ナカムラ アサコ中村 麻子教授Asako NAKAMURA
■研究者基本情報
経歴
委員歴
- 2024年07月 - 現在, 広報出版委員会副委員長, 日本放射線影響学会
- 2023年07月 - 現在, SITプログラム小委員会, 日本放射線影響学会
- 2020年06月 - 現在, 学術評議員, 日本放射線影響学会
- 2020年05月 - 2026年03月, 北茨城市創生推進会議委員, 北茨城市
- 2023年09月 - 2025年03月, 那珂市特産品ブランド推進協議会委員, 那珂市
- 2023年08月 - 2024年03月, 日立市におけるリカレント教育体制構築に係る事業アドバイザー, 日立市
- 2023年03月 - 2024年03月, 茨城県リスキリング推進協議会幹事会委員, 茨城県
- 2022年04月 - 2024年03月, 京都大学大学院生命科学研究科附属放射線生物研究センター運営委員会委員, 京都大学大学院生命科学研究科附属放射線生物研究センター
- 2022年03月 - 2024年03月, ダイバーシティ社会に向けたチャレンジ委員会委員, 茨城県水戸生涯学習センター
- 2020年05月 - 2024年03月, 茨城県地場産業等総合支援事業補助金審査会委員, 茨城県
- 2020年04月 - 2024年03月, いばらき子ども大学実行委員会委員, 茨城県教育委員会
- 2020年04月 - 2024年03月, 水戸黄門まつり実行委員会委員, 水戸市
- 2020年04月 - 2024年03月, 茨城県圏央道沿線地域産業・交流活性化協議会幹事, 茨城県
- 2020年04月 - 2024年03月, 第60回水戸黄門まつり実行委員会委員, 水戸市
- 2023年08月 - 2023年11月, 令和5年度漁港施設等指定管理者選定委員, 茨城県農林水産部
- 2020年05月 - 2023年03月, 関東近県生涯学習・社会教育実践研究交流会実行委員会委員, 茨城県
- 2022年07月 - 2022年10月, 令和4年度漁港施設等指定管理者選定委員会委員, 茨城県農林水産部
- 2020年08月 - 2022年06月, SITワークショップ準備検討小委員会委員, 日本放射線影響学会
- 2020年06月 - 2022年06月, 論文紹介企画小委員会委員, 日本放射線影響学会
- 2020年06月 - 2022年06月, キャリアパス・男女共同参画委員会, 日本放射線影響学会
- 2016年04月 - 2022年03月, 水戸第二高等学校SSH高大接続委員会委員, 水戸第二高等学校
- 2020年11月 - 2021年03月, アリーナを核としたスマートシティ推進協議会委員長, アリーナを核としたスマートシティ推進協議会
- 2016年10月 - 2020年11月, 重粒子線がん治療装置等共同利用運営委員会・議題採択評価部会委員, 量子科学技術研究開発機構
- 2016年04月 - 2020年03月, 共同利用・共同研究専門委員会委員, 京都大学放射線生物研究センター
研究者からのメッセージ
(研究者からのメッセージ)
Professional profile
• Radiation cellular biologist specializing in the mechanisms of genome integrity, DNA double-strand break repair and mammalian aging with more than fifteen years experience and more than 45 publications.
• Involved in the development of an assay for a new pharmacodynamics biomarker in response to chemo- and radio-therapeutic treatments in cancer patients.
• Co-developing a sensitive and accurate biomarker for exposure to radiation and genotoxic substances.
• Reviewer of several international journals (Oncogene, Journal of Nucleic Acid, Medical Molecular Morphology, and Journal of Radiation Research, etc.).
• Strong interest in pursuing translational studies which improve human health based on basic research
• Highly motivated individual with abilities to communicate both in English and Japanese, to adapt to new environments (flexibility), to think critically, and to solve scientific problems.
• Mentor for the National Institutes of Health summer student program.
• Teaching for anatomy and histology at Osaka Medical College.
• Teaching for cellular biology at Ibaraki University.
Education
• PhD of Pharmaceutical Science, Hiroshima University (Professor; Toshinori Ide and Kenshi Komatsu) (2002)
Research project: The function of Nijmegen Breakage syndrome (NBS1) protein in telomere maintenance and genome stability.
• MS of Pharmaceutical Science, Hiroshima University (Professor; Toshinori Ide and Kenshi Komatsu) (1999)
Research project: The genomic mutation analysis of Fanconi Anemia (FA) patients and the study of function of FA proteins in DNA repair mechanism.
• Awarded the degree of Pharmacist (Registration No. 327562) (1997)
• BA of Pharmaceutical Science, Hiroshima University (Professor; Toshinori Ide and Kenshi Komatsu) (1997)
Research project: The identification of response gene for radiation sensitivity in Chinese hamster ovary (CHO) mutant cells, xrs-2.
Professional Training
• Professor of Ibaraki University, College of Science (2017-current)
• Associate Professor of Ibaraki University, College of Science (2013- 2017)
• Junior Associate Professor of Osaka Medical College, Department of Anatomy and Cell Biology (Professor; Yoshinori Otsuki)
(2011-2013)
• Research Fellow of National Institutes of Health, National Cancer Institute, Laboratory of Molecular Pharmacology (Principal Investigator; William Bonner) (2009-2011)
• Visiting Fellow of National Institutes of Health, National Cancer Institute, Laboratory of Molecular Pharmacology (Principal Investigator; William Bonner) (2007-2009)
• Special volunteer of the Japan Society for Promotion of Science for Japanese Biomedical and Behavioral Researchers at NIH (Principal Investigator; William Bonner) (2004-2007)
• Post Doctoral Research Fellow of the Japan Society for the Promotion of Science (Professor; Kenshi Komatsu) (2002-2004)
■研究活動情報
受賞
- 2019年, 第６回バイオテックグランプリ ロート賞
国内学会・会議・シンポジウム等の賞 - 2019年, 第６回バイオテックグランプリ 吉野家賞
国内学会・会議・シンポジウム等の賞 - 2018年11月, 第３回茨城テックプラングランプリ 日本メクトロン賞
国内学会・会議・シンポジウム等の賞 - 2018年11月, 第3回茨城テックプラングランプリ オーディエンス賞
- 2018年, 平成30年度茨城大学学長学術表彰奨励賞
- 2018年, 第３回茨城テックプランター 日本メクトロン賞
国内学会・会議・シンポジウム等の賞 - 2017年, 平成29年度日本放射線影響学会岩崎民子賞
- 2015年, 平成27年度茨城大学学長学術表彰奨励賞
- 2014年, 平成26年度日本放射線影響学会奨励賞, 日本放射線影響学会
論文
- A novel microfluidic chip for on-site radiation risk evaluation.
Kenta Takahashi; Takahiro Tamura; Kosuke Yamada; Kaisei Suga; Yuri Aoki; Ryota Sano; Kentaro Koyama; Asako J Nakamura; Takaaki Suzuki, 責任著者, This paper proposes a microfluidic chip for on-site radiation risk evaluation using immunofluorescence staining for the DNA double-strand break (DSB) marker phosphorylated histone, H2AX (γ-H2AX). The proposed microfluidic chip separates lymphocytes, the cells of the DNA DSB evaluation target, from whole blood based on their size and traps them in the trap structure. The subsequent DNA DSB evaluation, γ-H2AX assay, can be performed on a chip, which saves space and simplifies the complicated operation of the assay, which conventionally requires a large experimental space. Therefore, this chip will enable the biological effect evaluation of radiation exposure to be completed on-site. Bead experiments with samples containing 10 μm and 27 μm diameter beads showed that the proposed chip introduced the sample into the flow channel only by centrifugal force and passively separated the two types of beads by the structure in the flow channel. In addition, bead experiments showed that isolated 10 μm diameter beads were trapped in more than 95% of the 1000 lymphocyte trap structures (LTSs). The feasibility of the proposed method for on-site radiation risk evaluation was demonstrated through cell-based experiments by performing the γ-H2AX assay in human lymphoblastoid TK6 cells. The experiment shows that LTSs in the flow channel are capable of trapping TK6 cells, and γ-H2AX foci which are markers of DNA DSBs are observed in the TK6 cells on the chip. Thus, the results suggest that the proposed microfluidic chip simplifies the γ-H2AX assay protocol and provides a novel method to perform the assay on-site, which is conventionally impracticable.
The Analyst, 2024年12月02日 - Senescence-Associated Heterochromatin Foci Suppress γ-H2AX Focus Formation Induced by Radiation Exposure.
Takashi Oizumi; Tomoya Suzuki; Junya Kobayashi; Asako J Nakamura, ラスト(シニア)オーサー, DNA damage is induced by both endogenous and exogenous factors. Repair of DNA double-strand break (DSB), a serious damage that threatens genome stability, decreases with senescence. However, the molecular mechanisms underlying the decline in DNA repair capacity during senescence remain unclear. We performed immunofluorescence staining for phosphorylated histone H2AX (γ-H2AX) in normal human fetal lung fibroblasts and human skin fibroblasts of different ages after chronic irradiation (total dose, 1 Gy; dose rate, 1 Gy/day) to investigate the effect of cellular senescence and organismal aging on DSB repair. Accumulation of DSBs was observed with cellular senescence and organismal aging, probably caused by delayed DSB repair. Importantly, the formation of γ-H2AX foci, an early event in DSB repair, is delayed with cellular senescence and organismal aging. These results suggest that the delay in γ-H2AX focus formation might delay the overall DSB repair. Interestingly, immediate γ-H2AX foci formation was suppressed in cells with senescence-associated heterochromatin foci (SAHF). To investigate the relationship between the γ-H2AX focus formation and SAHF, we used LiCl to relax the SAHFs, followed by irradiation. We demonstrated that LiCl rescued the delayed γ-H2AX foci formation associated with cellular senescence. This indicates that SAHF interferes with γ-H2AX focus formation and inhibits DSB repair in radiation-induced DSB. Our results suggest that therapeutic targeting of SAHFs have potential to resolve DSB repair dysfunction associated with cellular senescence.
International journal of molecular sciences, 2024年03月15日, ［査読有り］ - Nanoparticle as a Carrier of Cationic Porphyrin and Ratiometric Fluorescence pH Sensor.
Shinoda H; Higano R; Oizumi T; Nakamura AJ; Kamijo T; Takahashi M; Nagaoka M; Sato Y; Yamaguchi A.
ACS Appl Bio Mater., 2024年01月11日, ［査読有り］ - Prediction of late adverse events in pelvic cancer patients receiving definitive radiotherapy using radiation-induced gamma-H2AX foci assay.
Someya M; Hasegawa T; Nakamura AJ; Tsuchiya T; Kitagawa M; Gocho T; Mafune S; Ikeuchi Y; Tauchi H; Sakata KI.
J Radiat Res., 2023年11月21日, ［査読有り］ - Identification of Novel Senescent Markers in Small Extracellular Vesicles.
Misawa T; Hitomi K; Miyata K; Tanaka Y; Fujii R; Chiba M; Loo TM; Hanyu A; Kawasaki H; Kato H; Maezawa Y; Yokote K; Nakamura AJ; Ueda K; Yaegashi N; Takahashi A., Senescent cells exhibit several typical features, including the senescence-associated secretory phenotype (SASP), promoting the secretion of various inflammatory proteins and small extracellular vesicles (EVs). SASP factors cause chronic inflammation, leading to age-related diseases. Recently, therapeutic strategies targeting senescent cells, known as senolytics, have gained attention; however, noninvasive methods to detect senescent cells in living organisms have not been established. Therefore, the goal of this study was to identify novel senescent markers using small EVs (sEVs). sEVs were isolated from young and senescent fibroblasts using three different methods, including size-exclusion chromatography, affinity column for phosphatidylserine, and immunoprecipitation using antibodies against tetraspanin proteins, followed by mass spectrometry. Principal component analysis revealed that the protein composition of sEVs released from senescent cells was significantly different from that of young cells. Importantly, we identified ATP6V0D1 and RTN4 as novel markers that are frequently upregulated in sEVs from senescent and progeria cells derived from patients with Werner syndrome. Furthermore, these two proteins were significantly enriched in sEVs from the serum of aged mice. This study supports the potential use of senescent markers from sEVs to detect the presence of senescent cells in vivo.
Int J Mol Sci., 2023年01月26日, ［査読有り］ - 〔主要な業績〕An Enriched Environment Alters DNA Repair and Inflammatory Responses After Radiation Exposure
Sakama Sae; Kurusu Keisuke; Morita Mayu; Oizumi Takashi; Masugata Shinya; Oka Shohei; Yokomizo Shinya; Nishimura Mayumi; Morioka Takamitsu; Kakinuma Shizuko; Shimada Yoshiya; Nakamura Asako J., ラスト(シニア)オーサー, After the Fukushima Daiichi Nuclear Power Plant accident, there is growing concern about radiation-induced carcinogenesis. In addition, living in a long-term shelter or temporary housing due to disasters might cause unpleasant stress, which adversely affects physical and mental health. It’s been experimentally demonstrated that “eustress”, which is rich and comfortable, has beneficial effects for health using mouse models. In a previous study, mice raised in the enriched environment (EE) has shown effects such as suppression of tumor growth and enhancement of drug sensitivity during cancer treatment. However, it’s not yet been evaluated whether EE affects radiation-induced carcinogenesis. Therefore, to evaluate whether EE suppresses a radiation-induced carcinogenesis after radiation exposure, in this study, we assessed the serum leptin levels, radiation-induced DNA damage response and inflammatory response using the mouse model. In brief, serum and tissues were collected and analyzed over time in irradiated mice after manipulating the raising environment during the juvenile or adult stage. To assess the radiation-induced DNA damage response, we performed immunostaining for phosphorylated H2AX which is a marker of DNA double-strand break. Focusing on the polarization of macrophages in the inflammatory reaction that has an important role in carcinogenesis, we performed analysis using tissue immunofluorescence staining and RT-qPCR. Our data confirmed that EE breeding before radiation exposure improved the responsiveness to radiation-induced DNA damage and basal immunity, further suppressing the chronic inflammatory response, and that might lead to a reduction of the risk of radiation-induced carcinogenesis., Frontiers Media SA
Frontiers in Immunology, 2021年10月22日, ［査読有り］ - Decreased ionizing radiation-induced DNA damage repair function of cultured fibroblasts derived from patients with xeroderma pigmentosum variant
Toshihiro OTSUKA; Asako J. NAKAMURA; and Shinichi MORIWAKI
Bulletin of Osaka Medical and Pharmaceutical University, 2021年09月17日, ［査読有り］ - Health effects triggered by tritium: how do we get public understanding based on scientifically supported evidence?
Matsumoto H; Shimada Y; Nakamura AJ; Usami N; Ojima M; Kakinuma S; Shimada M; Sunaoshi M; Hirayama R; Tauchi H.
J Radiat Res., 2021年04月28日, ［査読有り］ - Repair Kinetics of DNA Double Strand Breaks Induced by Simulated Space Radiation.
Oizumi T; Ohno R; Yamabe S; Funayama T; Nakamura A.J, ラスト(シニア)オーサー, Radiation is unavoidable in space. Energetic particles in space radiation are reported to induce cluster DNA damage that is difficult to repair. In this study, normal human fibroblasts were irradiated with components of space radiation such as proton, helium, or carbon ion beams. Immunostaining for γ-H2AX and 53BP1 was performed over time to evaluate the kinetics of DNA damage repair. Our data clearly show that the repair kinetics of DNA double strand breaks (DSBs) induced by carbon ion irradiation, which has a high linear energy transfer (LET), are significantly slower than those of proton and helium ion irradiation. Mixed irradiation with carbon ions, followed by helium ions, did not have an additive effect on the DSB repair kinetics. Interestingly, the mean γ-H2AX focus size was shown to increase with LET, suggesting that the delay in repair kinetics was due to damage that is more complex. Further, the 53BP1 focus size also increased in an LET-dependent manner. Repair of DSBs, characterized by large 53BP1 foci, was a slow process within the biphasic kinetics of DSB repair, suggesting non-homologous end joining with error-prone end resection. Our data suggest that the biological effects of space radiation may be significantly influenced by the dose as well as the type of radiation exposure., MDPI
Life, 2020年12月10日, ［査読有り］ - DNA damage regulates senescence-associated extracellular vesicle release via the ceramide pathway to prevent excessive inflammatory responses.
Kazuhiro Hitomi; Ryo Okada; Tze Mun Loo; Kenichi Miyata; Asako J Nakamura; Akiko Takahashi, DNA damage, caused by various oncogenic stresses, can induce cell death or cellular senescence as an important tumor suppressor mechanism. Senescent cells display the features of a senescence-associated secretory phenotype (SASP), secreting inflammatory proteins into surrounding tissues, and contributing to various age-related pathologies. In addition to this inflammatory protein secretion, the release of extracellular vesicles (EVs) is also upregulated in senescent cells. However, the molecular mechanism underlying this phenomenon remains unclear. Here, we show that DNA damage activates the ceramide synthetic pathway, via the downregulation of sphingomyelin synthase 2 (SMS2) and the upregulation of neutral sphingomyelinase 2 (nSMase2), leading to an increase in senescence-associated EV (SA-EV) biogenesis. The EV biogenesis pathway, together with the autophagy-mediated degradation pathway, functions to block apoptosis by removing cytoplasmic DNA fragments derived from chromosomal DNA or bacterial infections. Our data suggest that this SA-EV pathway may play a prominent role in cellular homeostasis, particularly in senescent cells. In summary, DNA damage provokes SA-EV release by activating the ceramide pathway to protect cells from excessive inflammatory responses.
Int J Mol Sci., 2020年05月25日, ［査読有り］ - Space Radiation Biology for “Living in Space”
Satoshi Furukawa; Aiko Nagamatsu; Mitsuru Nenoi; Akira Fujimori; Shizuko Kakinuma; Takanori Katsube; Bing Wang; Chizuru Tsuruoka; Toshiyuki Shirai; Asako J. Nakamura; Asako Sakaue-Sawano; Atsushi Miyawaki; Hiroshi Harada; Minoru Kobayashi; Junya Kobayashi; Takekazu Kunieda; Tomoo Funayama; Michiyo Suzuki; Tatsuo Miyamoto; Jun Hidema; Yukari Yoshida; Akihisa Takahashi, Space travel has advanced significantly over the last six decades with astronauts spending up to 6 months at the International Space Station. Nonetheless, the living environment while in outer space is extremely challenging to astronauts. In particular, exposure to space radiation represents a serious potential long-term threat to the health of astronauts because the amount of radiation exposure accumulates during their time in space. Therefore, health risks associated with exposure to space radiation are an important topic in space travel, and characterizing space radiation in detail is essential for improving the safety of space missions. In the first part of this review, we provide an overview of the space radiation environment and briefly present current and future endeavors that monitor different space radiation environments. We then present research evaluating adverse biological effects caused by exposure to various space radiation environments and how these can be reduced. We especially consider the deleterious effects on cellular DNA and how cells activate DNA repair mechanisms. The latest technologies being developed, e.g., a fluorescent ubiquitination-based cell cycle indicator, to measure real-time cell cycle progression and DNA damage caused by exposure to ultraviolet radiation are presented. Progress in examining the combined effects of microgravity and radiation to animals and plants are summarized, and our current understanding of the relationship between psychological stress and radiation is presented. Finally, we provide details about protective agents and the study of organisms that are highly resistant to radiation and how their biological mechanisms may aid developing novel technologies that alleviate biological damage caused by radiation. Future research that furthers our understanding of the effects of space radiation on human health will facilitate risk-mitigating strategies to enable long-term space and planetary exploration.
BioMed Research International, 2020年04月08日, ［査読有り］ - Pilot clinical study of ascorbic acid treatment in cardiac catheterization.
Sun L; Igarashi T; Tetsuka R; Li YS; Kawasaki Y; Kawai K; Hirakawa H; Tsuboi K; Nakamura AJ; Moritake T
J Radiat Res., 2018年, ［査読有り］ - The Causal Relationship between DNA Damage Induction in Bovine Lymphocytes and the Fukushima Nuclear Power Plant Accident
Asako J. Nakamura; Masatoshi Suzuki; Christophe E. Redon; Yoshikazu Kuwahara; Hideaki Yamashiro; Yasuyuki Abe; Shintaro Takahashi; Tomokazu Fukuda; Emiko Isogai; William M. Bonner; Manabu Fukumoto, The Fukushima Daiichi Nuclear Power Plant (FNPP) accident, the largest nuclear incident since the 1986 Chernobyl disaster, occurred when the plant was hit by a tsunami triggered by the Great East Japan Earthquake on March 11, 2011. The subsequent uncontrolled release of radioactive substances resulted in massive evacuations in a 20-km zone. To better understand the biological consequences of the FNPP accident, we have been measuring DNA damage levels in cattle in the evacuation zone. DNA damage was evaluated by assessing the levels of DNA double-strand breaks in peripheral blood lymphocytes by immunocyto-fluorescence-based quantification of gamma-H2AX foci. A greater than two-fold increase in the fraction of damaged lymphocytes was observed in all animal cohorts within the evacuation zone, and the levels of DNA damage decreased slightly over the 700-day sample collection period. While the extent of damage appeared to be independent of the distance from the accident site and the estimated radiation dose from radiocesium, we observed age-dependent accumulation of DNA damage. Thus, this study, which was the first to evaluate the biological impact of the FNPP accident utilizing the gamma-H2AX assays, indicated the causal relation between high levels of DNA damage in animals living in the evacuation zone and the FNPP accident. (C) 2017 by Radiation Research Society, RADIATION RESEARCH SOC
RADIATION RESEARCH, 2017年05月, ［査読有り］ - 抗酸化物質Tempolによる放射線誘発のDNA損傷抑制効果の検討
加藤 正尊; 飯岡 俊英; 丸山 里奈; 澤井 裕一; 中村 麻子; 笹谷 めぐみ; 神谷 研二; 小林 純也; 小松 賢志; 志村 勉, (一社)日本放射線影響学会
日本放射線影響学会大会講演要旨集, 2016年10月 - Evidence for chromosome fragility at the frataxin locus in Friedreich ataxia.
Mutat Res., 2016年, ［査読有り］ - A Phase I Study of DMS612, a Novel Bi-functional Alkylating Agent.
Leonard J. Appleman; Sanjeeve Balasubramaniam; Robert A. Parise; Christine Bryla; Christophe E. Redon; Asako J. Nakamura; William M. Bonner; John J. Wright; Richard Piekarz; David R. Kohler; Yixing Jiang; Chandra P. Belani; Julie Eiseman; Edward Chu; Jan H. Beumer; Susan E. Bates, Purpose: DMS612 is a dimethane sulfonate analog with bifunctional alkylating activity and preferential cytotoxicity to human renal cell carcinoma (RCC) in the NCI-60 cell panel. This first-in-human phase I study aimed to determine dose-limiting toxicity (DLT), maximum tolerated dose (MTD), pharmacokinetics (PK), and pharmacodynamics (PD) of DMS612 administered by 10-minute intravenous infusion on days 1, 8, and 15 of an every-28-day schedule.
Experimental Design: Patients with advanced solid malignancies were eligible. Enrollment followed a 3+3 design. PKs of DMS612 and metabolites were assessed by mass spectroscopy and PD by gamma-H2AX immunofluorescence.
Results: A total of 31 patients, including those with colorectal (11), RCC (4), cervical (2), and urothelial (1) cancers, were enrolled. Six dose levels were studied, from 1.5 mg/m(2) to 12 mg/m(2). DLTs of grade 4 neutropenia and prolonged grade 3 thrombocytopenia were observed at 12 mg/m(2). The MTD was determined to be 9 mg/m(2) with a single DLT of grade 4 thrombocytopenia in 1 of 12 patients. Two patients had a confirmed partial response at the 9mg/m(2) dose level, in renal (1) and cervical (1) cancer. DMS612 was rapidly converted into active metabolites. gamma-H2AX immunofluorescence revealed dose-dependent DNA damage in both peripheral blood lymphocytes and scalp hairs.
Conclusions: The MTD of DMS12 on days 1, 8, and 15 every 28 days was 9 mg/m(2). DMS612 appears to be an alkylating agent with unique tissue specificities. Dose-dependent PD signals and two partial responses at the MTD support further evaluation of DMS612 in phase II trials. (C) 2014 AACR., AMER ASSOC CANCER RESEARCH
Clin Cancer Res., 2015年, ［査読有り］ - Systemic DNA damage accumulation under in vivo tumor growth can be inhibited by the antioxidant tempol.
Alexandros G. Georgakilas; Christophe E. Redon; Nicholas F. Ferguson; Thomas B. Kryston; Palak Parekh; Jennifer S. Dickey; Asako J. Nakamura; James B. Mitchell; William M. Bonner; Olga A. Martin, Recently we found that mice bearing subcutaneous non-metastatic tumors exhibited elevated levels of two types of complex DNA damage, i.e., double-strand breaks and oxidatively-induced clustered DNA lesions in various tissues throughout the body, both adjacent to and distant from the tumor site. This DNA damage was dependent on CCL2, a cytokine involved in the recruitment and activation of macrophages, suggesting that this systemic DNA damage was mediated via tumor-induced chronic inflammatory responses involving cytokines, activation of macrophages, and consequent free radical production. If free radicals are involved, then a diet containing an antioxidant may decrease the distant DNA damage. Here we repeated our standard protocol in cohorts of two syngeneic tumor-bearing C57BL/6NCr mice that were on a Tempol-supplemented diet. We show that double-strand break and oxidatively-induced clustered DNA lesion levels were considerably decreased, about two- to three fold, in the majority of tissues studied from the tumor-bearing mice fed the antioxidant Tempol compared to the control tumor-bearing mice. Similar results were also observed in nude mice suggesting that the Tempol effects are independent of functioning adaptive immunity. This is the first in vivo study demonstrating the effect of a dietary antioxidant on abscopal DNA damage in tissues distant from a localized source of genotoxic stress. These findings may be important for understanding the mechanisms of genomic instability and carcinogenesis caused by chronic stress-induced systemic DNA damage and for developing preventative strategies. (C) 2014 Elsevier Ireland Ltd. All rights reserved., ELSEVIER IRELAND LTD
Cancer Lett., 2014年 - Mito-Tempol and Dexrazoxane Exhibit Cardioprotective and Chemotherapeutic Effects through Specific Protein Oxidation and Autophagy in a Syngeneic Breast Tumor Preclinical Model.
•Dickey JS; Gonzalez Y; Aryal B; Mog S; Nakamura AJ; Redon CE; Baxa U; Rosen E; Cheng G; Zielonka J; Parekh P; Mason KP; Joseph J; Kalyanaraman B; Bonner WM; Herman E; Shacter E; Rao VA., Several front-line chemotherapeutics cause mitochondria-derived, oxidative stress-mediated cardiotoxicity. Iron chelators and other antioxidants have not completely succeeded in mitigating this effect. One hindrance to the development of cardioprotectants is the lack of physiologically-relevant animal models to simultaneously study antitumor activity and cardioprotection. Therefore, we optimized a syngeneic rat model and examined the mechanisms by which oxidative stress affects outcome. Immune-competent spontaneously hypertensive rats (SHRs) were implanted with passaged, SHR-derived, breast tumor cell line, SST-2. Tumor growth and cytokine responses (IL-1A, MCP-1, TNF-alpha) were observed for two weeks post-implantation. To demonstrate the utility of the SHR/SST-2 model for monitoring both anticancer efficacy and cardiotoxicity, we tested cardiotoxic doxorubicin alone and in combination with an established cardioprotectant, dexrazoxane, or a nitroxide conjugated to a triphenylphosphonium cation, Mito-Tempol (4) [Mito-T (4)]. As predicted, tumor reduction and cardiomyopathy were demonstrated by doxorubicin. We confirmed mitochondrial accumulation of Mito-T (4) in tumor and cardiac tissue. Dexrazoxane and Mito-T (4) ameliorated doxorubicin-induced cardiomyopathy without altering the antitumor activity. Both agents increased the pro-survival autophagy marker LC3-II and decreased the apoptosis marker caspase-3 in the heart, independently and in combination with doxorubicin. Histopathology and transmission electron microscopy demonstrated apoptosis, autophagy, and necrosis corresponding to cytotoxicity in the tumor and cardioprotection in the heart. Changes in serum levels of 8-oxo-dG-modified DNA and total protein carbonylation corresponded to cardioprotective activity. Finally, 2D-electrophoresis/mass spectrometry identified specific serum proteins oxidized under cardiotoxic conditions. Our results demonstrate the utility of the SHR/SST-2 model and the potential of mitochondrially-directed agents to mitigate oxidative stress-induced cardiotoxicity. Our findings also emphasize the novel role of specific protein oxidation markers and autophagic mechanisms for cardioprotection., PUBLIC LIBRARY SCIENCE
PloS One, 2013年, ［査読有り］ - Qg-H2AX, an analysis method for partial-body radiation exposure using γ-H2AX in non-human primate lymphocytes.
Redon CE; Nakamura AJ; Gouliaeva K; Rahman A; Blakely WF; Bonner WM, We previously used the gamma-H2AX assay as a biodosimeter for total-body irradiation (TBI) exposure (gamma-rays) in a rhesus macaque (Macaca mulatta) model. Utilizing peripheral blood lymphocytes and plucked hairs, we obtained statistically significant gamma-H2AX responses days after total-body exposure to 1-8.5 Gy (Co-60 gamma-rays at 55 cGy min(-1)). Here, we introduce a partial-body exposure analysis method, Q(gamma-H2AX), which is based on the number of gamma-H2AX foci per damaged cells as evident by having one or more gamma-H2AX foci per cell. Results from the rhesus monkey TBI study were used to establish Q(gamma-H2AX) dose-response calibration curves to assess acute partial-body exposures. gamma-H2AX foci were detected in plucked hairs for several days after in vivo irradiation demonstrating this assay's utility for dose assessment in various body regions. The quantitation of gamma-H2AX may provide a robust biodosimeter for analyzing partial-body exposures to ionizing radiation in humans. Published by Elsevier Ltd., PERGAMON-ELSEVIER SCIENCE LTD
Radiat. Meas., 2011年 - Hypothermia postpones DNA damage repair in irradiated cells and protects against cell killing.
Jackson-Baird B; Dickey JS; Nakamura AJ; Redon CE; Parekh P; Griko YV; Aziz K; Georgakilas AG; Bonner WM; Sedelnikova OA., Hibernation is an established strategy used by some homeothermic organisms to survive cold environments. In true hibernation, the core body temperature of an animal may drop to below 0 degrees C and metabolic activity almost cease. The phenomenon of hibernation in humans is receiving renewed interest since several cases of victims exhibiting core body temperatures as low as 13.7 degrees C have been revived with minimal lasting deficits. In addition, local cooling during radiotherapy has resulted in normal tissue protection. The experiments described in this paper were prompted by the results of a very limited pilot study, which showed a suppressed DNA repair response of mouse lymphocytes collected from animals subjected to 7-Gy total body irradiation under hypothermic (13 degrees C) conditions, compared to normothermic controls. Here we report that human BJ-hTERT cells exhibited a pronounced radioprotective effect on clonogenic survival when cooled to 13 degrees C during and 12h after irradiation. Mild hypothermia at 20 and 30 degrees C also resulted in some radioprotection. The neutral comet assay revealed an apparent lack on double strand break (DSB) rejoining at 13 degrees C. Extension of the mouse lymphocyte study to ex vivo-irradiated human lymphocytes confirmed lower levels of induced phosphorylated H2AX (gamma-H2AX) and persistence of the lesions at hypothermia compared to the normal temperature. Parallel studies of radiation-induced oxidatively clustered DNA lesions (0CDL5) revealed partial repair at 13 degrees C compared to the rapid repair at 37 degrees C. For both gamma-H2AX foci and OCDLs, the return of lymphocytes to 37 degrees C resulted in the resumption of normal repair kinetics. These results, as well as observations made by others and reviewed in this study, have implications for understanding the radiobiology and protective mechanisms underlying hypothermia and potential opportunities for exploitation in terms of protecting normal tissues against radiation. (C) 2011 Published by Elsevier B.V., ELSEVIER SCIENCE BV
Mutation Res., 2011年 - The use of γ-H2AX as a biodosimeter for total-body radiation exposure – application for acute partial-body exposure dose assessments.
Redon CE; Nakamura AJ; Gouliaeva K; Rahman A; Blakely WF; Bonner WM
PLoS One, 2010年 - Tumors induce complex DNA damage in proliferative tissues in vivo.
Redon CE; Dickey JS; Nakamura AJ; Kareva IG; Naf D; Nowsheen S; Kalogerinis PK; Bonner WM; Georgakilas AG and Sedelnikova OA., That tumors cause changes in surrounding tissues is well documented, but whether they also affect distant tissues is uncertain. Such knowledge may be important in understanding the relationship between cancer and overall patient health. To address this question, we examined tissues distant to sites of implanted tumors for genomic damage using cohorts of C57BL/6 and BALB/c mice with early-stage subcutaneous syngeneic grafts, specifically, B16 melanoma, MO5076 sarcoma, and COLON26 carcinoma. Here we report that levels of two serious types of DNA damage, double-strand breaks (DSBs) measured by gamma-H2AX focus formation and oxidatively induced non-DSB clustered DNA lesions (OCDLs), were elevated in tissues distant from the tumor site in tumor-bearing mice compared with their age-and sex-matched controls. Most affected were crypts in the gastrointestinal tract organs and skin, both highly proliferative tissues. Further investigation revealed that, compared with controls, tumor-bearing mice contained elevated amounts of activated macrophages in the distant gastrointestinal tissues, as well as elevated serum levels of several cytokines. One of these cytokines, CCL2/MCP-1, has been linked to several inflammation-related conditions and macrophage recruitment, and strikingly, CCL2-deficient mice lacked increased levels of DSBs and OCDLs in tissues distant from implanted tumors. Thus, this study is unique in being a direct demonstration that the presence of a tumor may induce a chronic inflammatory response in vivo, leading to increased systemic levels of DNA damage. Importantly, these findings suggest that tumors may have more profound effects on their hosts than heretofore expected., NATL ACAD SCIENCES
Proc. Natl. Acad. Sci. U. S. A., 2010年 - The complexity of phosphorylated H2AX foci formation and DNA repair assembly at DNA double-strand breaks.
Nakamura AJ; Rao AV; Pommier Y and Bonner WM., 筆頭著者, The maintenance of genome stability requires efficient DNA double-stranded break (DSB) repair mediated by the phosphorylation of multiple histone H2AX molecules near the break sites. The phosphorylated H2AX (gamma H2AX) molecules form foci covering many megabases of chromatin. The formation of gamma-H2AX foci is critical for efficient DNA damage response (DDR) and for the maintenance of genome stability, however, the mechanisms of protein organization in foci is largely unknown. To investigate the nature of gamma H2AX foci formation, we analyzed the distribution of gamma H2AX and other DDR proteins at DSB sites using a variety of techniques to visualize, expand and partially disrupt chromatin. We report here that gamma H2AX foci change composition during the cell cycle, with proteins 53BP1, NBS1 and MRE11 dissociating from foci in G 2 and mitosis to return at the beginning of the following G(1). In contrast, MDC1 remained colocalized with gamma-H2AX during mitosis. In addition, while gamma H2AX was found to span large domains flanking DSB sites, 53BP1 and NBS1 were more localized and MDC1 colocalized in doublets in foci. H2AX and MDC1 were found to be involved in chromatin relaxation after DSB formation. Our data demonstrates that the DSB repair focus is a heterogeneous and dynamic structure containing internal complexity., LANDES BIOSCIENCE
Cell Cycle, 2010年 - Expression of mutant RPA in human cancer cells causes telomere shortening.
Kobayashi Y; Sato K; Kibe T; Seimiya H; Nakamura A; Yukawa M; Tsuchiya E and Ueno M., Replication protein A (RIPA) binds to single-stranded DNA generated during DNA replication and other processes. The roles of RPA in telomere maintenance have been demonstrated in yeasts, but not in telomerase-positive human cells. In this study, we found that expression of mutant RPA70 in human cells caused telomere shortening, suggesting that RPA is required for telomere-length regulation in human cancer cells., TAYLOR & FRANCIS LTD
Biosci Biotechnol Biochem., 2010年 - ATM activation by transcription- and topoisomerase I-induced DNA double-strand breaks.
Sordet O; Redon CE; Gourouilh-Barbat J; Smith S; Solier S; Douarre C; Conti C; Nakamura AJ; Das B; Nicolas E; Kohn K; Bonner WM; Pommier Y
EMBO report, 2009年 - The role of DNA damage response pathways in chromosome fragility in Fragile X syndrome.
Kumari D; Somma V; Nakamura AJ; Bonner WM; D’Ambrosio E and Usdin K., FRAXA is one of a number of fragile sites in human chromosomes that are induced by agents like fluorodeoxyuridine (FdU) that affect intracellular thymidylate levels. FRAXA coincides with a > 200 CGG center dot CCG repeat tract in the 5' UTR of the FMR1 gene, and alleles prone to fragility are associated with Fragile X (FX) syndrome, one of the leading genetic causes of intellectual disability. Using siRNA depletion, we show that ATR is involved in protecting the genome against FdU-induced chromosome fragility. We also show that FdU increases the number of gamma-H2AX foci seen in both normal and patient cells and increases the frequency with which the FMR1 gene colocalizes with these foci in patient cells. In the presence of FdU and KU55933, an ATM inhibitor, the incidence of chromosome fragility is reduced, suggesting that ATM contributes to FdU-induced chromosome fragility. Since both ATR and ATM are involved in preventing aphidicolin-sensitive fragile sites, our data suggest that the lesions responsible for aphidicolin-induced and FdU-induced fragile sites differ. FRAXA also displays a second form of chromosome fragility in absence of FdU, which our data suggest is normally prevented by an ATM-dependent process., OXFORD UNIV PRESS
Nucleic Acids Res., 2009年 - Telomere-dependent and telomere-independent origins of endogenous DNA damage in tumor cells.
Nakamura AJ; Redon CE; Bonner WM and Sedelnikova OA., 筆頭著者, Human tumors and cultured cells contain elevated levels of endogenous DNA damage resulting from telomere dysfunction, replication and transcription errors, reactive oxygen species, and genome instability. However, the contribution of telomere-associated versus telomere-independent endogenous DNA lesions to this damage has never been examined. In this study, we characterized the relative amounts of these two types of DNA damage in five tumor cell lines by noting whether gamma-H2AX foci, generally considered to mark DNA double-strand breaks (DSBs), were on chromosome arms or at chromosome ends. We found that while the numbers of non-telomeric DSBs were remarkably similar in these cultures, considerable variation was detected in the level of telomeric damage. The distinct heterogeneity in the numbers of gamma-H2AX foci in these tumor cell lines was found to be due to foci associated with uncapped telomeres, and the amount of total telomeric damage also appeared to inversely correlate with the telomerase activity present in these cells. These results indicate that damaged telomeres are the major factor accounting for the variability in the amount of DNA DSB damage in tumor cells. This characterization of DNA damage in tumor cells helps clarify the contribution of non-telomeric DSBs and damaged telomeres to major genomic alterations., IMPACT JOURNALS LLC
Aging, 2009年 - Association of ionizing radiation-induced foci of NBS1 with chromosomal instability and breast cancer susceptibility
Masanori Someya; Koh-ichi Sakata; Hiroshi Tauchi; Yoshihisa Matsumoto; Asako Nakamura; Kenshi Komatsu; Masato Hareyama, NBS1, a protein essential for DNA double-strand break repair, relocalizes into subnuclear structures upon induction of DNA damage by ionizing radiation, forming ionizing radiation-induced foci. We compared radiation-induced NBS1 foci in peripheral blood lymphocytes (PBLs) from 46 sporadic breast cancer patients and 30 healthy cancer-free volunteers. The number of persistent radiation-induced NBS1 foci per nucleus at 24 h after irradiation for patients with invasive cancer was significantly higher than for normal healthy volunteers. The frequency of spontaneous chromosome aberration increased as the number of persistent radiation-induced NBS1 foci increased, indicating that the number of persistent radiation-induced NBS1 foci might be associated with chromosome instability. There was also an inverse correlation between the number of radiation-induced NBS1 foci and the activity of DNA-dependent protein kinase (DNA-PK), which plays an important role in the nonhomologous end-joining (NHEJ) path-way, another mechanism of DNA DSB repair, indicating a close interrelationship between homologous recombination (HR) and NHEJ in DNA DSB repair. In conclusion, the number of persistent radiation-induced NBS1 foci is associated with chromosomal instability and risk of sporadic breast cancer and hence might be used to select individuals for whom a detailed examination is necessary because of their increased susceptibility to breast cancer, although refinement of the techniques for technical simplicity and accuracy will be required for clinical use. (c) 2006 by Radiation Reseacch Society., RADIATION RESEARCH SOC
RADIATION RESEARCH, 2006年10月, ［査読有り］ - Nbs1 is essential for DNA repair by homologous recombination in higher vertebrate cells
H Tauchi; J Kobayashi; K Morishima; DC van Gent; T Shiraishi; NS Verkaik; D vanHeems; E Ito; A Nakamura; E Sonodo; M Takata; S Takeda; S Matsuura; K Komatsu, Double-strand breaks occur during DNA replication and are also induced by ionizing radiation. There are at least two pathways which can repair such breaks: non-homologous end joining and homologous recombination (HR). Although these pathways are essentially independent of one another, it is possible that the proteins Mre11, Rad50 and Xrs2 are involved in both pathways in Saccharomyces cerevisiae(1). In vertebrate cells, little is known about the exact function of the Mre11-Rad50-Nbs1 complex in the repair of double-strand breaks because Mre11-andRad50-null mutations are lethal(2). Here we show that Nbs1 is essential for HR-mediated repair in higher vertebrate cells. The disruption of Nbs1 reduces gene conversion and sister chromatid exchanges, similar to other HR-deficient mutants(3). In fact, a site-specific double-strand break repair assay showed a notable reduction of HR events following generation of such breaks in Nbs1-disrupted cells. The rare recombinants observed in the Nbs1-disrupted cells were frequently found to have aberrant structures, which possibly arise from unusual crossover events, suggesting that the Nbs1 complex might be required to process recombination intermediates., NATURE PUBLISHING GROUP
NATURE, 2002年11月, ［査読有り］ - NBS1 localizes to γ-H2AX foci through interaction with the FHA/BRCT domain
J. Kobayashi; H. Tauchi; S. Sakamoto; A. Nakamura; K.-I. Morishima; S. Matsuura; T. Kobayashi; K. Tamai; K. Tanimoto; K. Komatsu, DNA double-strand breaks represent the most potentially serious damage to a genome; hence, many repair proteins are recruited to nuclear damage sites by as yet poorly characterized sensor mechanisms. Here, we show that NBS1, the gene product defective in Nijmegen breakage syndrome (NBS) [1-3], physically interacts with histone, rather than damaged DNA, by direct binding to gamma-H2AX. We also demonstrate that NBS1 binding can occur in the absence of interaction with hMRE11 or BRCA1. Furthermore, this NBS1 physical interaction was reduced when anti-gamma-H2AX antibody was introduced into normal cells and was also delayed in AT cells, which lack the kinase activity for phosphorylation of H2AX. NBS1 has no DNA binding region but carries a combination of the fork-head associated (FHA) and the BRCA1 C-terminal domains (BRCT) [4]. We show that the FHA/BRCT domain of NBS1 is essential for this physical interaction, since NBS1 lacking this domain failed to bind to gamma-H2AX in cells, and a recombinant FHA/BRCT domain alone can bind to recombinant 7-H2AX. Consequently, the FHA/BRCT domain is likely to have a crucial role for both binding to histone and for relocalization of hMRE11/hRAD50 nuclease complex to the vicinity of DNA damage., CELL PRESS
Current Biology, 2002年10月, ［査読有り］ - The forkhead-associated domain of NBS1 is essential for nuclear foci formation after irradiation but not essential for hRAD50·hMRE11·-NBS1 complex DNA repair activity
H. Tauchi; J. Kobayashii; K.-I. Morishima; S. Matsuura; A. Nakamura; T. Shiraishi; E. Ito; D. Masnada; D. Delia; K. Komatsu, NBS1 (p95), the protein responsible for Nijmegen breakage syndrome, shows a weak homology to the yeast Xrs2 protein at the N terminus region, known as the forkhead-associated (FHA) domain and the BRCA1 C terminus domain. The protein interacts with hMRE11 to form a complex with a nuclease activity for initiation of both nonhomologous end joining and homologous recombination. Here, we show in vivo direct evidence that NBS1 recruits the hMRE11 nuclease complex into the cell nucleus and leads to the formation of foci by utilizing different functions from several domains. The amino acid sequence at 665-693 on the C terminus of NBS1, where a novel identical sequence with yeast Xrs2 protein was found, is essential for hMRE11 binding. The hMRE11-binding region is necessary for both nuclear localization of the complex and for cellular radiation resistance. On the other hand, the FHA domain regulates nuclear foci formation of the multiprotein complex in response to DNA damage but is not essential for nuclear transportation of the complex and radiation resistance. Because the FHA/BRCA1 C terminus domain is widely conserved in eukaryotic nuclear proteins related to the cell cycle, gene regulation, and DNA repair, the foci formation could be associated with many phenotypes of Nijmegen breakage syndrome other than radiation sensitivity., AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
Journal of Biological Chemistry, 2001年01月, ［査読有り］ - Expression of full-length NBS1 protein restores normal radiation responses in cells from Nijmegen breakage syndrome patients
Atsushi Ito; Hiroshi Tauchi; Junya Kobayashi; Kenichi Morishima; Asako Nakamura; Yutaka Hirokawa; Shinya Matsuura; Katsuhide Ito; Kenshi Komatsu, Cells from Nijmegen breakage syndrome (NBS) display multiple phenotypes, such as chromosomal instability, hypersensitivity to cell killing from ionizing radiation, and possibly abnormal cell cycle checkpoints. NBS1, a gene mutated in NBS patients, appears to encode a possible repair protein, which could form the foci of a sensor-like molecular complex capable of detecting DNA double strand breaks, however, it has no kinase domain for signaling DNA damage. Here, we report that the stable expression of NBS1 cDNA in NBS cells after transfection results in the complete restoration of foci formation in the nucleus, and in normal cell survival after irradiation. The prolonged G2 block observed after irradiation was also abolished by expression of NBS1, providing additional confirmation that the G2 checkpoint is abrogated in NBS cells. These results suggest that a defective NBS1 protein could be the sole cause of the NBS phenotype, and that NBS1 likely interacts with another protein(s) to produce the entire range of NBS phenotypic expression., Academic Press Inc.
Biochemical and Biophysical Research Communications, 1999年11月30日 - Sequence analysis of an 800-kb genomic DNA region on chromosome 8q21 that contains the Nijmegen breakage syndrome gene, NBS1
H Tauchi; S Matsuura; M Isomura; T Kinjo; A Nakamura; S Sakamoto; N Kondo; S Endo; K Komatsu; Y Nakamura, An 800-kb region on chromosome 8q21, which complements the phenotype of cells from Nijmegen breakage syndrome patients, is a candidate for the locus of the underlying gene, termed NBS1. The sequence of this 800-kb region of DNA indicated that the size of this segment is 755,832 bp with an additional 36-kb gap. From this region, we identified four genes including NBS1, a gene coding for a 27-kDa vitamin D-dependent calcium-binding protein (27-kDa calbindin), the mitochondrial 2,4-dienoyl-CoA reductase gene, and a novel gene, C8orf1/hT41. All four genes were aligned in a 250-kb centromeric portion of the region, and no gene was found in the remaining telomeric portion containing 500 kb. The genomic organization of the C8orf1/hT41 and NBS1 genes has been analyzed using the computer programs GRAIL 2 and GENSCAN. They predicted and successfully found more than 93% of the exons, even a small 54-bp exon, indicating that one or more exons in any gene can be identified by these programs. GENSCAN was more efficient at locating the four genes than GRAIL 2 and identified 15 of the 16 exons of the NBS1 gene. This 800-kb region contained repetitive sequences, including 179 copies of the Alu sequence (1 copy/4.2 kb), 123 copies of the L1 sequence (1 copy/6.1 kb), 107 copies of the LTR sequence (1 copy/7.1 kb), and 63 copies of the MER sequence (1 copy/12 kb). There was a slight but not significant difference in the repetitive content of the gene-rich region and the remaining noncoding region. Our results indicate that computer-assisted methods are useful and powerful for identifying exons of both known and novel genes. (C) 1999 Academic Press., ACADEMIC PRESS INC
GENOMICS, 1999年01月 - Four novel mutations of the Fanconi anemia group A gene (FAA) in Japanese patients
A Nakamura; S Matsuura; H Tauchi; R Hanada; H Ohashi; T Hasegawa; K Honda; M Masuno; K Imaizumi; K Sugita; T Ide; K Komatsu, Fanconi anemia (FA) is an autosomal recessive disorder characterized by pancytopenia, predisposition to cancers, and a diverse variety of congenital malformations. At least eight complementation groups, A through H, have been described. Recently, the FA-A gene (FAA) has been isolated, and a large number of distinct mutations reported in ethnically diverse FA-A patients. Here, we report on the mutation analysis of five FA patients by single-strand conformation polymorphism. Out of five patients, at least three were found to have mutations in the FAA gene. The first patient was a compound heterozygote with a l-bp deletion and a single-base substitution. The second patient had a heterozygous 2-bp deletion, which introduces a premature termination codon, and the third patient had a heterozygous splice donor site mutation in intron 27., SPRINGER-VERLAG TOKYO
JOURNAL OF HUMAN GENETICS, 1999年 - A polymorphic CA repeat marker at the human 27-kD calbindin (CALB1) locus
K Morishima; S Matsuura; H Tauchi; A Nakamura; K Komatsu, A polymorphic dinucleotide (CA) sequence was isolated from a BAC clone containing the human 27-kD calbindin (CALB1) gene at 8q21. This polymorphism will be a useful genetic marker to study genetic variations of the CALB1 gene., SPRINGER-VERLAG TOKYO
JOURNAL OF HUMAN GENETICS, 1999年 - Positional cloning of the gene for Nijmegen breakage syndrome
S Matsuura; H Tauchi; A Nakamura; N Kondo; S Sakamoto; S Endo; D Smeets; B Solder; BH Belohradsky; VMD Kaloustian; M Oshimura; M Isomura; Y Nakamura; K Komatsu, Nijmegen breakage syndrome (NBS), also known as ataxia-telangiectasia (AT) variant, is an autosomal recessive disorder characterized by microcephaly, growth retardation, severe combined immunodeficiency and a high incidence of lymphoid cancers. Cells from NBS patients display chromosome instability, hypersensitivity to ionizing radiation and abnormal cell-cycle regulation after irradiation, all of which are characteristics shared with AT. Recently, the NBS locus was mapped at 8q21 by two independent approaches, complementation studies(1) and linkage analysis(2). Here, we report the positional cloning of the NBS gene, NBS1, from an 800-kb candidate region. The gene comprises 50 kb and encodes a protein of 754 amino acids. The amino-terminal region of the protein shows weak homology to the yeast XRS2, MEK1, CDS1 and SPK1 proteins. The gene is expressed at high levels in the testes, suggesting that it might be involved in meiotic recombination. We detected the same 5-bp deletion in 13 individuals, and conclude that it is likely to be a founder mutation., NATURE AMERICA INC
NATURE GENETICS, 1998年06月, ［査読有り］ - Genetic mapping using microcell-mediated chromosome transfer suggests a locus for Nijmegen breakage syndrome at chromosome 8q21-24
S Matsuura; C Weemaes; D Smeets; H Takami; N Kondo; S Sakamoto; N Yano; A Nakamura; H Tauchi; S Endo; M Oshimura; K Komatsu, Nijmegen breakage syndrome (NBS) is an autosomal recessive disorder characterized by microcephaly, short stature, immunodeficiency, and a high incidence of cancer. Cultured cells from NBS show chromosome instability, an increased sensitivity to radiation-induced cell killing, and an abnormal cell-cycle regulation after irradiation. Hitherto, patients with NBS have been divided into the two complementation groups V1 and V2, on the basis of restoration of radioresistant DNA synthesis, suggesting that each group arises from a different gene, However, the presence of genetic heterogeneity in NBS has been considered to be controversial. To localize the NBS gene, we have performed functional complementation assays using somatic cell fusion between NBS-V1 and NBS-V2 cells, on the basis of hyper-radiosensitivity, and then have performed a genomewide search for the NBS locus, using microcell-mediated chromosome transfer followed by complementation assays based on radiosensitivity, We found that radiation resistance was not restored in the fused NBS-V1 and NBS-V2 cells and that only human chromosome 8 complements the sensitivity to ionizing radiation, in NBS cell lines. In complementation assays performed after the transfer of a reduced chromosome, merely the long arm of chromosome 8 was sufficient for restoring the defect. Our results strongly suggest that NBS is a homogeneous disorder and that the gene for NBS is located at 8q21-24., UNIV CHICAGO PRESS
AMERICAN JOURNAL OF HUMAN GENETICS, 1997年06月, ［査読有り］
MISC
- Beyond visualization of DNA double-strand breaks after radiation exposure.
Int J Radiat Biol., 2021年05月27日, ［査読有り］ - Use of the γ-H2AX assay to monitor DNA damage and repair in translational cancer research.
Ivashkevich A; Redon CE; Nakamura AJ; Martin RF; Martin OA
Cancer Lett., 2012年 - Systemic DNA damage related to cancer.
Martin OA; Redon CE; Nakamura AJ; Dickey JS; Georgakilas AG; Bonner WM.
Cancer Res., 2011年 - Para-inflammation mediates systemic DNA damage in response to tumor growth.
Martin OA; Redon CE; Dickey JS; Nakamura AJ; Bonner WM
Commun. Integr. Biol., 2011年 - Recent developments in the use of γ-H2AX as a quantitative DNA double-strand break biomarker.
Redon CE; Nakamura AJ; Martin OA; Parekh PR; Weyemi US; Bonner WM
Aging, 2011年 - Histone γ-H2AX and poly(ADP ribose) as clinical pharmacodynamics biomarker.
Redon CE; Nakamura AJ; Zhang Y; Jiz J; Bonner WM; Kinders RJ; Parchments R; Doroshow JH; Pommier Y
Clinical Cancer Res., 2010年 - DNA double-strand breakes and ATM activation by transcription-blocking DNA lesions.
Sordet O; Nakamura AJ; Redon CE and Pommier Y.
Cell Cycle, 2010年 - H2AX: functional role and potential applications.
Dickey JS; Redon CE; Nakamura AJ; Baird BJ; Bonner WM and Sedelnikova OA.
Chromosoma, 2009年 - Where did they come from? The origins of endogenous γ-H2AX foci in tumor cells.
Nakamura AJ; Redon CE; Sedelnikova OA
Cell Cycle, 2009年
筆頭著者 - γ-H2AX and cancer.
Bonner WM; Redon CE; Dickey JS; Nakamura AJ; Sedelnikova OA; Solier S; Pommier, Y
Nature Review Cancer, 2008年
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9784254301175 - Methods for the assessment of telomere status.
単著
Cell Senescence. Methods Mol. Biol., 2013年 - γ-H2AX formation and chromatin structure.
Nakamura AJ; Parekh P; martin OA; Bonner WM; Redon CE, 共著
Advances in Genet. Res., 2012年 - H2AX and DNA damage response.
Redon CE; Dickey JS; Nakamura AJ; Sedelnikova OA; Bonner WM, 共著
Current Cancer Research: Molecular Determinants of Radiation Response, 2011年 - γ-H2AX detection peripheral blood lymphocytes, splenocytes, bone marrow, xenografts, and skin.
Redon CE; Nakamura AJ; Sordet O; Dickey JS; Gouliaeva K; Tabb B; Lawrence S; Kinders RJ; Bonner WM; Sedelnikova OA, 共著
Methods Mol. Biol., 2011年 - Stress and γ-H2AX.
Dickey JS; Redon CE; Nakamura AJ; Baird BJ; Sedelnikova OA; Bonner WM, 共著
Handbook of cell signaling, Regulation of organelle and Cell compartment Signalling., 2010年 - Techniques for γ-H2AX detection.
Nakamura A; Sedelnikova OA; Redon C; Pilch DR; Sinogeeva NI; Shroff R; Michael L; Bonner WM, 共著
Methods in Enzymology, 2006年 - ナイミーヘン症候群における二本鎖DNA切断修復の異常
中村麻子、小松賢志, 共著
共立出版, 2001年06月
講演・口頭発表等
- DNA二本鎖切断レベルのモニタリングを利用したがん治療評価および有害事象リスク予測の将来展望
中村麻子
第34回日本乳癌検診学会学術総会, 2024年11月29日, ［招待有り］
20241129, 20241130 - 植物残渣抽出成分の放射線防護剤としての有用性検討
鈴木 智也; 大泉 昂之; 舟山 知夫; 中村 麻子1
QST高崎サイエンスフェスタ2022, 2022年12月16日 - Age dependence of radiation-induced cellular and tissue responses in mouse.
Takashi Oizumi; Rika Shitomi; Yi Shang; Shizuko Kakinuma; Asako J Nakamura
日本放射線影響学会第65回大会, 2022年09月17日
20220915, 20220917 - Analysis of the protective effect of Tempol against radiation-induced DNA damage and inflammatory responses in mice.
Masugata Shinya; Megumi Sasatani; Asako J. Nakamura
日本放射線影響学会第65回大会, 2022年09月16日
20220915, 20220917 - Evaluation of the radioprotective effect of Sugarcane extract and Hesperetin.
Tomoya Suzuki; Takashi Oizumi; Tomoo Funayama; Asako J. Nakamura
日本放射線影響学会第65回大会, 2022年09月16日
20220915, 20220917 - Analysis of the effects of housing in enriched environments on radiation carcinogenesis processes.
Yuri Matsugano; Shinya Yokomizo; Mayumi Nishimura,Takamitsu Morioka,Shizuko Kakinuma,Yoshiya Shimada,Asako J. Nakamura
日本放射線影響学会第65回大会, 2022年09月16日
20220915, 20220917 - Development of portable biodosimetry device using PDMS micro-fluidic chip.
Kenta Takahashi; Yuma Chihara; Takayuki Komori; Naohiro Fujisawa; Asako J. Nakamura
日本放射線影響学会第65回大会, 2022年09月15日
20220915, 20220917 - DNA二本鎖切断の検出から可視化する放射線の影響
第59回アイソトープ・放射線研究発表会, 2022年07月07日, ［招待有り］ - 宇宙環境における生物の健康影響評価のためのDNA損傷検出デバイスと宇宙環境ヘルケアビジネスへの展開
中村麻子
2022年AMO討論会, 2022年06月10日, ［招待有り］
担当経験のある科目（授業）
所属学協会
共同研究・競争的資金等の研究課題
- 光線力学を利用した新規がん診断・治療のためのセラノスティクスシステム開発およびがんリスク制御のための分子基盤確立
2023年10月 - 2028年03月 - 現場における生体内DNA損傷モニタリング手法を用いた放射線がん治療後の有害事象リスク予測システムの構築
2020年04月 - 2021年03月 - 大規模放射線災害に対応できる複数の生物学的指標を組み合わせた線量推定システムの技術基盤構築
放射線健康管理・健康不安対策事業（放射線の健康影響に係る研究調査事業）
2018年04月 - 2021年03月 - 長期的視点に立った放射線に関する科学リテラシー涵養とリスクコミュニケーション人材育成のための小中学校における「目で見る」放射線科学教育の実践研究
放射線健康管理・健康不安対策事業（放射線の健康影響に係る研究調査事業）
2020年04月 - 低線量放射線は循環器疾患のリスクを上げるか？低線量率放射線は？放射線関連循環器疾患の機序の解明
放射線健康管理・健康不安対策事業（放射線の健康影響に係る研究調査事業）
2016年04月 - 2019年03月 - DNA損傷によるストレスの解剖とストレスの見える化
社会貢献活動
- 令和5年度常陸大宮市市民大学講座「DNAのキズが見えると何が分かる？」
講師
常陸大宮市, 2023年07月05日 - 2023年07月29日 - 令和4年度IBARAKIドリームパスAWARD
コメンテーター
2023年02月18日 - 茨城県高等学校長協会研修会
講師
2022年09月26日 - 茨城大学図書館 土曜アカデミー「大学発ベンチャー立ち上げました：DNAのキズの見える化で何ができるか」
講師
2022年07月30日 - 令和3年度IBARAKIドリームパスAWARD
コメンテーター
2022年01月30日 - 高崎市立高崎経済大学附属高等学校 オンライン系統別模擬授業
講師
2021年07月07日 - 水戸第三高等学校出前授業
講師
2021年06月25日 - 2020年度IBARAKIドリームパス中間発表会講演
講師
2020年12月20日 - 紫西グローバルチャレンジII事業 下館第一高等学校 大学実験講座
講師
2020年11月21日 - 2020年11月22日 - 令和2年度茨城高校イバダイ特別講座
講師
2020年09月19日 - 茨城テックプランター2020キックオフイベント
講師
株式会社リバネス, 2020年09月16日 - 紫西グローバルチャレンジII事業 下館第一高等学校 大学実験講座
講師
2019年09月07日 - 2019年09月08日 - 緑岡高校出前授業
講師
2016年10月13日 - 女子高校生サイエンス＆テクノロジー教室
講師
2016年09月03日 - 土浦第三高等学校出前授業
講師
2016年06月15日 - 下妻第一高等学校出前授業
講師
2015年11月12日 - 青少年のための科学の祭典 第6回ひたちなか大会
講師
2014年11月02日 - 夢ナビライブ学びステーション
助言・指導
2014年07月12日
学術貢献活動
