteomics approach

    H. Ono, N. Suzuki, S. Kanno, K. Miyake, Y. Kitajima, R. Izumi, T. Takahashi, H. Warita, A. Yasui, M. Aoki

    NEUROMUSCULAR DISORDERS　26　S151-S152　2016/10

    DOI： 10.1016/j.nmd.2016.06.240 　

    ISSN： 0960-8966

    eISSN： 1873-2364

  17. Anomalous Ductal Structure in the Islet of Diabetic Cysteine414-Alanine-mCRY1 Transgenic Mice

    Satoshi Okano, Akira Yasui, Shin-Ichiro Kanno, Kiyoshi Hayasaka, Masahiko Igarashi, Osamu Nakajima

    DIABETES　65　A530-A530　2016/06

    ISSN： 0012-1797

    eISSN： 1939-327X

  18. 新規BRCA1/BARD1結合分子OLA1は中心体複製機構に関与する

    千葉奈津子, 菅野新一郎, 藤田拡樹, 安井明, 石岡千加史, 松澤綾子

    日本分子生物学会年会プログラム・要旨集(Web)　37th　3W10-9(3P-0408) (WEB ONLY)　2014

  19. 染色体分配における核膜孔複合体構成団子Nup188の機能

    伊藤剛, 杉野史郎, 池田真教, 水口万裕美, 菅野新一郎, ABDULLAHEL Amin Mohammed, 家村顕自, 安井明, 広田亨, 田中耕三

    生化学　85　(8)　722-722　2013/08/25

    Publisher: (公社)日本生化学会

    ISSN： 0037-1017

  20. Furryによるチューブリン脱アセチル化酵素SIRT2の活性制御と分裂期紡錘体微小管のアセチル化に対する役割

    永井友朗, 池田真教, 千葉秀平, 菅野新一郎, 水野健作

    日本分子生物学会年会プログラム・要旨集(Web)　36th　2013

  21. Furry is a positive regulator of microtubule acetylation in mitotic spindle

    T. Nagai, S. Chiba, M. Ikeda, S-I. Kanno, A. Yasui, K. Ohashi, K. Mizuno

    MOLECULAR BIOLOGY OF THE CELL　23　2012

    ISSN： 1059-1524

    eISSN： 1939-4586

  22. NDR is required for ciliogenesis through the phosphorylation of Rabin8

    S. Chiba, Y. Amagai, S. Kanno, A. Yasui, M. Fukuda, K. Mizuno

    MOLECULAR BIOLOGY OF THE CELL　22　2011

    ISSN： 1059-1524

  23. DNA損傷に続くBRCA1/BARD1発現レベルの制御メカニズム(Regulatory mechanism of the level of BRCA1/BARD1 expression following DNA damage)

    柵木 絵美子, 菅野 新一郎, 松澤 綾子, 柏木 梨佐, 柴田 峻, 古川 裕美子, 魏 雷震, 石岡 千加史, 安井 明, 千葉 奈津子

    日本生化学会大会・日本分子生物学会年会合同大会講演要旨集　83回・33回　2P-0462　2010/12

    Publisher: (公社)日本生化学会

  24. Rabin8のリン酸化制御と一次繊毛形成における機能解析

    天貝佑太, 千葉秀平, 菅野祐哉, 菅野新一郎, 安井明, 福田光則, 水野健作

    生化学　2010

    ISSN： 0037-1017

  25. 新規亜鉛フィンガーモチーフCYRドメインの構造機能解析

    磯貝信, 有吉眞理子, 杤尾豪人, 菅野新一郎, 池上貴久, 伊藤隆, 安井明, 白川昌宏

    生化学　4T4-5　2008

    ISSN： 0037-1017

  26. 新規亜鉛フィンガーモチーフCYRドメインの構造機能解析

    磯貝信, 有吉眞理子, 杤尾豪人, 池上貴久, 伊藤隆, 菅野新一郎, 安井明, 白川昌宏

    Abstr Annu Meet NMR Soc Jpn　46th　202-203　2007/09/11

  27. DNA損傷・修復と老化 (日本老年医学会雑誌)

    安井明, 菅野新一郎, 高尾雅

    日本老年医学会雑誌　40　(6)　593-595　2003/11

  28. Novel nuclear and mitochondrial glycosylases revealed by disruption of the mouse Nth1 gene encoding an endonuclease III homolog for repair of thymine glycols (vol 21, pg 3486, 2002)

    M Takao, S Kanno, T Shiromoto, R Hasegawa, H Ide, S Ikeda, AH Sarker, S Seki, JZ Xing, XC Le, M Weinfeld, K Kobayashi, J Miyazaki, M Muijtjens, JHJ Hoeijmakers, G van der Horst, A Yasui

    EMBO JOURNAL　21　(16)　4391-4391　2002/08

    ISSN： 0261-4189

  29. 寿命と老化を決める遺伝子 活性酸素によるDNA損傷と修復欠損 (基礎老化研究)

    安井明, 菅野新一郎, 高尾雅

    基礎老化研究　26　(1)　13-13　2002/04

  30. Cellular responses and repair of single-strand breaks introduced by UV damage endonuclease in mammalian cells :

    OKANO Satoshi, KANNO Shin-ichiro, NAKAJIMA Satoshi, YASUI Akira

    Journal of radiation research　41　(4)　462-462　2000

    Publisher: the Japan Radiation Research Society

    ISSN： 0449-3060

  31. Alternative Splicing of Human DNA Glycosylases and IR Response :

    TAKAO Masashi, KANNO Shin-ichiro, YASUI Akira

    Journal of radiation research　41　(4)　393-393　2000

    Publisher: the Japan Radiation Research Society

    ISSN： 0449-3060

  32. マウスCRY蛋白質の機能解析

    菅野 新一郎, 小林 久美子, 高尾 雅, 岸上 明生, 岡野 聡, 岡村 均, VAN DER HORST Gijsbertus T. J., 安井 明

    日本時間生物学会会誌: Journal of Chronobiology　5　(2)　43-43　1999/10/01

    ISSN： 1344-9389

  33. Expression of CPD and 64 photolyase Genes in Human Cells :

    NAKAJIMA Satoshi, TAKANO Riya, KANNO Shin-ichiro, TAKAO Masashi, YAMAMOTO Kazuo, YASUI Akira

    Journal of radiation research　39　(4)　365-365　1998

    Publisher: the Japan Radiation Research Society

    ISSN： 0449-3060

  34. Cloning and characterization of photolyase homolog from mouse : Cloning and characterization of photolyase homolog from mouse

    KOBAYASHI Kumiko, KANNO Shinichiro, YASUHIRA Shinji, TAKAO Masashi, YASUI Akira

    Journal of radiation research　37　(4)　340-340　1996

    Publisher: the Japan Radiation Research Society

    ISSN： 0449-3060

  35. BIOCHEMICAL-CHARACTERIZATION OF THE MEMBRANE-ASSOCIATED PHOSPHORYLATING PROTEINS INVOLVED IN THE ANTIPROLIFERATIVE EFFECT OF HUMAN RECOMBINANT INTERFERON-ALPHA-2A (RIFN-ALPHA-2A) IN DAUDI CELLS

    M YOKOYAMA, K KOIKE, SI KANNO, K OHTSUKI

    TOHOKU JOURNAL OF EXPERIMENTAL MEDICINE　160　(4)　343-359　1990/04

    ISSN： 0040-8727

    eISSN： 1349-3329

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Research Projects 13

  1. Elucidation of the pathogenesis of moyamoya disease through Endothelial-Smooth Muscle Interaction and RNF213

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (A)

    Institution: Tohoku University

    2023/04/01 - 2026/03/31

  2. Elucidation the roles of senescence-like phenotype in pancreatic beta-cells in diabetic mutant cryptochrome1 transgenic mice

    Okano Satoshi, SATOH KENNICHI, HAYASAKA KIYOSHI, KANNO SHINICHIROU, IGARASHI MASAHIKO

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (C)

    Institution: Yamagata University

    2015/04/01 - 2018/03/31

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    Our research group (the study network of Cryptochrome in Tohoku Area [principal investigator: Sstoshi Okano]) have showed that, from the research over 10 years, the zinc-binding site-mutant (C414A) mCRY1 Tg mice display diabetes characterized by β-cell dysfunction due to senescence-like features of pancreatic β-cells. To elucidate the pathogenesis, we conducted analyses of the pancreas of the aged Tg mice. We newly found that the extent of fibrosis of the islet was higher in Tg mice compared with wild-type controls. Unusual duct-like structures producing mucin developed inside islets in the Tg mice with age. Outside islets, PanIN-like ductal structures, which are surrounded by pancreatic duct glands (PDG), were prominently emerged in aged Tg mice. Our results strongly suggest that, SASP-like microenvironment in the islets of the Tg mice play stimulatory roles in the transdifferentiation of pancreatic β-cells to ductal cells and in the development of ductal dysplasia in the Tg mice.

  3. Maintenance of chromosomal stability by efficient chromosome alignment

    Tanaka Kozo, IKEDA Masanori, YASUI Akira, KANNO Shin-ichiro

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (B)

    Institution: Tohoku University

    2015/04/01 - 2018/03/31

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    We investigated the mechanisms of chromosome alignment on the spindle and faithful chromosome segregation. In the process of chromosome alignment, kinetochores on chromosomes first attach to the lateral surface of spindle microtubules (lateral attachment), and then attach to the end of microtubules (end-on attachment). We searched for molecules involved in lateral attachment, and found the involvement of the motor proteins, dynein and CENP-E. We also found that lateral attachment and end-on attachment cooperatively contribute to chromosome alignment and faithful chromosome segregation (Sci Rep, 2018). Furthermore, we revealed that a mitotic kinase Plk1 plays a role in the spindle assemble checkpoint, which is important for the maintenance of chromosomal stability (Sci Rep, 2017).

  4. Human APNX protein is a dual function enzyme that have AP endnuclease activity and acethyltransferase activity.

    Kanno Shin-ichiro

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (C)

    Institution: Tohoku University

    2014/04/01 - 2017/03/31

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    The CYR motif was first identified in the human repair protein, PALF (ALPF), and found in various proteins of DNA metabolism, such as DNA repair and the DNA damage checkpoint. We found CG1218-PA and its human ortholog protein (APNX) that have CYR motif and DUF2228 domain, a domain of unknown function by searching database. We here analyzed the function of CG1218-PA in DNA damage response and found that CG1218-PA and its human ortholog APNX harboring DUF2228 are apurinic/apyrimidinic (AP) endonuclease. APNX interacts tightly with PARP1 and contributes to its activation after treatment of cells with alkylating agents. On the other hand, APNX have a partial similarity sequence of Tip60 and putative acetylCoA binding site. In vitro assay, APNX possess acethyltransferase activities against APNX itself and Tip60 protein. APNX plays an important role for the repair of DNA strand breaks and signaling of DNA damage in higher eukaryotic cells.

  5. Function of the novel tumor suppressor in cell division and carcinogenesis

    Chiba Natsuko, WATABANE Toshio, KANNO Shin-ichiro, Sugimoto Asako

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (B)

    Institution: Tohoku University

    2012/04/01 - 2016/03/31

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    The breast and ovarian cancer specific tumor suppressor BRCA1 plays important roles in DNA repair and centrosome regulation. We identified Obg-like ATPase 1 (OLA1) that interacts with BRCA1. OLA1 directly bound to BRCA1 and a component of centrosome. OLA1 localized to centrosomes in interphase and to the spindle pole in mitotic phase, and its knockdown resulted centrosome amplification and the activation of microtubule aster formation. OLA1 with a mutation observed in breast cancer cell line failed to bind BRCA1 and rescue the OLA1 knockdown-induced centrosome amplification. BRCA1 variant found in familial breast cancer also abrogated the binding of BRCA1 to OLA1. These findings suggest that OLA1 plays an important role in centrosome regulation together with BRCA1.

  6. Regulatory system of chromosomal stability by molecules including a novel molecule, CAMP

    TANAKA Kozo, ITOH Go, HIROTA Toru, YASUI Akira, KANNO Shin-ichiro

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (B)

    Institution: Tohoku University

    2012/04/01 - 2015/03/31

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    We addressed the regulatory mechanism of chromosomal stability, and following findings were obtained. 1) A novel molecule CAMP functions as a complex with HP1, REV7, and POGZ. CAMP knockout mice die soon after birth. 2) A nuclear pore complex component Nup188 recruits NuMA to spindle poles for chromosome segregation. 3) A microtubule associated factor CLIP-170 regulates chromosome segregation through the mechanisms such as Plk1 recruitment to kinetochores. 4) Two motor molecules, Kid and CENP-E, function for chromosome alignment on the spindle.

  7. Basic research to overcome resistance to anti-mitotic drugs

    TANAKA Kozo, ITOH Go, HIROTA Toru, YASUI Akira, KANNO Shinichiro

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Challenging Exploratory Research

    Institution: Tohoku University

    2012/04/01 - 2014/03/31

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    We aimed to identify molecules involved in cell death after prolonged mitotic arrest by anti-cancer drugs. When cells depleted of CAMP, a novel molecule we identified, were treated with microtubule inhibitors, we found the acceleration of cell death after mitotic arrest specifically in cancer cell lines. There was a tendency that cancer cell lines showed higher expression of CAMP than normal cell lines, implying that cancer cell survival is dependent on CAMP. Expression of Mcl-1 and Bcl-xL, anti-apoptotic Bcl-2 family members, was decreased in CAMP-depleted cells, suggesting that CAMP can be a target for anti-cancer therapy.

  8. Characterization of the novel human AP endonuclease and poly-ADP-ribosyl transferase.

    KANNO Shin-ichiro

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (C)

    Institution: Tohoku University

    2011 - 2013

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    The CYR motif was first identified in the repair protein, PALF (ALPF), and found in various proteins of DNA metabolism and DNA repair. We newly identified the CYR motif containing proteins, Drosophila CG1218 and its human ortholog C4orf27, which contained a conserved DUF2228 domain. We hypothesized that these proteins have DNA metabolism related functions. We isolated cDNA of CG1218 and human C4orf27, and characterized these proteins. Here we show that; 1) a CG1218 protein accumulates at DNA damaged site and human C4orf27 protein forms a hetero dimmer with PARP1 and accumulates at DNA damaged site 2) CG1218 and C4orf27 possess endo/exonuclease activities against abasic site. 3) Suppression of the expression of C4orf27 using siRNA provided the cells with sensitivity to MMS, which produces methylated bases leading to single-strand breaks. These data suggest that DUF2228 protein CG1218-PA and C4orf27 play important roles in the repair of DNA base damage and single-strand breaks.

  9. Molecular mechanism of transcriptional regulation forDNA repair genes: Identification of partner proteins for CXXC5, a novel MLH1 transcriptional factor

    ARITA Michitsune, KANNO Shin-ichiro

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (C)

    Institution: Toho University

    2010 - 2012

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    In this study, CXXC5, DNA-binding protein recognizing the FP3CAT site of MLH1 promoter, was identified as an activator of MLH1 transcription. Co-immunoprecipitation and LC/MS/MS analysis revealed that CXXC5 and SYF2, previously screened as an FP3 site-binding protein, share common interacting protein HNRNPH1 and may co-operatively trans-activate MLH1. In hypoxia, all three protein levels were down-regulated and endogenous over-expression of them partially rescued MLH1 down-regulation. Hypoxic down-regulationof MLH1 may be mediated by CXXC5, SYF2, and HNRNPH1.

  10. Analysis of a novel BRCA1-associated protein for new cancer therapy

    CHIBA Natsuko, KANNO Shin-ichiro

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (C)

    Institution: Tohoku University

    2009 - 2011

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    Germline mutations in the breast cancer susceptibility gene BRCA1 predispose women to breast and ovarian cancers. BRCA1 plays important roles in DNA repair and centrosome regulation, along with its heterodimer partner BARD1. We identified a new protein that interacts with BARD1 (here we call it BARD1-interacting protein (BIP)). We found that BIP plays an important role in the regulation of centrosome amplification and cytokinesis together with BRCA1and BARD1.

  11. Molecular network supporting chromosomal stability

    TANAKA Kozo, YASUI Akira, ITOH Go, KANNO Shinichiro, TANAKA Tomoyuki

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (C)

    Institution: Tohoku University

    2009 - 2011

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    We searched for molecules involved in chromosomal stability, and identified a novel molecule, CAMP(chromosome alignment-maintaining phosphoprotein ; C13orf8, ZNF828). CAMP is supposed to contribute to chromosome segregation through the maintenance of kinetochore-microtubule attachment. Mutations in CAMP were suggested to be related to oncogenesis.

  12. Characterization of new identified novel human AP endonuclease

    KANNO Shin-ichiro

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (C)

    Institution: Tohoku University

    2008 - 2010

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    DUF2228 is a functionally unknown, conserved protein family distributed from worm to vertebrate including human. In insect and a part of worm DUF2228 protein has an additional domain containing a CYR motif (C2H2 zinc finger motif)in the N-terminal region. Since CYR motif was first identified in the human repair protein, PALF (ALPF), and found in various proteins of DNA metabolism, such as DNA repair and the DNA damage checkpoint, at their N-or C-termini, we hypothesized that DUF2228 family proteins have also DNA metabolism related functions. We isolated cDNA of Drosophila CG1218-PA and human C4orf27(APNX)belonging to DUF2228 and characterized these proteins. Here we show that ; 1)a Drosophila CG1218-PA protein accumulates at DNA damaged site in a poly-ADP-ribose-dependent manner. 2)Human APNX protein that lacks a CYR motif forms a hetero dimmer with PARP1 and accumulates at DNA damaged site in a PARP1-dependent manner. 3)CG1218-PA and APNX possess endo-and exonuclease activities against abasic site. 4)Suppression of the expression of APNX using siRNA in HeLa cells provided the cells with sensitivity to methyl methane sulfonate, which produces methylated bases leading to single-strand breaks. These data suggest that DUF2228 protein CG1218-PA and APNX play important roles in the repair of DNA base damage and single-strand breaks.

  13. Novel DNA damage responses and repair regulated by poly-ADP ribosylation and chromatin remodeling

    YASUI Akira, NAKAJIMA Satoshi, KANNO Shinichirou, TANAKA Kouzo, TAKAO Masashi

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (A)

    Institution: Tohoku University

    2008 - 2010

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    Using laser micro-irradiation of living human cell and identification of protein complexes recruited to DNA damaged site by proteomics, we have analyzed and identified DNA damage response of proteins within human cell. For DNA single-strand breaks we have identified two novel human proteins with DNA end-and exo-nuclease activities, which activate poly(ADP-ribose polymerase 1 (PARP1)by creating gap at a nick in DNA. For DNA double-strand breaks (DSB)we identified an ATP-dependent chromatin remodeling complex belonging to ISWI family, CHRAC, which is required for the loading of KU complex at DSB. Especially, ACF1 becomes bound to KU70 more tightly by treatment of cells with chemical agents creating DSB and initiates non-homologous end joining of DSB. Thus, we showed that chromatin remodeling is essential for the initiation of repair of DNA strand breaks.

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