| Project/Area Number |
26281029
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Partial Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Risk sciences of radiation and 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) |
須井 哉 一般財団法人食品薬品安全センター秦野研究所, 安全性事業部 安全性評価室, グループリーダー (50426433)
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| Project Period (FY) |
2014-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥15,990,000 (Direct Cost: ¥12,300,000、Indirect Cost: ¥3,690,000)
Fiscal Year 2017: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
Fiscal Year 2016: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000)
Fiscal Year 2015: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000)
Fiscal Year 2014: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000)
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| Keywords | 炎症 / 遺伝毒性 / 発がん / 酸化DNA損傷 / DNAポリメラーゼ カッパ / トランスリージョンDNA合成 / 突然変異 / 閾値 / ベンツピレン / DNAポリメラーゼ κ / DNAポリメラーゼ / リスク評価 / 環境変異原 |
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| Outline of Final Research Achievements |
DNA polymerase kappa (Polk) is a specialized DNA polymerase that bypasses several DNA lesions efficiently and accurately. We generated knock-in mice that express inactive Polk and crossed with gpt delta mice that possess reporter genes for mutations in vivo. The resulting mice were hypersensitive to mutations and tumor formation in colon induced by inflammation caused by treatments with dextran sulfate sodium. The results suggest that Polk mediates error-free bypass DNA synthesis across DNA lesions induced by inflammation and also that it suppresses inflammation-induced carcinogenesis, which accounts for 25% of human cancer. In regulatory toxicology, it is assumed that genotoxic carcinogens have no thresholds or safe dose. It is pointed out, however, that self-defense mechanisms may suppress genotoxicity at low doses, thereby constituting practical threshold. Polk may be a constituent of the practical threshold against genotoxic carcinogens that induce inflammation.
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| Academic Significance and Societal Importance of the Research Achievements |
DNAに傷を付けて突然変異を起こす発がん物質は遺伝毒性発がん物質と呼ばれ、その発がん作用に閾値は無いとして各種の規制が行われている。しかしヒトには各種の生体防御機能が備わっており、低用量であれば遺伝毒性発がん物質の作用を無毒化し事実上の閾値を形成する可能性が考えられる。DNAポリメラーゼκ (カッパ、Polkと略)は、DNA損傷を誤りなく乗り越えてDNA合成を続けるトランスリージョン型DNAポリメラーゼである。本研究は、Polkが遺伝毒性発がん物質の閾値形成に関与する可能性を検討し、炎症に基づく突然変異と発がんの閾値形成への寄与を示唆した。
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