| Project/Area Number |
10216206
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| Research Category |
Grant-in-Aid for Scientific Research on Priority Areas
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| Allocation Type | Single-year Grants |
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| Review Section |
Biological Sciences
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| Research Institution | Kyoto University |
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Principal Investigator |
TACHIBANA Akira Kyoto University, Radiation Biology Center, Associate Professor, 放射線生物研究センター, 助教授 (20188262)
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| Co-Investigator(Kenkyū-buntansha) |
EJIMA Yosuke Kyoto University, Radiation Biology Center, Associate Professor, 放射線生物研究センター, 助教授 (50127057)
SASAKI Masao Kyoto University, Radiation Biology Center, Professor, 放射線生物研究センター, 教授 (20013857)
TODO Takeshi Kyoto University, Radiation Biology Center, Professor, 放射線生物研究センター, 教授 (90163948)
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| Project Period (FY) |
1998 – 2002
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| Project Status |
Completed (Fiscal Year 2003)
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| Budget Amount *help |
¥31,100,000 (Direct Cost: ¥31,100,000)
Fiscal Year 2002: ¥4,300,000 (Direct Cost: ¥4,300,000)
Fiscal Year 2001: ¥4,500,000 (Direct Cost: ¥4,500,000)
Fiscal Year 2000: ¥6,200,000 (Direct Cost: ¥6,200,000)
Fiscal Year 1999: ¥6,600,000 (Direct Cost: ¥6,600,000)
Fiscal Year 1998: ¥9,500,000 (Direct Cost: ¥9,500,000)
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| Keywords | DNA rejoining / Bloom syndrome / DNA double-strand breaks / chromosome instability / RecQ hellcase / radiation damage / ataxia-telangiectasia / deletion mutation / 放射線適応応答 / p53 / 染色体異常 / 細胞内情報伝達系 / 非相同的組換え / DNA2本鎖切断修復 / 高発癌性劣性遺伝病 / p53遺伝子 / 相同的組換え |
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| Research Abstract |
Repair of DSBs is important to prevent chromosomal fragmentation, translocations and deletions. To investigate the process of NHEJ, we have established an in vitro system to clarify the measurement and analysis of the efficiency and the fidelity of rejoining of DSBs, and applied the method to investigate NHEJ in human cells derived from patients suffering from cancer-prone hereditary diseases. The efficiency of rejoining in the nuclear extract from an ataxia-telangiectasia (A-T) cell line was comparable to that from a control cell line. However, the accuracy of rejoining was much lower for the A-T cell extract than for the control cell extract. All mutations were deletions, most of which contained short direct repeats at the breakpoint junctions. The deletion spectrum caused by the A-T nuclear extract was distinct from that by the control extract. These results indicate that A-T cells have certain deficiencies in end-joining of double-strand breaks in DNA. The extract from Bloom syndro
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me cells also showed the similar activity and the lower fidelity of rejoing compared to that from normal cells. From the sequencing analysis of the junction o. DSBs, it is speculated that the defect in the BLM helicase might cause irregular rejoining of DSBs. Radioadaptive response is the acquirement of cellular resistance to ionizing radiation by prior exposure to low dose. We investigated the in vitro end-joining activity of DNA ends in radioadaptive cells. Both the efficiency and the fidelity of rejoining in the cells pre-exposed to low dose are increased comparing to those without pre-exposure. We also found that in p53-deficient cells, pre-irradiation caused no apparent alteration in both the efficiency and fidelity of end-joining. These results suggest that the exposure to low dose activates a cellular function to repair DSBs efficiently, which is dependent on p53. These results indicate that NHEJ pathway is regulated by many factors ; genetic regulation by ATM and BLM, and physiological conditions such as irradiation with ionizing radiation. The observations also suggest that in some occasions p53 might play a key role in NHEJ. Less
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