Induction of DNA double strand break by environmental genotoxic and carcinogenic agents

2010 Fiscal Year Final Research Report

• Project/Area Number: 18101002
• Research Category: Grant-in-Aid for Scientific Research (S)
• Allocation Type: Single-year Grants
• Research Field: Risk sciences of radiation/Chemicals
• Research Institution: Kyoto University
• Principal Investigator: KOMATSU Kenshi Kyoto University, 放射線生物研究センター, 教授 (80124577)
• Co-Investigator(Kenkyū-buntansha): YAGI Takasi 大阪府立大学, 産学官連携機構, 教授 (80182301) ; TAUCHI Hiroshi 茨城大学, 理学部, 教授 (70216597) ; KATO Akihiro 京都大学, 放射線生物研究センター, 研究員 (70423051) ; MORISIMA Kenichi 広島大学, 原爆放射線医科学研究所, 助教 (00363078) ; MATSUURA Shinya 広島大学, 原爆放射線医科学研究所, 教授 (90274133)
• Project Period (FY): 2006 – 2010
• Keywords: DNA修復 / 複製阻害 / H2AXリン酸化 / 環境変異原,NBS1

Research Abstract

By using phosphorylation of histone H2AX as a marker of DNA lesion, we showed here that DNA double strand breaks were generated by several environmental genotoxic and carcinogenic agents including UV and DNA cross-linking agents. These agents also induced gene mutations through translesional DNA synthesis, which is associated with NBS1. NBS1 is also involved in phosphorylation of H2AX and chromatin-remodeling at sites of DNA damage. Thus, NBS1 plays important roles in genome stability (inhibition of tumorigenesis) through DNA repair and cellular response to DNA lesions.

Research Products

• [Journal Article] Regulation of homologous recombination by RNF20-dependent H2B ubiquitination (2011)
  • Author(s): K.Nakamura, A.Kato, J.Kobayashi, H.Yanagihara, S.Sakamoto, D.V.N.P.Oliveira, M.Shimada, H.Tauchi, H.Suzuki, S.Tashiro, L.Zou, K.Komatsu.
  • Journal Title: Molecular Cell 41 Pages: 515-628
  • Peer Reviewed
• [Journal Article] Application of the DNA adductome approach to assess the DNA-damaging capability of in vitro micronucleus test-positive compounds (2011)
  • Author(s): Kato, K., Yamamura, E., Kawanishi, M., Yagi, T., Matsuda, T., Sugiyama, A., Uno.Y.
  • Journal Title: Mutat.Res. 721 Pages: 21-26
  • Peer Reviewed
• [Journal Article] Two unrelated patients with MRE11A mutations and Nijmegen breakage syndrome-like severe microcephaly. (2011)
  • Author(s): 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.
  • Journal Title: DNA Repair (Amst) 10 Pages: 314-321
  • Peer Reviewed
• [Journal Article] Bisbenzamidine derivative, pentamidine represses DNA damage response through inhibition of histone H2A acetylation. (2010)
  • Author(s): J.Kobayashi, A.Kato, Y.Ota, R.Ohba, K.Komatsu.
  • Journal Title: Mol.Cancer 9 Pages: 34
  • Peer Reviewed
• [Journal Article] Differential role of repair proteins, BRCA1/NBS1 and Ku70/DNA-PKcs, in radiation-induced centrosome over-duplication (2010)
  • Author(s): M.Shimada, J.Kobayashi, R.Hirayama, K.Komatsu.
  • Journal Title: Cancer Sci. 101 Pages: 2531-2537
  • Peer Reviewed
• [Journal Article] Gimeracil sensitizes cells to radiation via inhibition of homologous recombination. (2010)
  • Author(s): Takagi, M., Sakata, K., Someya, M., Tauchi, H., Iijima, K., Matsumoto, Y., Torigoe, T., Takahashi, A., Hareyama, M., Fukushima, M.
  • Journal Title: Radiotherapy & Oncology 96 Pages: 259-266
  • Peer Reviewed
• [Journal Article] WRN participates in translesion synthesis pathway through interaction with NBS1. (2010)
  • Author(s): J.Kobayashi, M.Okui, A.Asaithamby, S.Burma, B.P.Chen, K.Tanimoto, S.Matsuura, K.Komatsu, D.J.Chen.
  • Journal Title: Mechanisms of Ageing and Development 131 Pages: 436-444
  • Peer Reviewed
• [Journal Article] Acquired radioresistance of human tumor cells by DNA-PK/AKT/GSK3 β-mediated cyclinD1 overexpression. (2010)
  • Author(s): T.Shimura, S.Kakuda, Y.Ochiai, H.Nakagawa, Y.Kuwahara, Y.Takai, J.Kobayashi, K.Komatsu, M.Fukumoto.
  • Journal Title: Oncogene 29 Pages: 4826-4837
  • Peer Reviewed
• [Journal Article] Deletion of a novel F-box protein, MUS-10, in Neurospora crassa leads to altered mitochondrial morphology, instability of mtDNA and senescence. (2010)
  • Author(s): A.Kato, K.Kurashima, M.Chae, S.Sawada, S.Hatakeyama, S.Tanaka, H.Inoue.
  • Journal Title: Genetics. 185 Pages: 1257-1269
  • Peer Reviewed
• [Journal Article] Mutations of optineurin in amyotrophic lateral sclerosis. (2010)
  • Author(s): Maruyama H, Morino H, Ito H, Izumi Y, Kato H, Watanabe Y, Kinoshita Y, Kamada M, Nodera H, Suzuki H, Komure O, Matsuura S, Kobatake K, Morimoto N, Abe K, Suzuki N, Aoki M, Kawata A, Hirai T, Kato T, Ogasawara K, Hirano A, Takumi T, Kusaka H, Hagiwara K, Kaji R, Kawakami H.
  • Journal Title: Nature 465 Pages: 223-226
  • Peer Reviewed
• [Journal Article] HpSulf, a heparan sulfate 6-O-endosulfatase, is involved in the regulation of VEGF signaling during sea urchin development. (2010)
  • Author(s): Fujita K, Takechi E, Sakamoto N, Sumiyoshi N, Izumi S, Miyamoto T, Matsuura S, Tsurugaya T, Akasaka K, Yamamoto T.
  • Journal Title: Mech Dev 127 Pages: 235-245
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• [Journal Article] Sporadic neonatal Fanconi's anemia with VACTERL association. (2010)
  • Author(s): Kanemoto N, Fukushima T, Imoto N, Koike K, Kanemoto K, Matsuura S.
  • Journal Title: Pediatr Int 52 Pages: 141-142
  • Peer Reviewed
• [Journal Article] Two major factors involved in the reverse dose-rate effect for somatic mutation induction are the cell cycle position and LET value. (2009)
  • Author(s): H.Tauchi, H.Waku, E.Matsumoto, S.Yara, S.Okumura, Y.Iwata, K.Komatsu, Y.Furusawa, K.Eguchi-Kasai, A.Tachibana.
  • Journal Title: J Radiat Res. 50 Pages: 441-448
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• [Journal Article] DNA double strand break repair enzymes function at multiple steps in HIV-1 infection. (2009)
  • Author(s): Y.Sakurai, K.Komatsu, K.Agematsu, M.Matsuoka.
  • Journal Title: Retrovirology 6 Pages: 114
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• [Journal Article] Emerging connection between centrosome and DNA repair machinery. (2009)
  • Author(s): M.Shimada, K.Komatsu.
  • Journal Title: J Radiat Res. 50 Pages: 295-301
  • Peer Reviewed
• [Journal Article] Histone H2AX participates the DNA damage-induced ATM activation through interaction with NBS1. (2009)
  • Author(s): Kobayashi J, Tauchi H, Chen B, Bruma S, Tashiro S, Matsuura S, Tanimoto K, Chen DJ, Komatsu K.
  • Journal Title: Biochem Biophys Res Commun. 380 Pages: 752-757
  • Peer Reviewed
• [Journal Article] Genotoxicity of 3,6-dinitrobenzo [e]pyrene, a novel mutagen in ambient air and surface soil, in mammalian cells in vitro and in vivo. (2009)
  • Author(s): Kawanishi, M., Watanabe, T., Hagio, S., Ogo, S., Shimohara, C., Jouchi, R., Takayama, S., Hasei, T., Hirayama, T., Oda, Y., Yagi, T.
  • Journal Title: Mutagenesis 24 Pages: 279-284
  • Peer Reviewed
• [Journal Article] Genotoxicity of nano/microparticles in in vitro micronuclei, in vivo comet and mutation assay systems (2009)
  • Author(s): Totsuka, Y., Higuchi, T., Imai, T., Nishikawa, A., Nohmi, T., Kato, T., Masuda, S., Kinae, N., Hiyoshi, K., Ogo, S., Kawanishi, M., Yagi, T Ichinose, T., Sugimura, T., Wakabayashi, K.
  • Journal Title: Particle fibre toxicol. 6(23) Pages: 6-23
  • Peer Reviewed
• [Journal Article] Centrosome maintenance and genome instability. (2009)
  • Author(s): Shimada M.Komatsu K.
  • Journal Title: J Radiat Res in press
  • Peer Reviewed
• [Journal Article] Inactivation of the Nijmegen breakage syndrome gene NBS1 leads to excess centrosome duplication via the ATR/BRCA1 pathway. (2009)
  • Author(s): Shimada M, Sagae R, Kobayashi J, Habu T, Komatsu K.
  • Journal Title: Cancer Research 69 Pages: 1768-1775
  • Peer Reviewed
• [Journal Article] Current topics in DNA double-strand break repair. (2009)
  • Author(s): Kobayashi J, Iwabuchi K, Miyagawa K, Sonoda E, Suzuki K, Takata M, Tauchi H.
  • Journal Title: J Radiat Res 49 Pages: 93-103
  • Peer Reviewed
• [Journal Article] Establishment of a method for analyzing translesion DNA synthesis across a single bulky adduct in human cells. (2009)
  • Author(s): Sawai, T., Kawanishi, M., Takamura-Enya T., Yagi.T.
  • Journal Title: Genes Environ. 31 Pages: 24-30
  • Peer Reviewed
• [Journal Article] NBS1 prevents chromatid-type aberrations through ATM-dependent interactions with SMC1. (2008)
  • Author(s): Antoccia A, Sakamoto S, Matsuura S, Tauchi H, Komatsu K.
  • Journal Title: Radiat Res. 170 Pages: 345-352
  • Peer Reviewed
• [Journal Article] Absence of Ku70 gene obliterates X-ray-induced lacZ mutagenesis of small deletions in mouse tissues. (2008)
  • Author(s): Uehara Y, Ikehata H, Komura J, Ito A, Ogata M, Itoh T, Hirayama R, Furusawa Y, Ando K, Paunesku T, Woloschak GE, Komatsu K, Matsuura S, Ikura T, Kamiya K, Ono T.
  • Journal Title: Radiat Res. 170 Pages: 216-223
  • Peer Reviewed
• [Journal Article] Potential Link between Alternative Splicing of the NBS1 Gene and the DNA Damage/Environmental Stress. (2008)
  • Author(s): Takai K, Sakamoto S, Sakai T, Yasunaga J, Komatsu K, Matsuoka M.
  • Journal Title: Radiat Res. 170 Pages: 33-40
  • Peer Reviewed
• [Journal Article] NBS1 regulates a novel apoptotic pathway through Bax activation. (2008)
  • Author(s): Iijima K, Muranaka C, Kobayashi J, Sakamoto S, Komatsu K, Matsuura S, Kubota N, Tauchi H.
  • Journal Title: DNA Repair 7 Pages: 1705-1716
  • Peer Reviewed
• [Journal Article] Impaired removal of DNA interstrand cross-link in Nijmegen breakage syndrome and Fanconi anemia, but not in BRCA-defective group. (2008)
  • Author(s): Tsuchida K., Komatsu K.
  • Journal Title: Cancer Sci. 99 Pages: 2238-2243
  • Peer Reviewed
• [Journal Article] Polyaromatic hydrocarbons cause histone H2AX phosphorylation in the S-phase of the cell cycle. (2008)
  • Author(s): Shimohara, C., Sawai, T., Yagi, T.
  • Journal Title: Genes Environ. 30 Pages: 92-99
  • Peer Reviewed
• [Journal Article] Mutagenic specificity of N-acetoxy-3-aminobenzanthrone, a major metabolically activated form of 3-nitrobenzanthrone, in shuttle vector plasmids propagated in human cells. (2008)
  • Author(s): Nishida, H., Kawanishi, M., Takamura-Enya, T., Yagi, T.
  • Journal Title: Mutat.Res. 654 Pages: 82-87
  • Peer Reviewed
• [Journal Article] Rapid myeloid recovery as a possible mechanism of whole-body radioadaptive response. (2008)
  • Author(s): Ohtsuka, K., Koana, T., Tomita, M., Ogata, H., Tauchi, H.
  • Journal Title: Radiation Research 170 Pages: 307-315
  • Peer Reviewed
• [Journal Article] Dancing on damaged chromatin : Functions of ATM and the RAD50/MRE11/NBS1 complex in cellular responses to DNA damage. (2008)
  • Author(s): Iijima, K., Ohara, M., Seki, R., Tauchi, H.
  • Journal Title: Journal of Radiation Reseaeach 49 Pages: 451-464
  • Peer Reviewed
• [Journal Article] Combined BubR1 protein down-regulation and RASSF1A hypermethylation in Wilms tumors with diverse cytogenetic changes. (2008)
  • Author(s): Haruta M, Matsumoto Y, Izumi H, Watanabe N, Fukuzawa M, Matsuura S, Kaneko Y.
  • Journal Title: Mol Carcinog. 47 Pages: 660-666
  • Peer Reviewed
• [Journal Article] Centrosome amplification induced by survivin suppression enhances both chromosome instability and radiosensitivity in glioma cells. (2008)
  • Author(s): Saito T, Hama S, Izumi H, Yamasaki F, Kajiwara Y, Matsuura S, Morishima K, Hidaka T, Shrestha P, Sugiyama K, Kurisu K.
  • Journal Title: Br J Cancer. 98 Pages: 345-355
  • Peer Reviewed
• [Journal Article] Homologous recombination repair is regulated by domains at the N- and C-terminus of NBS1 and is dissociated with ATM functions. (2007)
  • Author(s): Sakamoto.S., Iijima.K., Mochizuki.D., Nakamura.K., Teshigawara.K., Kobayashi.J., Matsuura.S., Tauchi.H.Komatsu K.
  • Journal Title: Oncogene. 26 Pages: 6002-6009
  • Peer Reviewed
• [Journal Article] TopBP1 associates with NBS1 and is involved in homologous recombination repair. (2007)
  • Author(s): Morisima.K., Sakamoto.S., Kobayashi.J., Izumi.H., Suda.T., Matsumoto.Y., Tauchi.H., Ide.H., Komatsu K.Matsuura.S.
  • Journal Title: Biochem Biophys Res Commun. 362 Pages: 872-879
  • Peer Reviewed
• [Journal Article] Structural identification of DNA adducts derived from 3-nitrobenzanthrone, a potent carcinogen present in the atmosphere. (2007)
  • Author(s): Takamura-Enya, T., Kawanishi, M, Yagi, T., Hisamatsu, Y.
  • Journal Title: Chemistry an Asian Journal 2 Pages: 1174-1185
  • Peer Reviewed
• [Journal Article] DNA adduct formation in human hepatoma cells treated with 3-nitrobenzanthrone : analysis by the 32P-postlabeling method. (2007)
  • Author(s): Kanno, T., Kawanishi, M., Takamura-Enya, T., Arlt, V.M., Phillips, D.H., Yagi.T.
  • Journal Title: Mutat.Res. 634 Pages: 184-191
  • Peer Reviewed
• [Journal Article] Characterization of the plant homolog of Nijmegen breakage syndrome 1 : involvement in DNA repair and recombination. (2007)
  • Author(s): Akutsu, N., Iijima, K., Hinata, T., Tauchi, H.
  • Journal Title: Biochemical and Biophysical Research Communications 393 Pages: 394-398
  • Peer Reviewed
• [Journal Article] Association of DNA-PK activity and radiation-induced NBS1 foci formation in lymphocytes with clinical malignancy in breast cancer patients. (2007)
  • Author(s): Someya, M., Sakata, K., Matsumoto, Y., Tauchi, H., Narimatsu, H., Hareyama, M.
  • Journal Title: Oncology Report 18 Pages: 873-878
  • Peer Reviewed
• [Journal Article] Neurosprora crassa RAD5 homologue, mus-41, inactivation results in higher sensitivity to mutagens but has little effect on PCNA-ubiquitylation in response to UV-irradiation. (2007)
  • Author(s): T Kawabata, A.Kato, K.Suzuki, H.Inoue.
  • Journal Title: Current Genetics 52 Pages: 125-135
  • Peer Reviewed
• [Journal Article] Nijmegen Breakage Syndrome and Functions of the Responsible Protein, NBS1. (2006)
  • Author(s): Antoccia, J.Kobayashi, H.Tauchi, S.Matsuura, K.Komatsu.
  • Journal Title: Genome Dyn.Basel, Karger. 1 Pages: 191-205
  • Peer Reviewed
• [Journal Article] ATM Activation by a Sulfhydryl-Reactive Inflammatory Cyclopentenone Prostaglandin. (2006)
  • Author(s): M.Kobayashi, H.Ono, K.Mihara, H.Tauchi, K.Komatsu, H.Shimizu, K.Uchida, K.Yamamoto.
  • Journal Title: Genes Cells 11(7) Pages: 779-789
  • Peer Reviewed
• [Journal Article] Association of Ionizing Radiation-Induced Foci of NBS1 with Chromosomal Instability and Breast Cancer Susceptibility. (2006)
  • Author(s): M.Someya, K.Sakata, H.Tauchi, Y.Matsumoto, A.Nakamura, K.Komatsu, M.Hareyama.
  • Journal Title: Radiation Research. 166 Pages: 575-582
  • Peer Reviewed
• [Journal Article] Monoallelic BUB1B Mutations and Defective Mitotic-Spindle Checkpoint in Seven Families With Premature Chromatid Separation (PCS) Syndrome. (2006)
  • Author(s): S.Matsuura, Y.Matsumoto, K.Morishima, H.Izumi, H.Matsumoto, E.Ito, K.Tsutsui, J.Kobayashi, H.Tauchi, Y.Kajiwara, S.Hama, K.Kurisu, H.Tahara, M.Oshimura, K.Komatsu, Tatsuro Ikeuchi, Tadashi Kajii.
  • Journal Title: Amer J Med Genet. 140(4) Pages: 358-367
  • Peer Reviewed
• [Journal Article] Identification of three major DNA adducts formed by the carcinogenic air pollutant 3-nitrobenzanthrone in rat lung at the C8 and N2 position of guanine and at the N6 position of adenine. (2006)
  • Author(s): Arlt, V.M., Schmeiser, H.H., Osborne, M.R., Kawanishi, M., Kanno, T., Yagi, T., Phillips D.H., Takamura-Enya, T.
  • Journal Title: International Journal of Cancer 118 Pages: 2139-2146
  • Peer Reviewed
• [Journal Article] Activation of Antioxidative Enzymes Induced by Low-Dose-Rate Whole-Body gamma Irradiation : Adaptive Response in Terms of Initial DNA Damage. (2006)
  • Author(s): Otsuka, K., Koana, T., Tauchi, H., Sakai, K.
  • Journal Title: Radiation Reserch 166 Pages: 474-478
  • Peer Reviewed
• [Journal Article] Identification and comparative analysis of the large subunit mitochondrial ribosomal proteins of Neurospora crassa. (2006)
  • Author(s): X.Gan, K.Arita, S.Isono, M.Kitakawa, K.Yoshino, K.Yonezawa, A.Kato, H.Inoue, K.Isono.
  • Journal Title: FEMS Microbiology Letters 254(1) Pages: 157-164
  • Peer Reviewed
• [Journal Article] DNA Repair Defect in AT Cells and their Hypersensitivity to Low-Dose-Rate Radiation. (2006)
  • Author(s): H.Nakamura, Y.Yasui, N.Saito, A.Tachibana, K.Komatsu, K.Ishizaki.
  • Journal Title: Radiation research. 165 Pages: 277-282
  • Peer Reviewed
• [Presentation] Control of homologous recombination by H2B ubiquitination (2010)
  • Author(s): 小松賢志
  • Organizer: International Conference on Biomedical and Environmental Science & Technology
  • Place of Presentation: Beijing(招待講演)
  • Year and Date: 2010-05-10
• [Presentation] ヒストンH2Bユビキチン化による相同組み換え修復の制御 (2009)
  • Author(s): 小松賢志
  • Organizer: 第68回日本癌学会学術総会
  • Place of Presentation: 横浜(シンポジウム、招待講演)
  • Year and Date: 2009-10-02
• [Presentation] Establishment of Reporter Assay Yeasts Responding to Ligands of Various Human Nuclear Receptors, and Roles of AhR Ligands to Induce or Protect DNA Damage Formation. (2009)
  • Author(s): Yagi, T.
  • Organizer: 10th International Conference on Environmental Mutagens
  • Place of Presentation: Firenze, Italy.(招待講演)
  • Year and Date: 2009-08-21
• [Presentation] NBS1 foci formation and divergent roles in response to DNA damage-eliciting agents. International Workshop on Ataxia-Telangiectasia (A-T) and ATM. (2006)
  • Author(s): 小松賢志
  • Organizer: Banff
  • Place of Presentation: Canada(invited)
  • Year and Date: 2006-09-10
• [Remarks] ホームページ等
  • URL: http://www.rbc.kyoto-u.ac.jp/Genome/kiban/index.html
• [Patent(Industrial Property Rights)] DNA鎖間架橋の測定方法およびDNA鎖間架橋の修復速度の測定方法 (2007)
  • Inventor(s): 槌田謙、小松賢志
  • Industrial Property Rights Holder: 国立大学法人京都大学
  • Patent Publication Number: 特許,特開2007-020467
  • Acquisition Date: 2007-02-01