2013 Fiscal Year Final Research Report
Studies on mechanisms underlying genotoxic thresholds through genetic modification of DNA polymerase zeta
| Project/Area Number |
22241016
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Risk sciences of radiation/Chemicals
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| Research Institution | National Institute of Health Sciences |
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Principal Investigator |
NOHMI Takehiko 国立医薬品食品衛生研究所, 安全性生物試験研究センター, 客員研究員 (30150890)
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| Co-Investigator(Kenkyū-buntansha) |
MASUMURA Kenichi 国立医薬品食品衛生研究所, 変異遺伝部, 室長 (40291116)
YASUI Manabu 国立医薬品食品衛生研究所, 変異遺伝部, 主任研究官 (50435707)
SAJI Tetsuya (SUZUKI Tetsuya) 労働安全衛生総合研究所, 健康障害予防研究部, 研究員 (20573950)
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| Co-Investigator(Renkei-kenkyūsha) |
TOYODA Naomi (HOKAIWADO Naomi) 国立医薬品食品衛生研究所, 変異遺伝部, 非常勤職員 (70381853)
GRUZ Petr 国立医薬品食品衛生研究所, 変異遺伝部, 主任研究官 (10321853)
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| Project Period (FY) |
2010-04-01 – 2014-03-31
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| Keywords | 閾値 / 遺伝毒性発がん物質 / トランスリージョンDNA合成 / DNAポリメラーゼζ / 突然変異 / DNA損傷 |
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| Research Abstract |
In regulatory toxicology, it is an axiom that there is no threshold for the action of genotoxic chemicals. Thus, genotoxic agents are not allowed to be present in food additives and others even at very low concentrations. However, humans possess various self defense mechanisms, which may suppress genotoxicity of chemicals at low doses. It is expected that self-defense mechanisms may constitute practical threshold for genotoxicity. In this study, we examined the possibility whether DNA polymerase zeta involved in translesion DNA synthesis plays a role in the practical threshold. To this end, we engineered human cells that expressed genetically modified DNA polymerase zeta. The cells expressing a variant of DNA polymerase zeta with low activity exhibited much higher sensitivity to oxidative genotoxic agents than the wild-type cells. We concluded that DNA polymerase zeta is an important constituent of the practical threshold for genotoxicity.
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[Journal Article] in vivo evidence that phenylalanine 171 acts as a molecular brake for translesion DNA synthesis across benzo[a]pyrene DNA adducts by human DNA polymerase2014
Author(s)
A. Sassa, T. Suzuki, Y. Kanemaru, N. Niimi, H. Fujimoto, A. Katafuchi, P. Gruz, M. Yasui, R.C. Gupta, F. Johnson, T. Ohta, M. Honma, N. Adachi and T. Nohmi
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Journal Title
DNA Repair
Volume: 15
Pages: 21-28
DOI
Peer Reviewed
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[Journal Article] Integration of in vivo genotoxicity and short-term carcinogenicity assays using F344 gpt delta transgenic rats : in vivo mutagenicity of 2,4-diaminotoluene and 2,6-diaminotoluene structural isomers2010
Author(s)
N Toyoda-Hokaiwado, T. Inoue, K. Masumura, H. Hayashi, Y. Kawamura, Y. Kurata, M. Takamune, M. Yamada, H. Sanada, T. Umemura, A. Nishikawa and T. Nohmi
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Journal Title
Toxicol. Sci.
Volume: 114
Pages: 71-78
DOI
Peer Reviewed
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[Presentation] Genotoxic thresholds : identification of mutations in vivo and mechanistic studies in vitro2011
Author(s)
T. Nohmi, K. Masumura, P Gruz, N. Toyoda-Hokaiwado, M. Takamune, N. Niimi, T. Suzuki, Y. Kanemaru, M. Yasui, M. Yamada, M. Honma, N. Adachi and A. Nishikawa
Organizer
2nd International Symposium on Genotoxic and Carcinogenic Thresholds
Place of Presentation
Tokyo
Year and Date
2011-11-23
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