| Project/Area Number |
16310043
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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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 | KYUSHU UNIVERCITY |
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Principal Investigator |
TSUZUKI Teruhisa Kyushu University, Faculty of Medical Sciences, Department of Medical Physics and Radiation Biology, Professor, 大学院医学研究院, 教授 (40155429)
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| Co-Investigator(Kenkyū-buntansha) |
NAKATSU Yoshimichi Kyushu University, Faculty of Medical Sciences, Department of Medical Physics and Radiation Biology, Associate Professor, 大学院医学研究院, 助教授 (00207820)
HAYAKAWA Hiroshi Fukuoka Dental College, Department of Biochemistry, Professor, 歯学部, 教授 (70150422)
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| Project Period (FY) |
2004 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥15,800,000 (Direct Cost: ¥15,800,000)
Fiscal Year 2006: ¥3,000,000 (Direct Cost: ¥3,000,000)
Fiscal Year 2005: ¥4,600,000 (Direct Cost: ¥4,600,000)
Fiscal Year 2004: ¥8,200,000 (Direct Cost: ¥8,200,000)
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| Keywords | gene / nucleic acids / environment / genome / radiation / mutation / mutagenesis / oxidative stress / reactive oxygen species / 酸化的DNA損傷 / 8-オキソグアニン / 変異スペクトラム / 酸化的RNA損傷 / 細胞死 |
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| Research Abstract |
Oxygen radicals are produced through normal cellular metabolism, and formation of such radicals is enhanced further by ionizing radiation and by various chemicals. The oxygen radicals attack nucleic acids and generate various modified bases in DNA. Among them, 8-oxoguanine (8-oxoG) is the most abundant, and seems to play a critical role in mutagenesis as well as carcinogenesis and aging. 8-OxoG can pair with both cytosine and adenine during DNA synthesis, and as a result, G : C to T : A transversions are induced. Oxidation of guanine also occurs in the cellular nucleotide pool. 8-Oxo-dGTP, when formed, is a potent mutagenic substrate for DNA synthesis ; it is equally incorporated opposite both adenine and cytosine in DNA, resulting in both A : T to C : G and G : C to T : A transversions. In order to establish a sensitive assay system for detecting mutagenesis caused by oxidative DNA damage, we used the rpsL transgene as a reporter for the mutation assay, a suitable system for identifying a spectrum of base substitutions and single-base frameshifts. Using the resulting DNA repair-deficient mice with the rpsL transgene (rpsL hemizygotes), we examined oxidative stress-induced mutations occurring in the tissues of different DNA repair-deficient mouse lines. The frequency of G : C to T : A transversions was significantly increased both in Ogg1^<-/-> and Mutyh^<-/-> mice when administered with KBrO_3 in drinking water. We observed an increased incidence of G : C to A : T transitions in Ogg1^<-/-> mice after exposure to low dose X-ray irradiation (4 Gy). We further detected a characteristic spectra of A : T to G : C transitions in the spleens of X-ray-irradiated Mth1^<-/-> mice. In this study, we have shown a characteristic difference in the mutational spectra of wild-type mice and several DNA repair-deficient mice, such as Mth1,Ogg1,and Mutyh.
We also examined the interaction between mammalian enzymes and oxidatively damaged ribonucleotides/RNA.
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