Updated on 2022/04/08

写真a

 
OGI Tomoo
 
Organization
Research Institute of Environmental Medicine Division of Stress Adaptation and Protection Professor
Graduate School
Graduate School of Medicine
Title
Professor

Degree 1

  1. 博士(理学) ( 2001.3   京都大学 ) 

Research Interests 14

  1. DNA repair; human genetics; nucleotide excision repair; genome

  2. 転写と共役したヌクレオチド除去修復

  3. 突然変異

  4. 発がん

  5. 放射線DNA損傷

  6. Human Genetics

  7. 乳癌

  8. ヌクレオチド除去修復

  9. タンパク質間相互作用

  10. ゲノム医科学

  11. DNA損傷修復

  12. DNA repair; human genetics; nucleotide excision repair; genome

  13. DNA修復

  14. BRCA2

Research Areas 6

  1. Life Science / Dermatology

  2. Life Science / Pathological biochemistry

  3. Environmental Science/Agriculture Science / Radiation influence

  4. Life Science / Medical biochemistry

  5. Environmental Science/Agriculture Science / Chemical substance influence on environment

  6. Life Science / Molecular biology

▼display all

Research History 2

  1. Nagoya University   Research Institute of Environmental Medicine Division of Stress Adaptation and Protection   Professor

    2015.4

  2. Nagoya University   Research Institute of Environmental Medicine (RIeM)   Professor

    2015.4

 

Papers 105

  1. Expanding the phenotypic spectrum of ARCN1-related syndrome.

    Ritter AL, Gold J, Hayashi H, Ackermann AM, Hanke S, Skraban C, Cuddapah S, Bhoj E, Li D, Kuroda Y, Wen J, Takeda R, Bibb A, El Chehadeh S, Piton A, Ohl J, Kukolich MK, Nagasaki K, Kato K, Ogi T, Bhatti T, Russo P, Krock B, Murrell JR, Sullivan JA, Shashi V, Stong N, Hakonarson H, Sawano K, Torti E, Willaert R, Si Y, Wilcox WR, Wirgenes KV, Thomassen K, Carlotti K, Erwin A, Lazier J, Marquardt T, He M, Edmondson AC, Izumi K

    Genetics in medicine : official journal of the American College of Medical Genetics     2022.3

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:Genetics in Medicine  

    Purpose: This study aimed to describe the phenotypic and molecular characteristics of ARCN1-related syndrome. Methods: Patients with ARCN1 variants were identified, and clinician researchers were connected using GeneMatcher and physician referrals. Clinical histories were collected from each patient. Results: In total, we identified 14 cases of ARCN1-related syndrome, (9 pediatrics, and 5 fetal cases from 3 families). The clinical features these newly identified cases were compared to 6 previously reported cases for a total of 20 cases. Intrauterine growth restriction, micrognathia, and short stature were present in all patients. Other common features included prematurity (11/15, 73.3%), developmental delay (10/14, 71.4%), genitourinary malformations in males (6/8, 75%), and microcephaly (12/15, 80%). Novel features of ARCN1-related syndrome included transient liver dysfunction and specific glycosylation abnormalities during illness, giant cell hepatitis, hepatoblastoma, cataracts, and lethal skeletal manifestations. Developmental delay was seen in 73% of patients, but only 3 patients had intellectual disability, which is less common than previously reported. Conclusion: ARCN1-related syndrome presents with a wide clinical spectrum ranging from a severe embryonic lethal syndrome to a mild syndrome with intrauterine growth restriction, micrognathia, and short stature without intellectual disability. Patients with ARCN1-related syndrome should be monitored for liver dysfunction during illness, cataracts, and hepatoblastoma. Additional research to further define the phenotypic spectrum and possible genotype–phenotype correlations are required.

    DOI: 10.1016/j.gim.2022.02.005

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  2. Case of ichthyosis with confetti caused by KRT10 mutation, complicated with multiple malignant melanomas

    Ito Yasutoshi, Takeichi Takuya, Nakagawa Koichi, Tanahashi Kana, Muro Yoshinao, Ogi Tomoo, Akiyama Masashi

    JOURNAL OF DERMATOLOGY     2022.3

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    Language:Japanese   Publishing type:Research paper (scientific journal)   Publisher:Journal of Dermatology  

    DOI: 10.1111/1346-8138.16348

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  3. Clinical practice guidelines for pseudoxanthoma elasticum (2017): Clinical Practice Guidelines for Pseudoxanthoma Elasticum Drafting Committee

    Iwanaga A, Utani A, Koike Y, Okubo Y, Kuwatsuka Y, Endo Y, Tanizaki H, Wataya-Kaneda M, Hatamochi A, Minaga K, Ogi T, Yamamoto Y, Ikeda S, Tsuiki E, Tamura H, Maemura K, Kitaoka T, Murota H

    The Journal of dermatology   Vol. 49 ( 3 ) page: e91 - e98   2022.3

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    DOI: 10.1111/1346-8138.16301

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  4. Mutations in SAM syndrome and palmoplantar keratoderma patients suggest genotype/phenotype correlations in DSG1 mutations

    Takeuchi S., Takeichi T., Koike Y., Takama H., Tanahashi K., Okuno Y., Ishii N., Muro Y., Ogi T., Suga Y., Akiyama M.

    JOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY AND VENEREOLOGY   Vol. 36 ( 3 ) page: E215 - E218   2022.3

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    Language:Japanese   Publishing type:Research paper (scientific journal)   Publisher:Journal of the European Academy of Dermatology and Venereology  

    DOI: 10.1111/jdv.17752

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  5. Epithelioid cell granuloma formation in CARD14-associated papulosquamous eruptions

    Takeichi T., Ikeda K., Muro Y., Ogi T., Morizane S., Akiyama M.

    JOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY AND VENEREOLOGY     2021.12

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    Language:Japanese   Publishing type:Research paper (scientific journal)   Publisher:Journal of the European Academy of Dermatology and Venereology  

    DOI: 10.1111/jdv.17890

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  6. Next-Generation Sequencing to Detect Pathogens in Pediatric Febrile Neutropenia: A Single-Center Retrospective Study of 112 Cases

    Kazuhiro Horiba, Yuka Torii, Toshihiko Okumura, Suguru Takeuchi, Takako Suzuki, Jun-ichi Kawada, Hideki Muramatsu, Yoshiyuki Takahashi, Tomoo Ogi, Yoshinori Ito

    Open Forum Infectious Diseases   Vol. 8 ( 11 ) page: ofab223   2021.11

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    Language:Japanese   Publishing type:Research paper (scientific journal)   Publisher:Oxford University Press (OUP)  

    <title>Abstract</title>
    <sec>
    <title>Background</title>
    Febrile neutropenia (FN) is a frequent complication in immunocompromised patients. However, causative microorganisms are detected in only 10% of patients. This study aimed to detect the microorganisms that cause FN using next-generation sequencing (NGS) to idenjpgy the genome derived from pathogenic microorganisms in the bloodstream. Here, we implemented a metagenomic approach to comprehensively analyze microorganisms present in clinical samples from patients with FN.


    </sec>
    <sec>
    <title>Methods</title>
    FN is defined as 1) a neutrophil count &amp;lt; 500/µL, and 2) fever ≥ 37.5 °C. Plasma/serum samples of 112 pediatric patients with FN, 10 patients with neutropenia without fever (NE), were sequenced by NGS and analyzed by a metagenomic pipeline PATHDET.


    </sec>
    <sec>
    <title>Results</title>
    The putative pathogens were detected by NGS in 5 of 10 patients with FN with positive for blood culture results, 15 of 87 patients (17%) with negative for blood culture results, and 3 of 8 patients with NE. Several bacteria that were common in the oral, skin, and gut flora were commonly detected in blood samples, suggesting translocation of the human microbiota to the bloodstream in the setting of neutropenia. The cluster analysis of the microbiota in blood samples using NGS demonstrated that the representative bacteria of each cluster was mostly consistent with the pathogens in each patient.


    </sec>
    <sec>
    <title>Conclusions</title>
    NGS technique has a great potential for detecting causative pathogens in patients with FN. Cluster analysis, which extracts characteristic microorganisms from a complex microbial population, may be effective to detect pathogens in minute quantities of microbiota, such as those from the bloodstream.


    </sec>

    DOI: 10.1093/ofid/ofab223

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  7. Extensive multiple organ involvement in VEXAS syndrome

    Noriyuki Takahashi, Takuya Takeichi, Tetsuya Nishida, Yasuhiro Takahashi, Juichi Sato, Masahiro Yamamura, Tomoo Ogi, Masashi Akiyama

    Arthritis & Rheumatology   Vol. 73 ( 10 ) page: 1896 - 1897   2021.10

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    Language:Japanese   Publishing type:Research paper (scientific journal)   Publisher:Wiley  

    DOI: 10.1002/art.41775

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  8. Dealing with transcription-blocking DNA damage: Repair mechanisms, RNA polymerase II processing and human disorders

    Jia Nan, Guo Chaowan, Nakazawa Yuka, Heuvel Diana van den, Luijsterburg Martijn S., Ogi Tomoo

    DNA REPAIR   Vol. 106   page: 103192   2021.10

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    Language:Japanese   Publishing type:Research paper (scientific journal)   Publisher:DNA Repair  

    Transcription-blocking DNA lesions (TBLs) in genomic DNA are triggered by a wide variety of DNA-damaging agents. Such lesions cause stalling of elongating RNA polymerase II (RNA Pol II) enzymes and fully block transcription when unresolved. The toxic impact of DNA damage on transcription progression is commonly referred to as transcription stress. In response to RNA Pol II stalling, cells activate and employ transcription-coupled repair (TCR) machineries to repair cytotoxic TBLs and resume transcription. Increasing evidence indicates that the modification and processing of stalled RNA Pol II is an integral component of the cellular response to and the repair of TBLs. If TCR pathways fail, the prolonged stalling of RNA Pol II will impede global replication and transcription as well as block the access of other DNA repair pathways that may act upon the TBL. Consequently, such prolonged stalling will trigger profound genome instability and devastating clinical features. In this review, we will discuss the mechanisms by which various types of TBLs are repaired by distinct TCR pathways and how RNA Pol II processing is regulated during these processes. We will also discuss the clinical consequences of transcription stress and genotype-phenotype correlations of related TCR-deficiency disorders.

    DOI: 10.1016/j.dnarep.2021.103192

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  9. Successful dupilumab treatment for ichthyotic and atopic features of Netherton syndrome

    Murase C., Takeichi T., Taki T., Yoshikawa T., Suzuki A., Ogi T., Suga Y., Akiyama M.

    JOURNAL OF INVESTIGATIVE DERMATOLOGY   Vol. 141 ( 10 ) page: S177 - S177   2021.10

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  10. Protein instability associated with AARS1 and MARS1 mutations causes trichothiodystrophy

    Botta Elena, Theil Arjan F., Raams Anja, Caligiuri Giuseppina, Giachetti Sarah, Bione Silvia, Accadia Maria, Lombardi Anita, Smith Desiree E. C., Mendes Marisa I, Swagemakers Sigrid M. A., Van der Spek Peter J., Salomons Gajja S., Hoeijmakers Jan H. J., Yesodharan Dhanya, Nampoothiri Sheela, Ogi Tomoo, Lehmann Alan R., Orioli Donata, Vermeulen Wim

    HUMAN MOLECULAR GENETICS   Vol. 30 ( 18 ) page: 1711 - 1720   2021.9

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    Language:Japanese   Publishing type:Research paper (scientific journal)   Publisher:Human Molecular Genetics  

    Trichothiodystrophy (TTD) is a rare hereditary neurodevelopmental disorder defined by sulfur-deficient brittle hair and nails and scaly skin, but with otherwise remarkably variable clinical features. The photosensitive TTD (PS-TTD) forms exhibits in addition to progressive neuropathy and other features of segmental accelerated aging and is associated with impaired genome maintenance and transcription. New factors involved in various steps of gene expression have been identified for the different non-photosensitive forms of TTD (NPS-TTD), which do not appear to show features of premature aging. Here, we identify alanyl-tRNA synthetase 1 and methionyl-tRNA synthetase 1 variants as new gene defects that cause NPS-TTD. These variants result in the instability of the respective gene products alanyl- and methionyl-tRNA synthetase. These findings extend our previous observations that TTD mutations affect the stability of the corresponding proteins and emphasize this phenomenon as a common feature of TTD. Functional studies in skin fibroblasts from affected individuals demonstrate that these new variants also impact on the rate of tRNA charging, which is the first step in protein translation. The extension of reduced abundance of TTD factors to translation as well as transcription redefines TTD as a syndrome in which proteins involved in gene expression are unstable.

    DOI: 10.1093/hmg/ddab123

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  11. Cutaneous malignant melanoma in an elderly patient with intermediate junctional epidermolysis bullosa. International journal

    Yuta Yamashita, Tomoki Taki, Takuya Takeichi, Mao Okumura, Shoichiro Mori, Yasutoshi Ito, Tomoo Ogi, Motohito Yamada, Masashi Akiyama

    The Journal of dermatology   Vol. 48 ( 8 ) page: E384 - E385   2021.8

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

    DOI: 10.1111/1346-8138.15951

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  12. The sodium-glucose cotransporter-2 inhibitor Tofogliflozin prevents the progression of nonalcoholic steatohepatitis-associated liver tumors in a novel murine model

    Yoshioka Naoki, Tanaka Miyako, Ochi Kozue, Watanabe Akiko, Ono Kenji, Sawada Makoto, Ogi Tomoo, Itoh Michiko, Ito Ayaka, Shiraki Yukihiro, Enomoto Atsushi, Ishigami Masatoshi, Fujishiro Mitsuhiro, Ogawa Yoshihiro, Suganami Takayoshi

    BIOMEDICINE & PHARMACOTHERAPY   Vol. 140   page: 111738   2021.8

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    Language:Japanese   Publishing type:Research paper (scientific journal)   Publisher:Biomedicine and Pharmacotherapy  

    Background: Diabetes and obesity contribute to the pathogenesis of nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). However, how diabetes and obesity accelerate liver tumorigenesis remains to be fully understood. Moreover, to verify the therapeutic potential of anti-diabetic drugs, there exists a strong need for appropriate animal models that recapitulate human pathophysiology of NASH and HCC. Methods: We established a novel murine model of NASH-associated liver tumors using genetically obese melanocortin 4 receptor-deficient mice fed on Western diet in combination with a chemical procarcinogen, and verified the validity of our model in evaluating drug efficacy. Findings: Our model developed multiple liver tumors together with obesity, diabetes, and NASH within a relatively short period (approximately 3 months). In this model, sodium glucose cotransporter 2 inhibitor Tofogliflozin prevented the development of NASH-like liver phenotypes and the progression of liver tumors. Tofogliflozin attenuated p21 expression of hepatocytes in non-tumorous lesions in the liver. Interpretation: Tofogliflozin treatment attenuates cellular senescence of hepatocytes under obese and diabetic conditions. This study provides a unique animal model of NASH-associated liver tumors, which is applicable for assessing drug efficacy to prevent or treat NASH-associated HCC.

    DOI: 10.1016/j.biopha.2021.111738

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  13. Updated allele frequencies of SERPINB7 founder mutations in Asian patients with Nagashima-type palmoplantar keratosis/keratoderma

    Yasutoshi Ito, Takuya Takeichi, Kenta Ikeda, Kana Tanahashi, Takenori Yoshikawa, Yuya Murase, Yoshinao Muro, Yoshio Kawakami, Yasuo Nakamura, Kanako Matsuyama, Jun Muto, Naoki Oiso, Shin Morizane, Kazumitsu Sugiura, Yasushi Suga, Mariko Seishima, Akira Kawada, Tomoo Ogi, Masashi Akiyama

    Journal of Dermatological Science   Vol. 103 ( 2 ) page: 116 - 119   2021.8

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    Language:Japanese   Publishing type:Research paper (scientific journal)   Publisher:Elsevier BV  

    DOI: 10.1016/j.jdermsci.2021.06.002

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  14. Paradoxical Reaction in a Patient with Hidradenitis Suppurativa Undergoing Adalimumab Treatment. International journal

    Soichiro Ikeya, Takuya Takeichi, Tomoki Taki, Yoshinao Muro, Tomoo Ogi, Masashi Akiyama

    Acta dermato-venereologica   Vol. 101 ( 6 ) page: adv00484   2021.6

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    DOI: 10.2340/00015555-3844

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  15. Pediatric sepsis cases diagnosed with group B streptococcal meningitis using next-generation sequencing: a report of two cases

    Horiba Kazuhiro, Suzuki Michio, Tetsuka Nobuyuki, Kawano Yoshihiko, Yamaguchi Makoto, Okumura Toshihiko, Suzuki Takako, Torii Yuka, Kawada Jun-ichi, Morita Makoto, Hara Shinya, Ogi Tomoo, Ito Yoshinori

    BMC INFECTIOUS DISEASES   Vol. 21 ( 1 ) page: 531   2021.6

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    Language:Japanese   Publishing type:Research paper (scientific journal)   Publisher:BMC Infectious Diseases  

    Background: Group B Streptococcus (GBS) is an important cause of invasive infection in neonates and infants. Cerebrospinal fluid (CSF) findings and culture may not show evidence of infection early in GBS meningitis. Next-generation sequencing (NGS) has the potential to detect microbial genetic material in patients with infectious diseases. We report two cases of infantile sepsis of GBS meningitis with negative results for CSF culture tests, but positive results for NGS analysis. Case presentation: Patient 1 was a 22-day-old male infant diagnosed with sepsis and meningitis. His CSF findings showed pleocytosis, decreased glucose, and increased protein levels. However, CSF and blood culture results at admission were negative. He received a total of 3 weeks of treatment with ampicillin and cefotaxime, and showed clinical improvement. GBS was detected through NGS analysis of CSF collected at admission. Patient 2 was a 51-day-old male infant with sepsis. CSF findings on admission were normal, and blood and CSF cultures were also negative. Intravenous ampicillin and cefotaxime treatment were initiated. Treatment was de-escalated to ampicillin alone because Enterococcus faecalis was cultured from urine. He was discharged after a total of 1 week of antibiotic treatment. Six days after discharge, he was re-hospitalized for sepsis. Blood and CSF cultures were negative, and E. faecalis was again cultured from urine. He received a total of 3 weeks of ampicillin treatment for enterococcal-induced nephritis and did not relapse thereafter. NGS pathogen searches were retrospectively performed on both blood and CSF collected at the first and second admission. GBS was detected in the CSF collected at the first admission, but no significant pathogen was detected in the other samples. Inadequate treatment for GBS meningitis at the first admission may have caused the recurrence of the disease. Conclusion: Infantile sepsis may present bacterial meningitis that is not diagnosed by either culture testing or CSF findings. NGS analysis for CSF may be useful for confirming the diagnosis of bacterial meningitis.

    DOI: 10.1186/s12879-021-06231-3

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  16. Predominant cellular mitochondrial dysfunction in the TOP3A gene-caused Bloom syndrome-like disorder

    Jiang Wenjun, Jia Nan, Guo Chaowan, Wen Juan, Wu Lingqian, Ogi Tomoo, Zhang Huiwen

    BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE   Vol. 1867 ( 6 ) page: 166106   2021.6

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    Language:Japanese   Publishing type:Research paper (scientific journal)   Publisher:Biochimica et Biophysica Acta - Molecular Basis of Disease  

    TOP3A promotes processing of double Holliday junction dissolution and also plays an important role in decatenation and segregation of human mtDNA. Recently, TOP3A mutations have been reported to cause Bloom syndrome-like disorder. However, whether the two function play equal roles in the disease pathogenesis is unclear. We retrospectively studied the disease progression of two siblings with Bloom-like syndrome caused by two novel mutations of TOP3A, p.Q788* and p.D479G. Beside the common clinical manifestations, our patients exhibited liver lipid storage with hepatomegaly. In cellular and molecular biological studies, TOP3A deficiency moderately increased sister chromatid exchanges and decreased cell proliferation compared with BLM or RMI2 deficiency. These changes were rescued by ectopic expression of either of the wildtype TOP3A or TOP3A-D479G. In contrast, reduced mitochondrial ATP generation and oxygen consumption rates observed in TOP3A defective cells were rescued by over-expression of the wildtype TOP3A, but not TOP3A-D479G. Considering the different impact of the TOP3A-D479G mutation on the genome stability and mitochondrial metabolism, we propose that the impaired mitochondrial metabolism plays an important role in the pathogenesis of TOP3A-deficient Bloom-like disease.

    DOI: 10.1016/j.bbadis.2021.166106

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  17. Hereditary Mucoepithelial Dysplasia and Autosomal-Dominant IFAP Syndrome Is a Clinical Spectrum Due to SREBF1 Variants. International journal

    Chiaki Murase, Takuya Takeichi, Toshifumi Nomura, Tomoo Ogi, Masashi Akiyama

    The Journal of investigative dermatology   Vol. 141 ( 6 ) page: 1596 - 1598   2021.6

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    DOI: 10.1016/j.jid.2020.09.035

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  18. ELOF1 is a transcription-coupled DNA repair factor that directs RNA polymerase II ubiquitylation

    van der Weegen Yana, de Lint Klaas, van den Heuvel Diana, Nakazawa Yuka, Mevissen Tycho E. T., van Schie Janne J. M., San Martin Alonso Marta, Boer Daphne E. C., Gonzalez-Prieto Roman, Narayanan Ishwarya V., Klaassen Noud H. M., Wondergem Annelotte P., Roohollahi Khashayar, Dorsman Josephine C., Hara Yuichiro, Vertegaal Alfred C. O., de Lange Job, Walter Johannes C., Noordermeer Sylvie M., Ljungman Mats, Ogi Tomoo, Wolthuis Rob M. F., Luijsterburg Martijn S.

    NATURE CELL BIOLOGY   Vol. 23 ( 6 ) page: 595 - 607   2021.6

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    Language:Japanese   Publishing type:Research paper (scientific journal)   Publisher:Nature Cell Biology  

    Cells employ transcription-coupled repair (TCR) to eliminate transcription-blocking DNA lesions. DNA damage-induced binding of the TCR-specific repair factor CSB to RNA polymerase II (RNAPII) triggers RNAPII ubiquitylation of a single lysine (K1268) by the CRL4CSA ubiquitin ligase. How CRL4CSA is specifically directed towards K1268 is unknown. Here, we identify ELOF1 as the missing link that facilitates RNAPII ubiquitylation, a key signal for the assembly of downstream repair factors. This function requires its constitutive interaction with RNAPII close to K1268, revealing ELOF1 as a specificity factor that binds and positions CRL4CSA for optimal RNAPII ubiquitylation. Drug–genetic interaction screening also revealed a CSB-independent pathway in which ELOF1 prevents R-loops in active genes and protects cells against DNA replication stress. Our study offers key insights into the molecular mechanisms of TCR and provides a genetic framework of the interplay between transcriptional stress responses and DNA replication.

    DOI: 10.1038/s41556-021-00688-9

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  19. MEDNIK-like syndrome due to compound heterozygous mutations in AP1B1

    Ito Y., Takeichi T., Igari S., Mori T., Ono A., Suyama K., Takeuchi S., Muro Y., Ogi T., Hosoya M., Yamamoto T., Akiyama M.

    JOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY AND VENEREOLOGY   Vol. 35 ( 5 ) page: E345 - E347   2021.5

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    Language:Japanese   Publishing type:Research paper (scientific journal)   Publisher:Journal of the European Academy of Dermatology and Venereology  

    DOI: 10.1111/jdv.17098

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  20. Transcription-Coupled DNA Repair: From Mechanism to Human Disorder

    van den Heuvel Diana, van der Weegen Yana, Boer Daphne E. C., Ogi Tomoo, Luijsterburg Martijn S.

    TRENDS IN CELL BIOLOGY   Vol. 31 ( 5 ) page: 359 - 371   2021.5

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    Language:Japanese   Publishing type:Research paper (scientific journal)   Publisher:Trends in Cell Biology  

    DNA lesions pose a major obstacle during gene transcription by RNA polymerase II (RNAPII) enzymes. The transcription-coupled DNA repair (TCR) pathway eliminates such DNA lesions. Inherited defects in TCR cause severe clinical syndromes, including Cockayne syndrome (CS). The molecular mechanism of TCR and the molecular origin of CS have long remained enigmatic. Here we explore new advances in our understanding of how TCR complexes assemble through cooperative interactions between repair factors stimulated by RNAPII ubiquitylation. Mounting evidence suggests that RNAPII ubiquitylation activates TCR complex assembly during repair and, in parallel, promotes processing and degradation of RNAPII to prevent prolonged stalling. The fate of stalled RNAPII is therefore emerging as a crucial link between TCR and associated human diseases.

    DOI: 10.1016/j.tcb.2021.02.007

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  21. Successful dupilumab treatment for ichthyotic and atopic features of Netherton syndrome. International journal

    Chiaki Murase, Takuya Takeichi, Tomoki Taki, Takenori Yoshikawa, Akiko Suzuki, Tomoo Ogi, Yasushi Suga, Masashi Akiyama

    Journal of dermatological science   Vol. 102 ( 2 ) page: 126 - 129   2021.5

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

    DOI: 10.1016/j.jdermsci.2021.03.003

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  22. Odontogenic keratocysts are an important clue for diagnosing basal cell nevus syndrome.

    Kaori Kaibuchi-Ando, Takuya Takeichi, Yasutoshi Ito, So Takeuchi, Yuta Yamashita, Motohito Yamada, Yoshinao Muro, Tomoo Ogi, Masashi Akiyama

    Nagoya journal of medical science   Vol. 83 ( 2 ) page: 393 - 396   2021.5

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

    Basal cell nevus syndrome (BCNS) is an autosomal dominant skin disorder characterized by multiple basal cell nevi. Patients with BCNS tend to develop basal cell carcinoma (BCC) and frequently show skeletal abnormalities. Most cases of BCNS are caused by mutations in patched 1 (PTCH1). PTCH1 encodes a transmembrane receptor protein for the secreted molecule sonic hedgehog, which plays a key role in the development of animals ranging from insects to mammals. We analyzed two Japanese BCNS patients from two independent families. Both of our patients had multiple jaw keratocysts. In one patient, these were the key to noticing his BCNS, as he had no skin tumors. The early detection of PTCH1 mutations would enable BCNS patients to be carefully followed up for the occurrence of BCC. The diagnosis of BCC at the early stage leads to prompt surgical treatments, resulting in a good prognosis. The present cases suggest that keratocysts of the jaw might be an important clue for diagnosing BCNS.

    DOI: 10.18999/nagjms.83.2.393

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  23. [A case of Charcot-Marie-Tooth disease type 2Z caused by MORC2 S87L mutation mimicking spinal muscular atrophy].

    Yamamoto D, Oda R, Hisahara S, Ishikawa A, Ogi T, Shimohama S

    Rinsho shinkeigaku = Clinical neurology   Vol. 61 ( 4 ) page: 262 - 264   2021.4

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    Language:Japanese   Publishing type:Research paper (scientific journal)   Publisher:Clinical Neurology  

    A 33-year-old man with an unremarkable family history has had limb muscle weakness, joint contracture and skeleton deformation from early childhood. He was diagnosed with spinal muscular atrophy (SMA) by a pediatrician. He needed assistance and used orthoses in his daily life. There was no subjective sensory disturbance. However, physical examination showed slight sensory impairment, and nerve conduction study indicated sensory motor axonal neuropathy. This finding suggested Charcot-Marie-Tooth disease (CMT). Gene analysis detected MORC2 S87L mutation, leading to a diagnosis of CMT type 2Z. Patients with MORC2 S87L mutation are known to exhibit a severe phenotype, and may mimic SMA. It is important to demonstrate subclinical sensory neuropathy in patients with MORC2 S87L mutation mimicking SMA.

    DOI: 10.5692/clinicalneurol.cn-001542

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  24. Temporal dynamics of the plasma microbiome in recipients at early post-liver transplantation: a retrospective study

    Okumura Toshihiko, Horiba Kazuhiro, Kamei Hideya, Takeuchi Suguru, Suzuki Takako, Torii Yuka, Kawada Jun-ichi, Takahashi Yoshiyuki, Ogura Yasuhiro, Ogi Tomoo, Ito Yoshinori

    BMC MICROBIOLOGY   Vol. 21 ( 1 ) page: 104   2021.4

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    Language:Japanese   Publishing type:Research paper (scientific journal)   Publisher:BMC Microbiology  

    Background: Immunosuppression during liver transplantation (LT) enables the prevention and treatment of organ rejection but poses a risk for severe infectious diseases. Immune modulation and antimicrobials affect the plasma microbiome. Thus, determining the impact of immunosuppression on the microbiome may be important to understand immunocompetence, elucidate the source of infection, and predict the risk of infection in LT recipients. We characterized the plasma microbiome of LT recipients at early post-LT and assessed the association between the microbiome and clinical events. Results: In this study, 51 patients who received LT at Nagoya University Hospital from 2016 to 2018 were enrolled. Plasma samples were retrospectively collected at the following time points: 1) within a week after LT; 2) 4 ± 1 weeks after LT; 3) 8 ± 1 weeks after LT; and 4) within 2 days after a positive blood culture. A total of 111 plasma samples were analyzed using shotgun next-generation sequencing (NGS) with the PATHDET pipeline. Relative abundance of Anelloviridae, Nocardiaceae, Microbacteriaceae, and Enterobacteriaceae significantly changed during the postoperative period. Microbiome diversity was higher within a week after LT than that at 8 weeks after LT. Antimicrobials were significantly associated with the microbiome of LT recipients. In addition, the proportion of Enterobacteriaceae was significantly increased and the plasma microbiome diversity was significantly lower in patients with acute cellular rejection (ACR) than non-ACR patients. Sequencing reads of bacteria isolated from blood cultures were predominantly identified by NGS in 8 of 16 samples, and human herpesvirus 6 was detected as a causative pathogen in one recipient with severe clinical condition. Conclusions: The metagenomic NGS technique has great potential in revealing the plasma microbiome and is useful as a comprehensive diagnostic procedure in clinical settings. Temporal dynamics of specific microorganisms may be used as indirect markers for the determination of immunocompetence and ACR in LT recipients.

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  25. The wide-ranging clinical and genetic features in Japanese families with valosin-containing protein proteinopathy. International journal

    Takashi Ando, Ryoichi Nakamura, Satoshi Kuru, Daichi Yokoi, Naoki Atsuta, Haruki Koike, Masashi Suzuki, Kazuhiro Hara, Yohei Iguchi, Yumiko Harada, Yusuke Yoshida, Makoto Hattori, Ayuka Murakami, Seiya Noda, Seigo Kimura, Jun Sone, Tomohiko Nakamura, Yoji Goto, Kazuo Mano, Hisashi Okada, Satoshi Okuda, Ichizo Nishino, Tomoo Ogi, Gen Sobue, Masahisa Katsuno

    Neurobiology of aging   Vol. 100   page: 120.e1 - 120.e6   2021.4

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    Mutations in the valosin-containing protein (VCP) gene are known to cause various neurodegenerative disorders. Here, we report 8 Japanese patients [6 men, 2 women; median age at onset: 49.5 (range, 35-58) years] from 5 unrelated families with VCP missense mutations. Although 7 of 8 patients were diagnosed with either inclusion body myopathy or amyotrophic lateral sclerosis, 1 patient showed demyelinating polyneuropathy, which was confirmed by longitudinal nerve conduction studies. Sural nerve biopsy of the patient revealed intranuclear ubiquitin staining in Schwann cells. Three known pathogenic VCP mutations (p.Arg191Gln, p.Arg155Cys, and p.Ile126Phe) were detected. A novel mutation, c.293 A>T (p.Asp98Val), was also identified in a patient with amyotrophic lateral sclerosis and frontotemporal dementia. This mutation was predicted to be "deleterious" or "disease causing" using in silico mutation analyses. In conclusion, demyelinating polyneuropathy may be a novel phenotype caused by VCP mutations. The p.Asp98Val mutation was found to be a novel pathogenic mutation of VCP proteinopathy. We believe our cases represent a wide clinical spectrum of VCP mutations.

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  26. Two Cases of Porokeratosis with MVD Mutations, in Association with Bullous Pemphigoid. International journal

    Yuki Arisawa, Yasutoshi Ito, Kana Tanahashi, Yoshinao Muro, Tomoo Ogi, Takuya Takeichi, Masashi Akiyama

    Acta dermato-venereologica   Vol. 101 ( 3 ) page: adv00423   2021.3

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  27. Identification of a novel causative mutation in KRT1 in diffuse palmoplantar keratoderma, facilitated by whole-exome sequencing. International journal

    So Takeuchi, Takuya Takeichi, Yasutoshi Ito, Kana Tanahashi, Yoshinao Muro, Tomoo Ogi, Masashi Akiyama

    European journal of dermatology : EJD   Vol. 31 ( 2 ) page: 264 - 265   2021.3

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  28. Microglial gene signature reveals loss of homeostatic microglia associated with neurodegeneration of Alzheimer's disease. International journal

    Akira Sobue, Okiru Komine, Yuichiro Hara, Fumito Endo, Hiroyuki Mizoguchi, Seiji Watanabe, Shigeo Murayama, Takashi Saito, Takaomi C Saido, Naruhiko Sahara, Makoto Higuchi, Tomoo Ogi, Koji Yamanaka

    Acta neuropathologica communications   Vol. 9 ( 1 ) page: 1 - 1   2021.1

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    Microglia-mediated neuroinflammation has been implicated in the pathogenesis of Alzheimer's disease (AD). Although microglia in aging and neurodegenerative disease model mice show a loss of homeostatic phenotype and activation of disease-associated microglia (DAM), a correlation between those phenotypes and the degree of neuronal cell loss has not been clarified. In this study, we performed RNA sequencing of microglia isolated from three representative neurodegenerative mouse models, AppNL-G-F/NL-G-F with amyloid pathology, rTg4510 with tauopathy, and SOD1G93A with motor neuron disease by magnetic activated cell sorting. In parallel, gene expression patterns of the human precuneus with early Alzheimer's change (n = 11) and control brain (n = 14) were also analyzed by RNA sequencing. We found that a substantial reduction of homeostatic microglial genes in rTg4510 and SOD1G93A microglia, whereas DAM genes were uniformly upregulated in all mouse models. The reduction of homeostatic microglial genes was correlated with the degree of neuronal cell loss. In human precuneus with early AD pathology, reduced expression of genes related to microglia- and oligodendrocyte-specific markers was observed, although the expression of DAM genes was not upregulated. Our results implicate a loss of homeostatic microglial function in the progression of AD and other neurodegenerative diseases. Moreover, analyses of human precuneus also suggest loss of microglia and oligodendrocyte functions induced by early amyloid pathology in human.

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  29. Expanding the phenotype of biallelic loss-of-function variants in theNSUN2gene: Description of four individuals with juvenile cataract, chronic nephritis, or brain anomaly as novel complications

    Kato Kohji, Mizuno Seiji, Morton Jenny, Toyama Miho, Hara Yuichiro, Wasmer Evangeline, Lehmann Alan, Ogi Tomoo

    AMERICAN JOURNAL OF MEDICAL GENETICS PART A   Vol. 185 ( 1 ) page: 282 - 285   2021.1

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  30. Digenic mutations in ALDH2 and ADH5 impair formaldehyde clearance and cause a multisystem disorder, AMeD syndrome

    Yasuyoshi Oka, Motoharu Hamada, Yuka Nakazawa, Hideki Muramatsu, Yusuke Okuno, Koichiro Higasa, Mayuko Shimada, Honoka Takeshima, Katsuhiro Hanada, Taichi Hirano, Toshiro Kawakita, Hirotoshi Sakaguchi, Takuya Ichimura, Shuichi Ozono, Kotaro Yuge, Yoriko Watanabe, Yuko Kotani, Mutsumi Yamane, Yumiko Kasugai, Miyako Tanaka, Takayoshi Suganami, Shinichiro Nakada, Norisato Mitsutake, Yuichiro Hara, Kohji Kato, Seiji Mizuno, Noriko Miyake, Yosuke Kawai, Katsushi Tokunaga, Masao Nagasaki, Seiji Kito, Keiichi Isoyama, Masafumi Onodera, Hideo Kaneko, Naomichi Matsumoto, Fumihiko Matsuda, Keitaro Matsuo, Yoshiyuki Takahashi, Tomoji Mashimo, Seiji Kojima, Tomoo Ogi

    Science Advances   Vol. 6 ( 51 ) page: eabd7197 - eabd7197   2020.12

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    Rs671 in the aldehyde dehydrogenase 2 gene (<italic>ALDH2</italic>) is the cause of Asian alcohol flushing response after drinking. ALDH2 detoxifies endogenous aldehydes, which are the major source of DNA damage repaired by the Fanconi anemia pathway. Here, we show that the rs671 defective allele in combination with mutations in the alcohol dehydrogenase 5 gene, which encodes formaldehyde dehydrogenase (<italic>ADH5<sup>FDH</sup></italic>), causes a previously unidentified disorder, AMeD (aplastic anemia, mental retardation, and dwarfism) syndrome. Cellular studies revealed that a decrease in the formaldehyde tolerance underlies a loss of differentiation and proliferation capacity of hematopoietic stem cells. Moreover, <italic>Adh5<sup>−/−</sup>Aldh2</italic><sup>E506K/E506K</sup> double-deficient mice recapitulated key clinical features of AMeDS, showing short life span, dwarfism, and hematopoietic failure. Collectively, our results suggest that the combined deficiency of formaldehyde clearance mechanisms leads to the complex clinical features due to overload of formaldehyde-induced DNA damage, thereby saturation of DNA repair processes.

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  31. Astrocytic phagocytosis is a compensatory mechanism for microglial dysfunction. International journal

    Hiroyuki Konishi, Takayuki Okamoto, Yuichiro Hara, Okiru Komine, Hiromi Tamada, Mitsuyo Maeda, Fumika Osako, Masaaki Kobayashi, Akira Nishiyama, Yosky Kataoka, Toshiyuki Takai, Nobuyuki Udagawa, Steffen Jung, Keiko Ozato, Tomohiko Tamura, Makoto Tsuda, Koji Yamanaka, Tomoo Ogi, Katsuaki Sato, Hiroshi Kiyama

    The EMBO journal   Vol. 39 ( 22 ) page: e104464   2020.11

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    Microglia are the principal phagocytes that clear cell debris in the central nervous system (CNS). This raises the question, which cells remove cell debris when microglial phagocytic activity is impaired. We addressed this question using Siglechdtr mice, which enable highly specific ablation of microglia. Non-microglial mononuclear phagocytes, such as CNS-associated macrophages and circulating inflammatory monocytes, did not clear microglial debris. Instead, astrocytes were activated, exhibited a pro-inflammatory gene expression profile, and extended their processes to engulf microglial debris. This astrocytic phagocytosis was also observed in Irf8-deficient mice, in which microglia were present but dysfunctional. RNA-seq demonstrated that even in a healthy CNS, astrocytes express TAM phagocytic receptors, which were the main astrocytic phagocytic receptors for cell debris in the above experiments, indicating that astrocytes stand by in case of microglial impairment. This compensatory mechanism may be important for the maintenance or prolongation of a healthy CNS.

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  32. A heterozygous SERPINB7 mutation is a possible modifying factor for epidermolytic palmoplantar keratoderma. International journal

    Takenori Yoshikawa, Takuya Takeichi, Tomoo Ogi, Yasushi Suga, Yoshinao Muro, Masashi Akiyama

    Journal of dermatological science   Vol. 100 ( 2 ) page: 148 - 151   2020.11

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    DOI: 10.1016/j.jdermsci.2020.05.001

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  33. Comprehensive pathogen detection in sera of Kawasaki disease patients by high-throughput sequencing: a retrospective exploratory study

    Torii Yuka, Horiba Kazuhiro, Hayano Satoshi, Kato Taichi, Suzuki Takako, Kawada Jun-ichi, Takahashi Yoshiyuki, Kojima Seiji, Okuno Yusuke, Ogi Tomoo, Ito Yoshinori

    BMC PEDIATRICS   Vol. 20 ( 1 ) page: 482   2020.10

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    DOI: 10.1186/s12887-020-02380-7

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  34. Gene Expression Profile at the Motor Endplate of the Neuromuscular Junction of Fast-Twitch Muscle. International journal

    Kun Huang, Jin Li, Mikako Ito, Jun-Ichi Takeda, Bisei Ohkawara, Tomoo Ogi, Akio Masuda, Kinji Ohno

    Frontiers in molecular neuroscience   Vol. 13   page: 154 - 154   2020.9

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    The neuromuscular junction (NMJ) is a prototypic chemical synapse between the spinal motor neuron and the motor endplate. Gene expression profiles of the motor endplate are not fully elucidated. Collagen Q (ColQ) is a collagenic tail subunit of asymmetric forms of acetylcholinesterase and is driven by two distinct promoters. pColQ1 is active throughout the slow-twitch muscle, whereas pColQ1a is active at the motor endplate of fast-twitch muscle. We made a transgenic mouse line that expresses nuclear localization signal (NLS)-attached Cre recombinase under the control of pColQ1a (pColQ1a-Cre mouse). RiboTag mouse expresses an HA-tagged ribosomal subunit, RPL22, in cells expressing Cre recombinase. We generated pColQ1a-Cre:RiboTag mouse, and confirmed that HA-tagged RPL22 was enriched at the NMJ of tibialis anterior (TA) muscle. Next, we confirmed that Chrne and Musk that are specifically expressed at the NMJ were indeed enriched in HA-immunoprecipitated (IP) RNA, whereas Sox10 and S100b, markers for Schwann cells, and Icam1, a marker for vascular endothelial cells, and Pax3, a marker for muscle satellite cells, were scarcely detected. Gene set enrichment analysis (GSEA) of RNA-seq data showed that "phosphatidylinositol signaling system" and "extracellular matrix receptor interaction" were enriched at the motor endplate. Subsequent analysis revealed that genes encoding diacylglycerol kinases, phosphatidylinositol kinases, phospholipases, integrins, and laminins were enriched at the motor endplate. We first characterized the gene expression profile under translation at the motor endplate of TA muscle using the RiboTag technique. We expect that our gene expression profiling will help elucidate molecular mechanisms of the development, maintenance, and pathology of the NMJ.

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  35. NUS1 mutation in a family with epilepsy, cerebellar ataxia, and tremor. Reviewed International journal

    Kunihiko Araki, Ryoichi Nakamura, Daisuke Ito, Kohji Kato, Yohei Iguchi, Kentaro Sahashi, Miho Toyama, Kensuke Hamada, Nobuhiko Okamoto, Yoshinao Wada, Tomohiko Nakamura, Tomoo Ogi, Masahisa Katsuno

    Epilepsy research   Vol. 164   page: 106371 - 106371   2020.8

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    We report on familial 5 epilepsy patients with autosomal dominant inheritance of a novel heterozygous NUS1 frameshift mutation. All patients had cerebellar ataxia and tremor. Three patients were diagnosed with childhood absence epilepsy, 1 patient with generalized epilepsy, and 1 patient with parkinsonism without epilepsy. Our cases and previously reported cases with deletions of chromosome 6q22 that include NUS1 share these common symptoms. In a cellular experiment, NUS1 mutation led to a substantial reduction of the protein level of NUS1. NUS1 mutation could contribute to epilepsy pathogenesis and also constitute a distinct syndromic entity with cerebellar ataxia and tremor.

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  36. Topoisomerase I-driven repair of UV-induced damage in NER-deficient cells. Reviewed International journal

    Liton Kumar Saha, Mitsuo Wakasugi, Salma Akter, Rajendra Prasad, Samuel H Wilson, Naoto Shimizu, Hiroyuki Sasanuma, Shar-Yin Naomi Huang, Keli Agama, Yves Pommier, Tsukasa Matsunaga, Kouji Hirota, Shigenori Iwai, Yuka Nakazawa, Tomoo Ogi, Shunichi Takeda

    Proceedings of the National Academy of Sciences of the United States of America   Vol. 117 ( 25 ) page: 14412 - 14420   2020.6

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    Nucleotide excision repair (NER) removes helix-destabilizing adducts including ultraviolet (UV) lesions, cyclobutane pyrimidine dimers (CPDs), and pyrimidine (6-4) pyrimidone photoproducts (6-4PPs). In comparison with CPDs, 6-4PPs have greater cytotoxicity and more strongly destabilizing properties of the DNA helix. It is generally believed that NER is the only DNA repair pathway that removes the UV lesions as evidenced by the previous data since no repair of UV lesions was detected in NER-deficient skin fibroblasts. Topoisomerase I (TOP1) constantly creates transient single-strand breaks (SSBs) releasing the torsional stress in genomic duplex DNA. Stalled TOP1-SSB complexes can form near DNA lesions including abasic sites and ribonucleotides embedded in chromosomal DNA. Here we show that base excision repair (BER) increases cellular tolerance to UV independently of NER in cancer cells. UV lesions irreversibly trap stable TOP1-SSB complexes near the UV damage in NER-deficient cells, and the resulting SSBs activate BER. Biochemical experiments show that 6-4PPs efficiently induce stable TOP1-SSB complexes, and the long-patch repair synthesis of BER removes 6-4PPs downstream of the SSB. Furthermore, NER-deficient cancer cell lines remove 6-4PPs within 24 h, but not CPDs, and the removal correlates with TOP1 expression. NER-deficient skin fibroblasts weakly express TOP1 and show no detectable repair of 6-4PPs. Remarkably, the ectopic expression of TOP1 in these fibroblasts led them to completely repair 6-4PPs within 24 h. In conclusion, we reveal a DNA repair pathway initiated by TOP1, which significantly contributes to cellular tolerance to UV-induced lesions particularly in malignant cancer cells overexpressing TOP1.

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  37. InMeRF: prediction of pathogenicity of missense variants by individual modeling for each amino acid substitution

    Jun-ichi Takeda, Kentaro Nanatsue, Ryosuke Yamagishi, Mikako Ito, Nobuhiko Haga, Hiromi Hirata, Tomoo Ogi, Kinji Ohno

    NAR Genomics and Bioinformatics   Vol. 2 ( 2 ) page: lqaa038   2020.6

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    <title>Abstract</title>
    In predicting the pathogenicity of a nonsynonymous single-nucleotide variant (nsSNV), a radical change in amino acid properties is prone to be classified as being pathogenic. However, not all such nsSNVs are associated with human diseases. We generated random forest (RF) models individually for each amino acid substitution to differentiate pathogenic nsSNVs in the Human Gene Mutation Database and common nsSNVs in dbSNP. We named a set of our models ‘Individual Meta RF’ (InMeRF). Ten-fold cross-validation of InMeRF showed that the areas under the curves (AUCs) of receiver operating characteristic (ROC) and precision–recall curves were on average 0.941 and 0.957, respectively. To compare InMeRF with seven other tools, the eight tools were generated using the same training dataset, and were compared using the same three testing datasets. ROC-AUCs of InMeRF were ranked first in the eight tools. We applied InMeRF to 155 pathogenic and 125 common nsSNVs in seven major genes causing congenital myasthenic syndromes, as well as in VANGL1 causing spina bifida, and found that the sensitivity and specificity of InMeRF were 0.942 and 0.848, respectively. We made the InMeRF web service, and also made genome-wide InMeRF scores available online (https://www.med.nagoya-u.ac.jp/neurogenetics/InMeRF/).

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  38. Ubiquitination of DNA Damage-Stalled RNAPII Promotes Transcription-Coupled Repair. Reviewed International journal

    Yuka Nakazawa, Yuichiro Hara, Yasuyoshi Oka, Okiru Komine, Diana van den Heuvel, Chaowan Guo, Yasukazu Daigaku, Mayu Isono, Yuxi He, Mayuko Shimada, Kana Kato, Nan Jia, Satoru Hashimoto, Yuko Kotani, Yuka Miyoshi, Miyako Tanaka, Akira Sobue, Norisato Mitsutake, Takayoshi Suganami, Akio Masuda, Kinji Ohno, Shinichiro Nakada, Tomoji Mashimo, Koji Yamanaka, Martijn S Luijsterburg, Tomoo Ogi

    Cell   Vol. 180 ( 6 ) page: 1228 - +   2020.3

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    Transcription-coupled nucleotide excision repair (TC-NER) is initiated by the stalling of elongating RNA polymerase II (RNAPIIo) at DNA lesions. The ubiquitination of RNAPIIo in response to DNA damage is an evolutionarily conserved event, but its function in mammals is unknown. Here, we identified a single DNA damage-induced ubiquitination site in RNAPII at RPB1-K1268, which regulates transcription recovery and DNA damage resistance. Mechanistically, RPB1-K1268 ubiquitination stimulates the association of the core-TFIIH complex with stalled RNAPIIo through a transfer mechanism that also involves UVSSA-K414 ubiquitination. We developed a strand-specific ChIP-seq method, which revealed RPB1-K1268 ubiquitination is important for repair and the resolution of transcriptional bottlenecks at DNA lesions. Finally, RPB1-K1268R knockin mice displayed a short life-span, premature aging, and neurodegeneration. Our results reveal RNAPII ubiquitination provides a two-tier protection mechanism by activating TC-NER and, in parallel, the processing of DNA damage-stalled RNAPIIo, which together prevent prolonged transcription arrest and protect against neurodegeneration.

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  39. Severe achondroplasia due to two de novo variants in the transmembrane domain of FGFR3 on the same allele: A case report. Reviewed International journal

    Tadashi Nagata, Masaki Matsushita, Kenichi Mishima, Yasunari Kamiya, Kohji Kato, Miho Toyama, Tomoo Ogi, Naoki Ishiguro, Hiroshi Kitoh

    Molecular genetics & genomic medicine   Vol. 8 ( 3 ) page: e1148   2020.3

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    BACKGROUND: Achondroplasia (ACH), the most common form of short-limbed skeletal dysplasia, is caused by gain-of-function mutations in the fibroblast growth factor receptor 3 (FGFR3) gene. More than 97% of patients result from a heterozygous p.G380R mutation in the FGFR3 gene. We present here a child who had two de novo variants in the FGFR3 on the same allele, a common p.G380R mutation and a novel p.S378N variant. METHODS: A 3-year-old Japanese girl born from non-consanguineous healthy parents showed more severe clinical and radiological phenotypes than classic ACH, including severe short-limbed short stature with marked ossification defects in the metaphysis and epiphysis, hydrocephalus and cervicomedullary compression due to foramen magnum stenosis, prolonged pulmonary hypoplasia, and significant delay in the gross motor development. Genomic DNA was extracted from the proband and whole-exome sequencing was performed. The variants were subsequently confirmed by Sanger sequencing. RESULTS: Mutation analysis demonstrated that the proband had p.S378N (c.1133G>A) and p.G380R (c.1138G>A) variants in the FGFR3 gene. Both variants were not detected in her parents and therefore considered de novo. An allele-specific PCR was developed in order to determine whether these mutations were on the same allele (cis) or on different alleles (trans). The c.1138G>A mutation was found in the PCR product generated with the primer for the mutant 1133A, but it was not detected in the product with the wild-type 1133G, confirming that p.S378N and p.G380R variants were located on the same allele (cis). CONCLUSION: This is the second case who had two FGFR3 variants in the transmembrane domain on the same allele. The p.S378N variant may provide an additive effect on the activating receptor with the p.G380R mutation and alter the protein function, which could be responsible for the severe phenotype of the present case.

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  40. Reduced stratum corneum acylceramides in autosomal recessive congenital ichthyosis with a NIPAL4 mutation. Reviewed International journal

    Yuya Murase, Takuya Takeichi, Akane Kawamoto, Kana Tanahashi, Yusuke Okuno, Hiroyuki Takama, Eri Shimizu, Junko Ishikawa, Tomoo Ogi, Masashi Akiyama

    Journal of dermatological science   Vol. 97 ( 1 ) page: 50 - 56   2020.1

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    BACKGROUND: NIPAL4, encoding the NIPA-like domain containing 4 protein (NIPAL4), is one of the causative genes of autosomal recessive congenital ichthyosis (ARCI). The physiological role of NIPAL4 and the pathogenetic mechanisms of ARCI caused by NIPAL4 mutations remain unclear. OBJECTIVE: To clarify the changes of ceramide components in the lesional stratum corneum (SC) and the gene expression profile in the lesional skin of an ARCI patient with a novel frameshift mutation in NIPAL4. METHODS: We performed ultrastructural and immunohistochemical analyses of the skin. We used RNA sequencing to determine the mRNA expression in the skin of the patient and healthy individuals. We investigated ceramide components using tape stripped SC samples from the patient. RESULTS: mRNA expression profiling in the patient's skin showed significant upregulation of IL-17/TNFα-related genes (IL17C, IL36A, IL36G, S100A7A, S100A9) and psoriasis hallmark genes (VNN3, LCE3D, PLA2G4D), and significant downregulation of lipid-associated genes (GAL, HAO2, FABP7). Ceramide analysis in the patient's SC revealed amounts of CER[NS] with carbon chain-length (C) 32-52 were increased, while amounts of most acylceramide with C66:2 - C72:2 were reduced relatively to those in healthy individuals. After the retinoid treatment, CER[NS] with carbon chains C46-54, CER[EOH] and CER[EOP] increased. CONCLUSION: IL-17C and IL-36 family cytokines might be involved in the pathogenetic process of ARCI with NIPAL4 mutations. Reduced amounts of the acylceramides in the SC are associated with the skin phenotype due to NIPAL4 mutations. Efficacy of the oral retinoid treatment might be due to restored amounts of CER[EOH] and CER[EOP] in the SC.

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  41. Whole Exome Sequencing Contributes to Genetic Diagnosis of IBMFS Patients

    Muramatsu Hideki, Hamada Motoharu, Okuno Yusuke, Wakamatsu Manabu, Taniguchi Rieko, Narita Koutarou, Kawashima Nozomu, Kitazawa Hironobu, Ichikawa Daisuke, Nishikawa Eri, Kawashima Nazomu, Narita Atsushi, Nishio Nobuhiro, Kojima Seiji, Ogi Tomoo, Takahashi Yoshiyuki

    PEDIATRIC BLOOD & CANCER   Vol. 66   page: S63 - S64   2019.12

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  42. Whole Exome Sequencing Contributes to Genetic Diagnosis of IBMFS Patients

    Muramatsu Hideki, Hamada Motoharu, Okuno Yusuke, Wakamatsu Manabu, Taniguchi Rieko, Narita Koutarou, Kawashima Nozomu, Kitazawa Hironobu, Ichikawa Daisuke, Nishikawa Eri, Kawashima Nazomu, Narita Atsushi, Nishio Nobuhiro, Kojima Seiji, Ogi Tomoo, Takahashi Yoshiyuki

    PEDIATRIC BLOOD & CANCER   Vol. 66   page: S63-S64   2019.12

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  43. Comprehensive Mutational Analysis of Juvenile Myelomonocytic Leukemia Using Whole-Genome Sequencing

    Okuno Yusuke, Muramatsu Hideki, Murakami Norihiro, Kawashima Nozomu, Wakamatsu Manabu, Kitazawa Hironobu, Ogi Tomoo, Takahashi Yoshiyuki

    BLOOD   Vol. 134   2019.11

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    DOI: 10.1182/blood-2019-121681

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  44. Biallelic VPS35L pathogenic variants cause 3C/Ritscher-Schinzel-like syndrome through dysfunction of retriever complex.

    Kato K, Oka Y, Muramatsu H, Vasilev FF, Otomo T, Oishi H, Kawano Y, Kidokoro H, Nakazawa Y, Ogi T, Takahashi Y, Saitoh S

    Journal of medical genetics     2019.11

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  45. A novel NCSTN missense mutation in the signal peptide domain causes hidradenitis suppurativa, which has features characteristic of an autoinflammatory keratinization disease

    Takeichi T., Matsumoto T., Nomura T., Takeda M., Niwa H., Kono M., Shimizu H., Ogi T., Akiyama M.

    BRITISH JOURNAL OF DERMATOLOGY     2019.10

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    DOI: 10.1111/bjd.18445

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  46. Hailey-Hailey disease with oesophageal involvement due to a previously unreported ATP2C1 mutation. Reviewed International journal

    Michihiro Kono, Masanari Kodera, Yu Inasaka, Izumi Hasegawa, Yoshinao Muro, Yuka Nakazawa, Tomoo Ogi, Masashi Akiyama

    European journal of dermatology : EJD   Vol. in press   2019.8

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  47. Bi-allelic TARS Mutations Are Associated with Brittle Hair Phenotype

    Thei Arjan F., Botta Elena, Raams Anja, Smith Desiree E. C., Mendes Marisa I, Caligiuri Giuseppina, Giachetti Sarah, Bione Silvia, Carriero Roberta, Liberi Giordano, Zardoni Luca, Swagemakers Sigrid M. A., Salomons Gajja S., Sarasin Alain, Lehmann Alan, van der Spek Peter J., Ogi Tomoo, Hoeijmakers Jan H. J., Vermeulen Wim, orioli Donata

    AMERICAN JOURNAL OF HUMAN GENETICS   Vol. 105 ( 2 ) page: 434-440   2019.8

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    DOI: 10.1016/j.ajhg.2019.06.017

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  48. Unravelling the pivotal role of DDA1 in transcription-coupled nucleotide excision repair

    Pines A., Guo C., Akita M., Theil A., Quist B., Wienholz F., Marteijn J., Demmers J., van Attikum H., Vertegaal A., Vermeulen M., Ogi T., Vermeulen W.

    BRITISH JOURNAL OF DERMATOLOGY   Vol. 180 ( 6 ) page: E230 - E230   2019.6

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  49. Unravelling the pivotal role of DDA1 in transcription-coupled nucleotide excision repair

    Pines A, Guo C, Akita M, Theil A, Quist B, Wienholz F, Marteijn J, Demmers J, van Attikum H, Vertegaal A, Vermeulen M, Ogi T, Vermeulen W

    BRITISH JOURNAL OF DERMATOLOGY   Vol. 180 ( 6 ) page: E230-E230   2019.6

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  50. JAK/STAT3 and NF-κB Signaling Pathways Regulate Cancer Stem-Cell Properties in Anaplastic Thyroid Cancer Cells Reviewed

    Ken Shiraiwa, Michiko Matsuse, Yuka Nakazawa, Tomoo Ogi, Keiji Suzuki, Vladimir Saenko, Shuhang Xu, Kazuo Umezawa, Shunichi Yamashita, Kazuhiro Tsukamoto, Norisato Mitsutake

    Thyroid   Vol. 29 ( 5 ) page: 674 - 682   2019.5

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:Mary Ann Liebert Inc  

    DOI: 10.1089/thy.2018.0212

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    Other Link: https://www.liebertpub.com/doi/pdf/10.1089/thy.2018.0212

  51. A Japanese Case of Galli-Galli Disease due to a Previously Unreported POGLUT1 Mutation

    Kono Michihiro, Sawada Masaki, Nakazawa Yuka, Ogi Tomoo, Muro Yoshinao, Akiyama Masashi

    ACTA DERMATO-VENEREOLOGICA   Vol. 99 ( 4 ) page: 458-459   2019.4

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    DOI: 10.2340/00015555-3119

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  52. Functional Comparison of XPF Missense Mutations Associated to Multiple DNA Repair Disorders

    Marin Maria, Jose Ramirez Maria, Carmona Miriam Aza, Jia Nan, Ogi Tomoo, Bogliolo Massimo, Surralles Jordi

    GENES   Vol. 10 ( 1 )   2019.1

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    DOI: 10.3390/genes10010060

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  53. Functional and clinical relevance of novel mutations in a large cohort of patients with Cockayne syndrome

    Calmels Nadege, Botta Elena, Jia Nan, Fawcett Heather, Nardo Tiziana, Nakazawa Yuka, Lanzafame Manuela, Moriwaki Shinichi, Sugita Katsuo, Kubota Masaya, Obringer Cathy, Spitz Marie-Aude, Stefanini Miria, Laugel Vincent, Orioli Donata, Ogi Tomoo, Lehmann Alan Robert

    JOURNAL OF MEDICAL GENETICS   Vol. 55 ( 5 ) page: 329-343   2018.5

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    DOI: 10.1136/jmedgenet-2017-104877

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  54. Erratum: Author Correction: Phosphorylated HBO1 at UV irradiated sites is essential for nucleotide excision repair (Nature communications (2017) 8 (16102)) Reviewed

    Niida H, Matsunuma R, Horiguchi R, Uchida C, Nakazawa Y, Motegi A, Nishimoto K, Sakai S, Ohhata T, Kitagawa K, Moriwaki S, Nishitani H, Ui A, Ogi T, Kitagawa M

    Nature communications   Vol. 9   page: 16214   2018.4

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    DOI: 10.1038/ncomms16214

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    Other Link: http://orcid.org/0000-0002-5492-9072

  55. An adolescent case of xeroderma pigmentosum variant confirmed by the onset of sun exposure-related skin cancer during Crohn's disease treatment

    Terada Aoi, Aoshima Masahiro, Tanizaki Hideaki, Nakazawa Yuka, Ogi Tomoo, Tokura Yoshiki, Moriwaki Shinichi

    JOURNAL OF CUTANEOUS IMMUNOLOGY AND ALLERGY   Vol. 1 ( 1 ) page: 23-26   2018.4

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    DOI: 10.1002/cia2.12011

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  56. Whole exome sequencing of 14 schizophrenia multiplex families in Japan

    Toyama Miho, Takasaki Yuto, Aleksic Branko, Ogi Tomoo, Ozaki Norio

    HUMAN GENOMICS   Vol. 12   page: .   2018.3

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  57. Whole exome sequencing of 14 schizophrenia multiplex families in Japan Reviewed

    Toyama Miho, Takasaki Yuto, Aleksic Branko, Ogi Tomoo, Ozaki Norio

    HUMAN GENOMICS   Vol. 12   2018.3

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  58. Novel function of HATs and HDACs in homologous recombination through acetylation of human RAD52 at double-strand break sites

    Yasuda Takeshi, Kagawa Wataru, Ogi Tomoo, Kato Takamitsu A., Suzuki Takehiro, Dohmae Naoshi, Takizawa Kazuya, Nakazawa Yuka, Genet Matthew D., Saotome Mika, Hama Michio, Konishi Teruaki, Nakajima Nakako Izumi, Hazawa Masaharu, Tomita Masanori, Koike Manabu, Noshiro Katsuko, Tomiyama Kenichi, Obara Chizuka, Gotoh Takaya, Ui Ayako, Fujimori Akira, Nakayama Fumiaki, Hanaoka Fumio, Sugasawa Kaoru, Okayasu Ryuichi, Jeggo Penny A., Tajima Katsushi

    PLOS GENETICS   Vol. 14 ( 3 ) page: e1007277   2018.3

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    DOI: 10.1371/journal.pgen.1007277

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  59. Cerebellar ataxia-dominant phenotype in patients with ERCC4 mutations.

    Doi H, Koyano S, Miyatake S, Nakajima S, Nakazawa Y, Kunii M, Tomita-Katsumoto A, Oda K, Yamaguchi Y, Fukai R, Ikeda S, Kato R, Ogata K, Kubota S, Hayashi N, Takahashi K, Tada M, Tanaka K, Nakashima M, Tsurusaki Y, Miyake N, Saitsu H, Ogi T, Aihara M, Takeuchi H, Matsumoto N, Tanaka F

    Journal of human genetics     2018.2

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    DOI: 10.1038/s10038-017-0408-5

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  60. Disorders with deficiency in TC-NER: Molecular pathogenesis of cockayne syndrome and UV-Sensitive syndrome

    Guo C.

    DNA Repair Disorders     page: 25-40   2018.1

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    DOI: 10.1007/978-981-10-6722-8_2

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  61. Common TFIIH recruitment mechanism in global genome and transcription-coupled repair subpathways

    Okuda Masahiko, Nakazawa Yuka, Guo Chaowan, Ogi Tomoo, Nishimura Yoshifumi

    NUCLEIC ACIDS RESEARCH   Vol. 45 ( 22 ) page: 13043-13055   2017.12

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    DOI: 10.1093/nar/gkx970

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  62. ALC1/CHD1L, a chromatin-remodeling enzyme, is required for efficient base excision repair

    Tsuda Masataka, Cho Kosai, Ooka Masato, Shimizu Naoto, Watanabe Reiko, Yasui Akira, Nakazawa Yuka, Ogi Tomoo, Harada Hiroshi, Agama Keli, Nakamura Jun, Asada Ryuta, Fujiike Haruna, Sakuma Tetsushi, Yamamoto Takashi, Murai Junko, Hiraoka Masahiro, Koike Kaoru, Pommier Yves, Takeda Shunichi, Hirota Kouji

    PLOS ONE   Vol. 12 ( 11 ) page: e0188320   2017.11

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    DOI: 10.1371/journal.pone.0188320

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  63. Transplantation of bioengineered rat lungs recellularized with endothelial and adipose-derived stromal cells

    Doi Ryoichiro, Tsuchiya Tomoshi, Mitsutake Norisato, Nishimura Satoshi, Matsuu-Matsuyama Mutsumi, Nakazawa Yuka, Ogi Tomoo, Akita Sadanori, Yukawa Hiroshi, Baba Yoshinobu, Yamasaki Naoya, Matsumoto Keitaro, Miyazaki Takuro, Kamohara Ryotaro, Hatachi Go, Sengyoku Hideyori, Watanabe Hironosuke, Obata Tomohiro, Niklason Laura E., Nagayasu Takeshi

    SCIENTIFIC REPORTS   Vol. 7 ( 1 ) page: 8447   2017.8

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    DOI: 10.1038/s41598-017-09115-2

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  64. Phosphorylated HBO1 at UV irradiated sites is essential for nucleotide excision repair

    Niida Hiroyuki, Matsunuma Ryoichi, Horiguchi Ryo, Uchida Chiharu, Nakazawa Yuka, Motegi Akira, Nishimoto Koji, Sakai Satoshi, Ohhata Tatsuya, Kitagawa Kyoko, Moriwaki Shinichi, Nishitani Hideo, Ui Ayako, Ogi Tomoo, Kitagawa Masatoshi

    NATURE COMMUNICATIONS   Vol. 8   page: 16102   2017.7

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    DOI: 10.1038/ncomms16102

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  65. An XPA gene splicing mutation resulting in trace protein expression in an elderly patient with xeroderma pigmentosum group A without neurological abnormalities

    Takahashi Y., Endo Y., Kusaka-Kikushima A., Nakamaura S., Nakazawa Y., Ogi T., Uryu M., Tsuji G., Furue M., Moriwaki S.

    BRITISH JOURNAL OF DERMATOLOGY   Vol. 177 ( 1 ) page: 253-257   2017.7

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    DOI: 10.1111/bjd.15051

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  66. Calcification in dermal fibroblasts from a patient with GGCX syndrome accompanied by upregulation of osteogenic molecules

    Okubo Yumi, Masuyama Ritsuko, Iwanaga Akira, Koike Yuta, Kuwatsuka Yutaka, Ogi Tomoo, Yamamoto Yosuke, Endo Yuichiro, Tamura Hiroshi, Utani Atsushi

    PLOS ONE   Vol. 12 ( 5 ) page: e0177375   2017.5

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    DOI: 10.1371/journal.pone.0177375

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  67. PCNA ubiquitylation ensures timely completion of unperturbed DNA replication in fission yeast

    Daigaku Yasukazu, Etheridge Thomas J., Nakazawa Yuka, Nakayama Mayumi, Watson Adam T., Miyabe Izumi, Ogi Tomoo, Osborne Mark A., Carr Antony M.

    PLOS GENETICS   Vol. 13 ( 5 ) page: e1006789   2017.5

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    DOI: 10.1371/journal.pgen.1006789

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  68. Analysis of clinical symptoms and ABCC6 mutations in 76 Japanese patients with pseudoxanthoma elasticum. Reviewed

    Iwanaga A, Okubo Y, Yozaki M, Koike Y, Kuwatsuka Y, Tomimura S, Yamamoto Y, Tamura H, Ikeda S, Maemura K, Tsuiki E, Kitaoka T, Endo Y, Mishima H, Yoshiura KI, Ogi T, Tanizaki H, Wataya-Kaneda M, Hattori T, Utani A

    The Journal of dermatology     2017.2

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    DOI: 10.1111/1346-8138.13727

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  69. A 10-year follow-up of a child with mild case of xeroderma pigmentosum complementation group D diagnosed by whole-genome sequencing. Reviewed

    Ono R, Masaki T, Mayca Pozo F, Nakazawa Y, Swagemakers SM, Nakano E, Sakai W, Takeuchi S, Kanda F, Ogi T, van der Spek PJ, Sugasawa K, Nishigori C

    Photodermatology, photoimmunology & photomedicine   Vol. 32 ( 4 ) page: 174-80   2016.7

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    DOI: 10.1111/phpp.12240

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  70. XRCC4 deficiency in human subjects causes a marked neurological phenotype but no overt immunodeficiency.

    The Journal of allergy and clinical immunology   Vol. 136 ( 4 ) page: 1007-17   2015.10

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    DOI: 10.1016/j.jaci.2015.06.007

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  71. Novel compound heterozygous DNA ligase IV mutations in an adolescent with a slowly-progressing radiosensitive-severe combined immunodeficiency.

    Tamura S, Higuchi K, Tamaki M, Inoue C, Awazawa R, Mitsuki N, Nakazawa Y, Mishima H, Takahashi K, Kondo O, Imai K, Morio T, Ohara O, Ogi T, Furukawa F, Inoue M, Yoshiura K, Kanazawa N

    Clinical immunology (Orlando, Fla.)   Vol. 160 ( 2 ) page: 255-60   2015.10

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    DOI: 10.1016/j.clim.2015.07.004

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  72. SETDB1, HP1 and SUV39 promote repositioning of 53BP1 to extend resection during homologous recombination in G2 cells.

    Alagoz M, Katsuki Y, Ogiwara H, Ogi T, Shibata A, Kakarougkas A, Jeggo P

    Nucleic acids research   Vol. 43 ( 16 ) page: 7931-44   2015.9

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    DOI: 10.1093/nar/gkv722

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  73. Sensitivity and dose dependency of radiation-induced injury in hematopoietic stem/progenitor cells in mice.

    Guo CY, Luo L, Urata Y, Goto S, Huang WJ, Takamura S, Hayashi F, Doi H, Kitajima Y, Ono Y, Ogi T, Li TS

    Scientific reports   Vol. 5   page: 8055   2015.1

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    DOI: 10.1038/srep08055

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  74. A rapid, comprehensive system for assaying DNA repair activity and cytotoxic effects of DNA-damaging reagents.

    Jia N, Nakazawa Y, Guo C, Shimada M, Sethi M, Takahashi Y, Ueda H, Nagayama Y, Ogi T

    Nature protocols   Vol. 10 ( 1 ) page: 12-24   2015.1

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    DOI: 10.1038/nprot.2014.194

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  75. Hypomorphic PCNA mutation underlies a human DNA repair disorder.

    Baple EL, Chambers H, Cross HE, Fawcett H, Nakazawa Y, Chioza BA, Harlalka GV, Mansour S, Sreekantan-Nair A, Patton MA, Muggenthaler M, Rich P, Wagner K, Coblentz R, Stein CK, Last JI, Taylor AM, Jackson AP, Ogi T, Lehmann AR, Green CM, Crosby AH

    The Journal of clinical investigation   Vol. 124 ( 7 ) page: 3137-46   2014.7

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    DOI: 10.1172/JCI74593

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  76. PRKDC mutations in a SCID patient with profound neurological abnormalities.

    Woodbine L, Neal JA, Sasi NK, Shimada M, Deem K, Coleman H, Dobyns WB, Ogi T, Meek K, Davies EG, Jeggo PA

    The Journal of clinical investigation   Vol. 123 ( 7 ) page: 2969-80   2013.7

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    DOI: 10.1172/JCI67349

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  77. Malfunction of nuclease ERCC1-XPF results in diverse clinical manifestations and causes Cockayne syndrome, xeroderma pigmentosum, and Fanconi anemia.

    Kashiyama K, Nakazawa Y, Pilz DT, Guo C, Shimada M, Sasaki K, Fawcett H, Wing JF, Lewin SO, Carr L, Li TS, Yoshiura K, Utani A, Hirano A, Yamashita S, Greenblatt D, Nardo T, Stefanini M, McGibbon D, Sarkany R, Fassihi H, Takahashi Y, Nagayama Y, Mitsutake N, Lehmann AR, Ogi T

    American journal of human genetics   Vol. 92 ( 5 ) page: 807-19   2013.5

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    DOI: 10.1016/j.ajhg.2013.04.007

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  78. [Molecular cloning and characterisation of UVSSA, the responsible gene for UV-sensitive syndrome].

    Ogi T, Nakazawa Y, Sasaki K, Guo C, Yoshiura K, Utani A, Nagayama Y

    Seikagaku. The Journal of Japanese Biochemical Society   Vol. 85 ( 3 ) page: 133-44   2013.3

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  79. Functional characterization of the novel BRAF complex mutation, BRAF(V600delinsYM) , identified in papillary thyroid carcinoma.

    Matsuse M, Mitsutake N, Tanimura S, Ogi T, Nishihara E, Hirokawa M, Fuziwara CS, Saenko VA, Suzuki K, Miyauchi A, Yamashita S

    International journal of cancer. Journal international du cancer   Vol. 132 ( 3 ) page: 738-43   2013.2

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    DOI: 10.1002/ijc.27709

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  80. miR-196a downregulation increases the expression of type I and III collagens in keloid fibroblasts.

    Kashiyama K, Mitsutake N, Matsuse M, Ogi T, Saenko VA, Ujifuku K, Utani A, Hirano A, Yamashita S

    The Journal of investigative dermatology   Vol. 132 ( 6 ) page: 1597-604   2012.6

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    DOI: 10.1038/jid.2012.22

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  81. Mutations in UVSSA cause UV-sensitive syndrome and impair RNA polymerase IIo processing in transcription-coupled nucleotide-excision repair.

    Nakazawa Y, Sasaki K, Mitsutake N, Matsuse M, Shimada M, Nardo T, Takahashi Y, Ohyama K, Ito K, Mishima H, Nomura M, Kinoshita A, Ono S, Takenaka K, Masuyama R, Kudo T, Slor H, Utani A, Tateishi S, Yamashita S, Stefanini M, Lehmann AR, Yoshiura K, Ogi T

    Nature genetics   Vol. 44 ( 5 ) page: 586-92   2012.5

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    DOI: 10.1038/ng.2229

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  82. Identification of the first ATRIP-deficient patient and novel mutations in ATR define a clinical spectrum for ATR-ATRIP Seckel Syndrome.

    Ogi T, Walker S, Stiff T, Hobson E, Limsirichaikul S, Carpenter G, Prescott K, Suri M, Byrd PJ, Matsuse M, Mitsutake N, Nakazawa Y, Vasudevan P, Barrow M, Stewart GS, Taylor AM, O'Driscoll M, Jeggo PA

    PLoS genetics   Vol. 8 ( 11 ) page: e1002945   2012

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    DOI: 10.1371/journal.pgen.1002945

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  83. Two unrelated patients with MRE11A mutations and Nijmegen breakage syndrome-like severe microcephaly.

    Matsumoto Y, Miyamoto T, Sakamoto H, Izumi H, Nakazawa Y, Ogi T, Tahara H, Oku S, Hiramoto A, Shiiki T, Fujisawa Y, Ohashi H, Sakemi Y, Matsuura S

    DNA repair   Vol. 10 ( 3 ) page: 314-21   2011.3

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    DOI: 10.1016/j.dnarep.2010.12.002

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  84. A semi-automated non-radioactive system for measuring recovery of RNA synthesis and unscheduled DNA synthesis using ethynyluracil derivatives.

    Nakazawa Y, Yamashita S, Lehmann AR, Ogi T

    DNA repair   Vol. 9 ( 5 ) page: 506-16   2010.5

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    DOI: 10.1016/j.dnarep.2010.01.015

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  85. Three DNA polymerases, recruited by different mechanisms, carry out NER repair synthesis in human cells.

    Ogi T, Limsirichaikul S, Overmeer RM, Volker M, Takenaka K, Cloney R, Nakazawa Y, Niimi A, Miki Y, Jaspers NG, Mullenders LH, Yamashita S, Fousteri MI, Lehmann AR

    Molecular cell   Vol. 37 ( 5 ) page: 714-27   2010.3

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    DOI: 10.1016/j.molcel.2010.02.009

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  86. Collaborative action of Brca1 and CtIP in elimination of covalent modifications from double-strand breaks to facilitate subsequent break repair.

    Nakamura K, Kogame T, Oshiumi H, Shinohara A, Sumitomo Y, Agama K, Pommier Y, Tsutsui KM, Tsutsui K, Hartsuiker E, Ogi T, Takeda S, Taniguchi Y

    PLoS genetics   Vol. 6 ( 1 ) page: e1000828   2010.1

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    DOI: 10.1371/journal.pgen.1000828

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  87. A rapid non-radioactive technique for measurement of repair synthesis in primary human fibroblasts by incorporation of ethynyl deoxyuridine (EdU).

    Limsirichaikul S, Niimi A, Fawcett H, Lehmann A, Yamashita S, Ogi T

    Nucleic acids research   Vol. 37 ( 4 ) page: e31   2009.3

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    DOI: 10.1093/nar/gkp023

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  88. Translesion synthesis: Y-family polymerases and the polymerase switch.

    Lehmann AR, Niimi A, Ogi T, Brown S, Sabbioneda S, Wing JF, Kannouche PL, Green CM

    DNA repair   Vol. 6 ( 7 ) page: 891-9   2007.7

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    DOI: 10.1016/j.dnarep.2007.02.003

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  89. Differential Bvg phase-dependent regulation and combinatorial role in pathogenesis of two Bordetella paralogs, BipA and BcfA.

    Sukumar N, Mishra M, Sloan GP, Ogi T, Deora R

    Journal of bacteriology   Vol. 189 ( 10 ) page: 3695-704   2007.5

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    DOI: 10.1128/JB.00009-07

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  90. The Y-family DNA polymerase kappa (pol kappa) functions in mammalian nucleotide-excision repair.

    Ogi T, Lehmann AR

    Nature cell biology   Vol. 8 ( 6 ) page: 640-2   2006.6

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    DOI: 10.1038/ncb1417

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  91. Involvement of vertebrate Polkappa in translesion DNA synthesis across DNA monoalkylation damage.

    Takenaka K, Ogi T, Okada T, Sonoda E, Guo C, Friedberg EC, Takeda S

    The Journal of biological chemistry   Vol. 281 ( 4 ) page: 2000-4   2006.1

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    DOI: 10.1074/jbc.M506153200

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  92. Binding and transcriptional activation of non-flagellar genes by the Escherichia coli flagellar master regulator FlhD2C2.

    Stafford GP, Ogi T, Hughes C

    Microbiology (Reading, England)   Vol. 151 ( Pt 6 ) page: 1779-88   2005.6

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    DOI: 10.1099/mic.0.27879-0

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  93. Up-regulation of the error-prone DNA polymerase {kappa} promotes pleiotropic genetic alterations and tumorigenesis.

    Bavoux C, Leopoldino AM, Bergoglio V, O-Wang J, Ogi T, Bieth A, Judde JG, Pena SD, Poupon MF, Helleday T, Tagawa M, Machado C, Hoffmann JS, Cazaux C

    Cancer research   Vol. 65 ( 1 ) page: 325-30   2005.1

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  94. Localisation of human Y-family DNA polymerase kappa: relationship to PCNA foci.

    Ogi T, Kannouche P, Lehmann AR

    Journal of cell science   Vol. 118 ( Pt 1 ) page: 129-36   2005.1

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    DOI: 10.1242/jcs.01603

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  95. Elevated expression of DNA polymerase kappa in human lung cancer is associated with p53 inactivation: Negative regulation of POLK promoter activity by p53.

    Wang Y, Seimiya M, Kawamura K, Yu L, Ogi T, Takenaga K, Shishikura T, Nakagawara A, Sakiyama S, Tagawa M, O-Wang J

    International journal of oncology   Vol. 25 ( 1 ) page: 161-5   2004.7

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  96. Mammalian Pol kappa: regulation of its expression and lesion substrates.

    Ohmori H, Ohashi E, Ogi T

    Advances in protein chemistry   Vol. 69   page: 265-78   2004

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    DOI: 10.1016/S0065-3233(04)69009-7

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  97. The absence of DNA polymerase kappa does not affect somatic hypermutation of the mouse immunoglobulin heavy chain gene.

    Shimizu T, Shinkai Y, Ogi T, Ohmori H, Azuma T

    Immunology letters   Vol. 86 ( 3 ) page: 265-70   2003.5

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  98. Identification, timing, and signal specificity of Pseudomonas aeruginosa quorum-controlled genes: a transcriptome analysis.

    Schuster M, Lostroh CP, Ogi T, Greenberg EP

    Journal of bacteriology   Vol. 185 ( 7 ) page: 2066-79   2003.4

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  99. Polkappa protects mammalian cells against the lethal and mutagenic effects of benzo[a]pyrene.

    Ogi T, Shinkai Y, Tanaka K, Ohmori H

    Proceedings of the National Academy of Sciences of the United States of America   Vol. 99 ( 24 ) page: 15548-53   2002.11

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

    DOI: 10.1073/pnas.222377899

    PubMed

  100. [Biochemical studies of human DNA polymerase kappa and its transcriptional regulation].

    Ohashi E, Ogi T, Ohmori H

    Seikagaku. The Journal of Japanese Biochemical Society   Vol. 74 ( 3 ) page: 218-23   2002.3

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

    PubMed

  101. Expression of human and mouse genes encoding polkappa: testis-specific developmental regulation and AhR-dependent inducible transcription.

    Ogi T, Mimura J, Hikida M, Fujimoto H, Fujii-Kuriyama Y, Ohmori H

    Genes to cells : devoted to molecular & cellular mechanisms   Vol. 6 ( 11 ) page: 943-53   2001.11

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

    PubMed

  102. [Mutagenesis by Escherichia coli DinB and its mammalian homolog Pol kappa].

    Ogi T, Ohashi E, Ohmori H

    Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme   Vol. 46 ( 8 Suppl ) page: 1155-61   2001.6

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

    PubMed

  103. Error-prone bypass of certain DNA lesions by the human DNA polymerase kappa.

    Ohashi E, Ogi T, Kusumoto R, Iwai S, Masutani C, Hanaoka F, Ohmori H

    Genes & development   Vol. 14 ( 13 ) page: 1589-94   2000.7

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    PubMed

  104. Identification of additional genes belonging to the LexA regulon in Escherichia coli.

    Molecular microbiology   Vol. 35 ( 6 ) page: 1560-72   2000.3

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    PubMed

  105. Mutation enhancement by DINB1, a mammalian homologue of the Escherichia coli mutagenesis protein dinB.

    Ogi T, Kato T Jr, Kato T, Ohmori H

    Genes to cells : devoted to molecular & cellular mechanisms   Vol. 4 ( 11 ) page: 607-18   1999.11

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

    PubMed

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Books 1

  1. Disorders with deficiency in TC-NER: Molecular pathogenesis of cockayne syndrome and UV-Sensitive syndrome

    Guo C., Ogi T.( Role: Sole author)

    DNA Repair Disorders  2018.1  ( ISBN:9789811067211

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    Language:Japanese

    Nucleotide excision repair (NER) is one of the most important DNA repair systems involved in removing a wide range of DNA damage from the genome. NER consists of two sub-pathways: the global genome nucleotide excision repair (GG-NER) pathway, which removes DNA lesions generated in the whole genome (as described in Chap. 1 of this book), and the transcription-coupled nucleotide excision repair (TC-NER) pathway, which removes lesions specifically from the transcribed strands of actively transcribed genes. At least 20 factors are involved in the TC-NER process, and mutations in the genes responsible for coding these factors may mainly result in two human genetic disorders: Cockayne syndrome (CS) and UV-sensitive syndrome (UVSS). Despite similar molecular defects in TC-NER, CS and UVSS show distinct clinical phenotypes. CS patients display severe developmental and neurological abnormalities as well as premature ageing, whereas UVSS individuals only show milder cutaneous abnormalities, such as hypersensitivity to UV light. The molecular basis for the difference in the clinical features remains unclear. In this chapter, we will specifically describe the historical progress and recent findings of TC-NER and summarize the current understanding of the molecular pathogenesis of CS and UVSS.

    DOI: 10.1007/978-981-10-6722-8_2

    Scopus

Presentations 2

  1. 希少未診断疾患におけるゲノム解析およびデータ評価パイプラインの構築

    中沢由華, 原雄一郎, 遠山美穂, 岡泰由, 荻朋男

    第4回名大医薬系3部局交流シンポジウム  2019.10.31 

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    Language:English   Presentation type:Poster presentation  

  2. RNA polymerase IIのユビキチン化修飾による転写共役修復開始反応の分子機構とその破綻により発症する哺乳類の神経変性のメカニズム

    荻朋男

    第42回日本分子生物学会年会  2019.12.5 

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    Language:English   Presentation type:Oral presentation (invited, special)  

Works 17

  1. 紫外線感受性症候群責任因子によるRNAポリメラーゼユビキチン化と待避機構の解析

    2012
    -
    2014

  2. ヌクレオチド除去修復欠損性日光過敏症のウイルス発現系とゲノム解析による網羅的探索

    2012
    -
    2014

  3. 放射線損傷DNA修復過程における複製忠実度の 低いDNAポリメラーゼによる突然変異誘発機構の解析

    2011
    -
    2012

  4. ヌクレオチド除去修復過程における修復DNA合成の分子メカニズムの解明

    2010
    -
    2011

  5. DNA修復過程でのヌクレオシドの取り込みを指標とした不正確な修復合成を誘発するDNA修復因子の探索

    2010
    -
    2011

  6. DNA損傷の修復合成過程におけるDNAポリメラーゼの選択機構と、複製エラーを伴うDNA修復による突然変異誘発機構の解明

    2010
    -
    2011

  7. 紫外線DNA損傷修復研究

    2010
    -
    2011

  8. 紫外線DNA損傷修復研究

    2010
    -
    2011

  9. 放射線DNA損傷の新たな修復メカニズムの解明と放射線誘発がん予防のためのリスク評価

    2009
    -
    2011

  10. DNA損傷修復過程における複製忠実度の低いDNAポリメラーゼの機能解析

    2009
    -
    2010

  11. 化粧品添加物および日光過敏症新薬開発を目的とする光DNA損傷修復遺伝子のスクリーニング

    2009
    -
    2010

  12. 紫外線防護効果の高い化粧品添加物の高速スクリーニング技術の開発

    2009
    -
    2010

  13. 養蜂製品の光DNA損傷修復促進効果に関する基礎的研究と 高機能化粧品添加物としての有用性評価

    2009
    -
    2010

  14. DNA損傷修復過程において複製精度の低いDNAポリメラーゼが選択される仕組みと、DNA修復に起因する突然変異の蓄積に伴う発がんメカニズムの解明

    2009
    -
    2010

  15. DNA修復過程における複製忠実度の低いDNAポリメラーゼの機能解析

    2009
    -
    2010

  16. 放射線損傷DNA修復過程における複製忠実度の 低いDNAポリメラーゼによる突然変異誘発機構の解析

    2009
    -
    2010

  17. 修復DNA合成過程でのポリメラーゼ選択機構と複製忠実度の低いDNAポリメラーゼの作用による突然変異誘発メカニズムの解明

    2009
    -
    2010

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Research Project for Joint Research, Competitive Funding, etc. 7

  1. 中部東海地区IRUDゲノム解析拠点-先端情報技術の融合による包括的遺伝子診断の提供

    2018.3 - 2021.3

    AMED難治性疾患実用化研究事業 

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    Grant type:Competitive

  2. 中部東海地区IRUDゲノム解析拠点-先端情報技術の融合による包括的遺伝子診断の提供

    2018.3 - 2021.3

    AMED難治性疾患実用化研究事業 

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    Grant type:Competitive

  3. ゲノム不安定性疾患群を中心とした希少難治性疾患の次世代マルチオミクス診断拠点構築

    2017.4 - 2020.3

    AMED難治性疾患実用化研究事業 

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    Grant type:Competitive

  4. DNA修復・損傷応答機構の異常により発症するゲノム不安定性疾患の分子病態解明研究

    2017.4 - 2020.3

    科学研究費助成事業 

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    Grant type:Competitive

  5. ゲノム不安定性疾患群を中心とした希少難治性疾患の次世代マルチオミクス診断拠点構築

    2017.4 - 2020.3

    AMED難治性疾患実用化研究事業 

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    Grant type:Competitive

  6. ゲノム不安定性を誘発する先天性稀少疾患と小児がんコホートの分子遺伝疫学調査

    2015.4 - 2018.3

    科学研究費助成事業 

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    Grant type:Competitive

  7. 転写共役ヌクレオチド除去修復開始反応のin vitro再構成

    2014.4 - 2018.3

    科学研究費助成事業 

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    Grant type:Competitive

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KAKENHI (Grants-in-Aid for Scientific Research) 29

  1. 転写共役修復 (TCR)の分子メカニズム解明とTCR欠損ヒト遺伝性疾患の分子病態

    Grant number:21H02399  2021.4 - 2024.3

    科学研究費助成事業  基盤研究(B)

    中沢 由華, 荻 朋男

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    Authorship:Coinvestigator(s) 

    転写と共役したDNA修復機構 (transcription coupled repair: TCR)は、転写が活発に行われている領域に生じたDNA損傷を効率良く修復するシステムであり、生体の恒常性維持に重要なメカニズムである。本研究では、DNA損傷箇所で停止したRNA合成酵素がユビキチン化修飾を受けてTCRを開始・制御する分子機構の詳細解明に取り組むとともに、TCRの破綻により発症するヒト疾患の病態を明らかにすることを目指す。

  2. ロングリード配列決定法による放射線被ばく刻印の同定

    Grant number:20K21718  2020.7 - 2022.3

    科学研究費助成事業  挑戦的研究(萌芽)

    光武 範吏, 鈴木 啓司, 荻 朋男

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    Authorship:Coinvestigator(s) 

    放射線被ばくによって癌が発生するのは明らかであるが、あるひとつの癌が放射線で引き起こされたものか、その他の原因で起きたものかを区別する方法は今のところない。放射線はクラスター損傷と呼ばれる複雑な異常をDNAに引き起こし、マイクロホモロジーを伴う欠失や逆位を生じさせるとされるが、これらを全ゲノムレベルで解析する手法は今までなかった。本研究では、様々な線量の放射線を照射し樹立したHPRT変異細胞クローンと、新規技術であるロングリードシークエンシングを用い、上記の欠失や逆位を全ゲノムレベルで解析し、放射線刻印とも呼べる放射線特異的なゲノム変化の有無を明らかにする。
    本研究の目的は、最新のゲノム解析技術、特にロングリード解析を用い、放射線ゲノム刻印の存在を明らかにし、放射線リスク研究に、集団ではなく個々の癌における放射線影響の有無を調べる手段を提供することである。そのため、長年様々な研究で使用されている放射線誘発HPRT変異クローンを用いた。これらのクローンは、放射線に寄って引き起こされた変異を持つことがほぼ確実であり、線量依存性や化学物質によって得られたクローンとの比較解析も容易にできる。本年度は、主としてHPRT変異クローンの作成とゲノム解析の準備を行った。
    正常ヒト線維芽細胞をヒトテロメラーゼ(hTERT)遺伝子にて不死化したBJ1-hTERT細胞を用いた。無処理、137Csによるガンマ線照射(1, 3, 6 Gy)、またはN-ethyl-N-nitrosourea(ENU, 1 mM, 1 hr)による処理を行い、6-thioguanine(6-TG, 40 mM)存在下で培養を行い、それぞれ10~30個程度の6-TG耐性クローンを単離・樹立し、全クローンよりゲノムDNAを抽出した。次に、各エクソンの欠失状態を調べるため、HPRT遺伝子のそれぞれのエクソンを増幅できるプライマーを設定し、定量PCRにて各エクソンの欠失状態を確認した。無処理や低線量ではエクソンの欠失はほとんど見られなかったが、線量とともにエクソンの欠失が増加し、6 Gyでは全エクソンが欠失しているクローンが多く見られた。
    研究打ち合わせの予定変更や試薬や消耗品の供給不足による購入の遅れのため
    全ゲノムシークエンスを施行し、詳細な解析を行っていく。

  3. MYRF遺伝子を起点とした発熱時言動異常の病態解明

    Grant number:20K08241  2020.4 - 2024.3

    科学研究費助成事業  基盤研究(C)

    倉橋 宏和, 岡田 洋平, 奥村 彰久, 荻 朋男

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    Authorship:Coinvestigator(s) 

    我が国において、発熱に伴ってうわごとを言うなどの意識障害は稀ではなく、重篤な場合はインフルエンザ感染に伴う異常言動のように社会問題となりえます。MERS(可逆性脳梁膨大部病変を有する軽症脳炎・脳症)は、発熱に伴い異常言動を呈する代表的な急性脳症です。我々は、2家系のMERS家族例においてMYRF遺伝子変異を同定しました。この研究は、MYRF遺伝子に着目して、その遺伝学的背景をより明らかにすること、また、変異MYRFについてモデル動物やモデル細胞を作成し、その特徴を明らかにすることを目的としています。
    MERS(可逆性脳梁膨大部病変を有する軽症脳炎・脳症)は、発熱に伴い異常言動を呈する急性脳症である。急性期の頭部MRIで脳梁膨大部に異常信号を呈することが特徴で、大脳白質の主要な構成要素であるミエリンの障害が示唆されていた。我々は、2家系のMERS-異常言動スペクトラム家族例においてMYRF遺伝子変異を同定し、発熱時の異常言動と深く関わっている可能性を見出した。MYRFはオリゴデンデンドロサイトに発現し、ミエリン化・髄鞘維持に必要である。本研究の目的は、MYRF遺伝子に着目してMERS-異常言動スペクトラムの病態を解明することである。この目的を達成するために以下の研究を行なっている。1)MERS-異常言動スペクトラム症例に対する次世代シークエンス解析: MYRFにより発現が制御される遺伝子のうちミエリンに発現するものは約700あると報告されている。我々はMERS反復例・家族例を収集し、MYRF遺伝子に加えて、これらのMYRF遺伝子により発現が制御されうる遺伝子に注目してバリアントの解析を行っている。2)iPS細胞用いた研究:iPS細胞からオリゴデンドロサイトへの分化をより効率的に行うための実験を行なっている。初年度は培養環境中の酸素濃度に着目した。iPS細胞からオリゴデンドロサイト前駆物質に分化する際に、低酸素条件で分化誘導を行うことで誘導効率が上がると報告されている。我々は低酸素によりオリゴデンドロサイト前駆物質からオリゴデンドロサイトへの分化の効率も改善するかどうかの確認のためiPS細胞を3つの酸素条件に分けて培養した。しかしながら、低酸素状態ではオリゴデンドロサイト前駆物質までの分化は進んだものの、オリゴデンドロサイトへの分化は得られなかった。今後も条件を変えて分化誘導を試みる。また同時に、患者検体からのiPS細胞樹立を進める。
    MERS-異常言動スペクトラム症例に対する次世代シークエンス解析:MYRF遺伝子変異を認めた家系以外の症例を集積し、MERS反復例・家族例に対し次世代シークエンス解析を行った。MYRFが発現に関与している可能性のある遺伝子のバリアントに着目して解析を行った。その結果、遺伝子全体でのバリアントの数は対照群と差がなく、高頻度でバリアントを認める遺伝子も同定できなかったものの、低頻度ながらバリアントを認める遺伝子は対照群とは異なっていた。
    iPS細胞を用いた研究:オリゴデンドロサイトへの分化を短時間で効率的に行うために、我々は酸素条件に着目した。iPS細胞からオリゴデンドロサイト前駆物質に分化する際に、低酸素条件で分化誘導を行うことで誘導効率が上がると報告されている。低酸素条件でのオリゴデンドロサイト前駆物質からオリゴデンドロサイトへの分化の効率の確認のためiPS細胞を3つの酸素条件に分けて培養した。しかしながら、低酸素状態ではオリゴデンドロサイト前駆物質までの分化は進んだものの、オリゴデンドロサイトへの分化は得られなかった。次世代シークエンス解析については、今後も新規症例を集積し解析を継続する。低酸素状態においてはオリゴデンドロサイト前駆物質へは効率よく分化するが、オリゴデンドロサイト前駆物質からオリゴデンドロサイトへの分化の効率が落ちる可能性があることが示唆された。しかしながら、iPS細胞の種類により特性が異なる可能性もあり、他の種類のiPS細胞を用いて条件の確認を行う必要がある。
    次世代シークエンス解析については、今後も新規症例を集積し解析を継続する。低酸素状態においてはオリゴデンドロサイト前駆物質へは効率よく分化するが、オリゴデンドロサイト前駆物質からオリゴデンドロサイトへの分化の効率が落ちる可能性があることが示唆された。しかしながら、iPS細胞の種類により特性が異なる可能性もあり、他の種類のiPS細胞を用いて条件の確認を行う必要がある。

  4. Molecular pathogenesis of human disorders associated with deficiencies in the DNA repair and environmental stress response systems

    Grant number:20H00629  2020.4 - 2023.3

      More details

    Authorship:Principal investigator 

    Grant amount:\45370000 ( Direct Cost: \34900000 、 Indirect Cost:\10470000 )

  5. DNA損傷部位特異的に集積する転写共役修復因子群を同定・評価する新規技術の開発

    Grant number:19H04266  2019.4 - 2022.3

    科学研究費助成事業  基盤研究(B)

    橋本 悟, 寺林 健, 岡 泰由, 荻 朋男

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    Authorship:Coinvestigator(s) 

    RNA合成酵素が転写伸長中にDNA損傷と衝突した際に生じていると考えられている、バックトラッキング(DNA損傷部位から転写と逆方向にRNA合成酵素がスライドする現象)の観察が可能となる新しい実験系を開発する。この実験系を用いて、転写と共役したDNA修復異常を来す各種疾患群の病態メカニズム解明を目指す。
    DNA損傷を修復する最初のステップは、DNA損傷の認識から始まる。この損傷認識機構の一つとして、転写中のRNAポリメラーゼが重要な役割を担っていることが知られているが、その詳細なメカニズムは不明である。その原因として、細胞内においてDNA損傷とRNAポリメラーゼが衝突したゲノム上における部位特異的な現象を評価する実験系が無いためである。本研究ではDNA損傷に衝突したRNAポリメラーゼを評価する新しい実験系を開発し、RNAポリメラーゼによる損傷認識機構の解明を目的とし、DNA損傷認識機構の破綻に伴って生じるDNA修復異常疾患群の病態解明を目指す。
    前年度までに、光架橋オリゴを用いてゲノム上における時間・空間的に任意のDNA損傷を導入する実験系を開発している。この実験系を用い、導入したDNA架橋部位付近でのRNAポリメラーゼによるRNA合成を、RNA免疫沈降法にて検出することに成功した。しかしながら、開発した実験方法では検出感度が低いことが問題点として浮き上がった。
    また開発した実験系では、DNA架橋を導入する際に紫外線の照射が必要となっている。このため、架橋の導入に必要な紫外線量では細胞死の誘導が生じないことをを確認した。しかしながら、紫外線を使用しているため、DNAの酸化損傷が誘導されている可能性も否定できない。このため、可視光によるDNA損傷導入技術の開発を開始した。
    他にも、種々のDNA修復欠損病態モデルマウスの皮膚より角化細胞の樹立を行った。
    感度は低いが、DNA損傷導入部位でのRNAポリメラーゼの停止を検出する事が可能になったため。
    今後は、問題となっている実験評価系の感度を改善する。さらに光技術を用い、DNA架橋以外のDNA損傷を、ゲノム上の時間・空間特異的に作成する技術を開発する。また、マウスの皮膚角化細胞を用い、様々な条件下での遺伝子発現プロファイリングの比較を行い、病態の違い、特に発癌リスクの違いを検証する。

  6. 次世代シークエンスによる包括的な重症感染症リキッドバイオプシー

    Grant number:19K08298  2019.4 - 2022.3

    科学研究費助成事業  基盤研究(C)

    伊藤 嘉規, 川田 潤一, 荻 朋男

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    近年の分子生物学の進展を応用し、侵襲性の少ない、包括的(微生物と生体情報をともに含む)な重症診断法開発の基盤となる研究を行う。病原微生物である、細菌、ウイルス、真菌などは、培養や核酸検出など様々な方法で検出されるが、次世代シークエンスは網羅的な微生物検出が可能である。他方、血液などの体液中には、細胞から分泌されるエクソソーム、Cell-free DNA、マイクロRNAが存在する。これらの微小な細胞由来分子を分離・解析し、重症感染症患者の炎症反応、免疫応答や臓器障害に関する評価を行い、リキッドバイオプシー(体液による病態解析・診断)を可能とするアッセイシステムを構築する。
    小児期には急性脳炎・脳症、劇症肝炎・急性肝不全、心筋炎などの重篤な感染症が存在する。基礎疾患や免疫抑制剤の投与により易感染性を示す患者は、血流感染症などの重症感染症のリスクがある。これら重症感染症では、病原微生物は幅広く、通常は複数の検査により病原微生物同定を試みる。重症感染症では、早期診断と適切な抗微生物薬の選択が予後を左右する。次世代シークエンス法は、一度のアッセイで、1,000万~10億程度のリード(DNA・RNA断片のシークエンス数)を得ることができ、臨床検体中の核酸断片を網羅的・定量的に解析できる。さらに薬剤耐性も同時に解析可能である。重症感染症における病原微生物診断は現状では不十分であり、多くの症例で診断できれば、抗微生物薬の効率的な使用が可能になり、感染症診療に大きな進展が予想される。次世代シークエンス法を臨床応用できる基盤的研究を推進し、重症感染症の病原を早期に網羅的に診断できる方法を開発する。
    2020年度は、150bpの断片配列を読むショートリード法、網羅的な解析であるショットガン法の組み合わせにより、血液培養・核酸検出法に比べて、病原微生物検出における次世代シークエンスの優位性を引き続き検討した。シークエンスデータの解析は、2019年12月にウェブ上で公開した解析パイプライン「PATHDET」(新規に開発)を使用した。発熱性好中球減少症(FN)の病原微生物確定診断例は10~20%であり、多くは原因不明である。10例の血液培養陽性例を含む112例のFNにおける次世代シークエンス法による病原微生物の診断は、20.6%であった。他に、原因微生物不明感染症例の解析では、2例の髄膜炎症例において、培養検査では同定できなかったB群レンサ球菌を検出した。次世代シークエンスの病態解析への応用を目指し、EBウイルス難治性疾患におけるリンパ球のシングルセル解析に着手した。
    2020年度は発熱性好中球減少症の血漿検体を解析した結果を報告すると共に、原因微生物不明症例の解析も行い、2例の髄膜炎症例において、病原と疑われる細菌を検出した。ショートリード・ショットガン法の病原微生物次世代シークエンス診断法の診断法としての優位性をさらに検証した。重症感染症の血液中リンパ球の次世代シークエンス・シングルセル解析を、EBウイルス関連血球貪食性リンパ組織球症で開始し、ウイルス感染細胞の性状や免疫反応、炎症反応の性質について、検討を進めている。
    次世代シークエンスを用いた病原微生物診断に関しては、ロングリードシークエンス法の優位性を検討すると共に、解析パイプライン「PATHDET」のアップデートを行う。
    重症感染症の血液・髄液検体のcell-free DNAおよびmiRNAの分離・解析を進め、感染症の急性期に病態把握につながる結果が得られないか、引き続き検討する。重症感染症におけるリンパ球検体を用いたシングルセル次世代シークエンス解析により、免疫応答を多面的に解析できないか、検討する。

  7. Interactome analysis after induction of DNA damage in human cells

    Grant number:18K11639  2018.4 - 2021.3

    Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    Kurotani Kenichi

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    DNA damage response (DDR) is a crucial response for genome stability. A detailed understanding of their protein-protein interaction networks enables us to know the cellular function of DDR proteins. In this project, we performed the interactome analysis of DDR proteins in human cells using a high resolution mass spectrometry. In the results of our study, we identified several factors that interact with POLR2A/RPB1, the largest subunit of RNA polymerase II, after induction of DNA damage in human cells.

  8. プロテオーム解析によるDNA損傷応答システムの破綻により生じる疾患発症因子の同定

    Grant number:18H03372  2018.4 - 2021.3

    岡 泰由

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    DNA損傷応答 (DNA damage response, DDR)システムの破綻によって、ヒトでは様々な病態を示す遺伝性疾患を発症することが知られているが、依然として、疾患発症原因が不明なものが多く残されている。昨今の大規模ゲノム解析研究から、健常人のゲノムにも数多くの遺伝子変異が存在することが明らかにされてきた。エクソーム解析を行ったとしても、疾患原因遺伝子変異の絞り込みが困難なため、確定診断に至るのは20-30%程度といわれている。本研究の目的は、ゲノム解析結果とプロテオーム解析データを統合することで、ゲノム解析のみでは候補遺伝子を絞り込むことができなかった、DDRシステムの破綻によって発症した遺伝性疾患の発症因子を特定し、DDRシステムと多様な病態を示す遺伝性疾患との関連性を明らかにすることである。
    エクソーム解析のみでは候補遺伝子変異の絞り込みには至らなかった、DDRシステムの破綻によって発症することが知られているゼッケル症候群疑いと診断された患者由来の不死化血球系細胞について、プロテオーム解析を実施した。その結果、核酸代謝関連酵素の蛋白質発現が健常人由来細胞と比較して顕著に低下していること、当該蛋白質が細胞内で相互作用している因子の発現量が低下していることが明らかとなった。エクソーム解析では、当該遺伝子の病的変異の同定には至らなかったため、全ゲノム解析ならびにRNA-seq解析を実施した。その結果、当該遺伝子イントロン深部に疾患発症に関連することが予想される変異を同定し、その領域を含んだ異常スプライシング産物が患者細胞特異的に合成されていることを見出した。
    これまでに、エクソーム解析のみでは候補遺伝子変異の絞り込みには至らなかった、DDRシステムの破綻によって発症したことが疑われる症例について、プロテオーム解析により疾患発症の原因となり得る候補因子を絞り込み、疾患発症関連因子の蛋白質発現低下に加えて、細胞内で疾患発症関連因子と複合体を形成することで安定化している蛋白質についても発現量の低下を検出することができている。さらに、全ゲノム解析とRNA-seq解析により、当該遺伝子のイントロン深部に病的変異を見出し、異常スプライシング産物が患者細胞において合成されていることを明らかとしたため。
    プロテオーム解析により絞り込みに成功した症例については、患者細胞において、核酸代謝酵素機能低下の有無を、分子生物学的実験手法を用いて明らかにする。エクソーム解析のみでは候補遺伝子変異の絞り込みには至らなかった、DDRシステムの破綻によって発症したことが疑われる症例について、引き続きプロテオーム解析を実施する。DDRシステムの破綻によって発症したことが疑われる症例の追加収集を行う。

  9. 中部東海地区IRUDゲノム解析拠点-先端情報技術の融合による包括的遺伝子診断の提供

    2018.3 - 2021.3

    科学研究費補助金  その他

  10. DNA修復・損傷応答機構の異常により発症するゲノム不安定性疾患の分子病態解明研究

    2017.4 - 2020.3

    科学研究費補助金  基盤研究(A)

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  11. DNA修復・損傷応答機構の異常により発症するゲノム不安定性疾患の分子病態解明研究

    2017.4 - 2020.3

    科学研究費補助金  その他

  12. ゲノム不安定性疾患群を中心とした希少難治性疾患の次世代マルチオミクス診断拠点構築

    2017.4 - 2020.3

    科学研究費補助金  その他

  13. Molecular pathogenesis of human genetic disorders associated with deficiency in the DNA repair and damage response system

    Grant number:17H00783  2017.4 - 2020.3

    OGI Tomoo

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    Grant amount:\42770000 ( Direct Cost: \32900000 、 Indirect Cost:\9870000 )

    We have investigated on human genetic disorders associated with genome instability. Patients with these syndromes have developed various clinical manifestations due to malfunctions of DNA repair and damage response system. We have collected undiagnosed cases and tried to elucidate the genetic cause of diseases using the Multi-omics approach that involves next-generation sequencing, high-accurate mass spectrometry, and precise DNA repair assays. Once we identified pathogenic variants, we have performed in vitro and in vivo analyses as well as animal studies so that we could get new insights into the molecular pathogenesis of the diseases. Recently, we have reported a detailed molecular mechanism of the initiation of transcription-coupled repair, which is compromised in Cockayne syndrome.

  14. DNA double strand break repair factors mutated in a new syndrome with microcephaly

    Grant number:17H01877  2017.4 - 2020.3

    NAKAZAWA Yuka

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    In this study, we have focused on microcephaly as a commonly observed clinical feature of DNA repair deficiency disorders. We have identified several new pathogenic variants in DNA repair genes from microcephaly cases and tried to elucidate their molecular pathogenesis. We have generated mice with mutations in those newly determined genes; however, we often experienced lack of expected phenotypes. This is partly due to greater tolerance to DNA damages in mice; we decided to cross the animals with other mice with deficiency in different DNA repair processes so that overload DNA damage to elicit a phenotype. From this approach, we found that microcephaly and some types of neurodegeneration diseases can be explained by prolonged arrest of RNA polymerases at DNA damage sites during transcription. DNA damage stalled RNA polymerases are ubiquitinated to facilitate DNA repair; when this process is compromised, various neurodegenerative phenotypes, as shown in Cockayne syndrome, come up.

  15. Genetic diagnosis of microcephaly

    Grant number:16K15526  2016.4 - 2018.3

    OGI Tomoo

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    Grant amount:\3510000 ( Direct Cost: \2700000 、 Indirect Cost:\810000 )

    Primary microcephaly is partially caused by deficiencies in DNA Damage Response system (DDR system). As prevalence of these genetic disorders are very rare and the patients usually display overlapping clinical features, we often face with difficulties in the clinical diagnosis.
    In this project, we aimed to develop a system helpful in the differential diagnosis of microcephaly and similar conditions. The developed system comprises next generation DNA sequencing (NGS) as well as DDR activity assays for detecting deficiencies in double strand break (DSB) repair and nucleotide excision repair (NER).

  16. 小頭症を発症する遺伝性疾患の鑑別診断技術開発

    2016.4 - 2017.3

    科学研究費補助金  研究成果公開促進費 (研究成果公開発表)

    荻 朋男

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  17. 小頭症を発症する遺伝性疾患の鑑別診断技術開発

    2016.4 - 2017.3

    科学研究費助成事業  挑戦的研究(萌芽)

    荻 朋男

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\2080000 ( Direct Cost: \1600000 、 Indirect Cost:\480000 )

  18. Molecular regions of BRCA proteins responsible for cancer suppression

    Grant number:15K06833  2015.4 - 2019.3

    Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    Takenaka Katsuya

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    BRCA2 germline mutations account for the majority of heredity breast and ovarian cancer. A major function of BRCA2 is known as a regulator of homologous recombination in DNA damage repair. In addition, BRCA2 also plays an important role in centrosomal regulation, whose dysfunction might be involved inthe tumorigenesis of breast cancer. Though, detail molecular mechanism was not uncovered. In the present study, we tried to locate a molecular region of BRCA2 responsible for this function. Numbers of centrosome in a cell are counted to see if an overexpression of a specific fragment of BRCA proteins could impair a numerical integrity of centrosomes. For this purpose we developed an automated centrosome-counting system based on image recognition, which allows us to judge a large number of transfected cells without human bias.

  19. ゲノム不安定性を誘発する先天性稀少疾患と小児がんコホートの分子遺伝疫学調査

    2015.4 - 2018.3

    科学研究費補助金  基盤研究(A)

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  20. ゲノム不安定性を誘発する先天性稀少疾患と小児がんコホートの分子遺伝疫学調査

    2015.4 - 2018.3

    科学研究費補助金  その他

  21. Molecular epidemiology studies on rare genetic disorders and pediatric cancer cohorts associated with genome instability

    Grant number:15H02654  2015.4 - 2018.3

    OGI Tomoo

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    Authorship:Principal investigator 

    Grant amount:\42900000 ( Direct Cost: \33000000 、 Indirect Cost:\9900000 )

    Genomic DNA is constitutively exposed to various DNA damaging sources; therefore, the DNA repair and damage response system is essential for the maintenance and stable transmission of the genetic information. A failure in this system elicits genome instability and causes carcinogenesis and ageing. In this study, we have collected various hereditary disorder cases world-widely to identify genetic factors associated with congenital genome instability. We generated a pathogenic mutation database as well as a cell-bank from the analysis of collected samples. We have identified several new DNA repair genes with novel pathogenic mutations. We are currently working on the molecular pathogenesis of newly identified mutations and their associated genetic disorders.

  22. Biochemical analysis of transcription coupled nucleotide excision repair factors

    Grant number:15K00541  2015.4 - 2018.3

    KARATA Kiyonobu

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    The detailed function of TC-NER-specific factors, CSA, CSB and UVSSA, remains to be defined. In order to elucidate their function biochemically, we tried to reconstitute in vitro TC-NER assay system using DNA templates harboring a site-directed DNA damage. In addition, we have developed the purification method of UVSSA protein for its X-ray crystal structure analysis.

  23. The molecular epidemiological study of DNA repair-related genes in post-Chernobyl radiation-induced thyroid cancers

    Grant number:26293142  2014.4 - 2019.3

    MITSUTAKE Norisato

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    Mutation data were obtained by next-generation sequencing using genomic DNA of 56 post-Chernobyl radiation-induced pediatric thyroid cancer cases and 55 controls who were also lived in the same area and exposed but without development of thyroid cancer. Although several candidate genes related to carcinogenesis were found, further research is needed. No obvious accumulation of mutations was identified among DNA repair genes. Through this project, we were able to acquire comprehensive genomic data of the invaluable samples and established the basis of continuous research in future.

  24. 転写共役ヌクレオチド除去修復開始反応のin vitro再構成

    2014.4 - 2018.3

    科学研究費補助金  基盤研究(B)

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  25. 転写共役ヌクレオチド除去修復開始反応のin vitro再構成

    2014.4 - 2018.3

    科学研究費補助金  その他

  26. In vitro reconstitution of the initiation process of transcription-coupled nucleotide-excision repair

    Grant number:26291005  2014.4 - 2018.3

    OGI Tomoo

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    Authorship:Principal investigator 

    Grant amount:\16640000 ( Direct Cost: \12800000 、 Indirect Cost:\3840000 )

    Transcription-coupled nucleotide-excision repair (TC-NER) is one of the versatile DNA repair process that removes major UV-induced DNA lesions from actively transcribed genes. To investigate the initiation process of TC-NER reaction, we focused on a molecular mechanism that involves DNA-damage induced ubiquitination of RNA polymerase IIo (RNA pol IIo). The process is dependent on a recently identified TC-NER factor, UVSSA.
    To determine the ubiquitination sites, we performed in vitro ubiquitination assay as well as SILAC-based High-Resolution Accurate Mass (HRAM) spectrometry. From the studies, we identified UVSSA-dependent ubiquitination sites required for the efficient TC-NER activity.

  27. Mechanism of genomic DNA damage response mediated by acetylation of non-histone proteins

    Grant number:26281026  2014.4 - 2018.3

    YASUDA Takeshi

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    We newly identified several non-histone proteins involved in DNA damage response, which are acetylated by p300 and CBP histone acetyltransferases in vitro. Among the identified acetylated proteins, we showed that p300/CBP acetylate RAD52, a human homologous recombination (HR) DNA repair protein, at DNA double strand break (DSB) sites. We identified 13 acetylation sites in RAD52. We revealed that non-acetylated RAD52 initially accumulates at DSB sites, but dissociates prematurely from them. In the absence of RAD52 acetylation, RAD51, which plays a central role in HR, also dissociates prematurely from DSB sites, and hence HR is impaired. Furthermore, we demonstrated that the acetylation of RAD52 is linked to ATM signaling. Our findings clarify the importance of RAD52 acetylation in HR.

  28. -

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    Grant type:Competitive

  29. -

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    Grant type:Competitive

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