| Project/Area Number |
15310039
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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 | HIROSHIMA UNIVERSITY |
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Principal Investigator |
MIYAGAWA Kiyoshi Hiroshima University, Research Institute for Radiation Biology and Medicine, Professor, 原爆放射線医科学研究所, 教授 (40200133)
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| Project Period (FY) |
2003 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥15,800,000 (Direct Cost: ¥15,800,000)
Fiscal Year 2004: ¥7,600,000 (Direct Cost: ¥7,600,000)
Fiscal Year 2003: ¥8,200,000 (Direct Cost: ¥8,200,000)
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| Keywords | Radiation sensitivity / XRCC3 / Homologous recombination / Endoreduplication / DNA metabolism / ゲノム不安定 / DNA修復 / 乳がん / 染色体異常 / 相同組み換え / ゲノム不安定性 |
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| Research Abstract |
It is of great importance that radiation sensitivity can be predicted before radiation therapy because radiation sensitivity is significantly associated with efficacy of therapy and side effects. In addition, radiation sensitivity is also associated with disease occurrence in radiation casualty. Thus, radiation sensitivity is very important in radiation medicine. However, molecular mechanisms of radiation sensitivity are largely unknown. To address this issue, we have analysed biological significance of genetic polymorphisms associated with radiation sensitivity by generating human cells deficient in DNA double-strand break repair genes. We successfully generated human cell lines deficient in XRCC3, a gene involved in homologous recombinational repair. XRCC3-deficient cells show hypersensitivity to DNA-damaging agents, a defect in homologous recombination and chromosome breaks. Furthermore, the frequency of endoreduplication is significantly increased in these cells, suggesting that XRCC3 maintains chromosome integrity by preventing DNA rereplication. The T241M variation has been shown to be associated with cancer risk. The biological significance of this variation was examined by the introduction of this variant in XRCC3-deficient cells. To our surprise, this variant shows intact reoombinational repair activity but loses the ability to prevent endoreduplication. This finding suggests that 241M contributes to cancer risk by inducing numeral chromosome aberrations by promoting endoreduplication. Thus, genetic polymorphisms are often associated with DNA metabolic networks but are not necessarily associated with DNA repair activity.
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