| Project/Area Number |
12672201
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Human genetics
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| Research Institution | HIROSHIMA UNIVERSITY |
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Principal Investigator |
MATSUURA Shinya Research Institute for Radiation Biology and Medicine, Hiroshima University, Associate Professor, 原爆放射能医学研究所, 助教授 (90274133)
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| Co-Investigator(Kenkyū-buntansha) |
SHINOHARA Miki Research Institute for Radiation Biology and Medicine, Hiroshima University, Research Assosiate, 原爆放射能医学研究所, 助手 (80335687)
KOMATSU Kenshi Research Institute for Radiation Biology and Medicine, Hiroshima University, Professor, 原爆放射能医学研究所, 教授 (80124577)
田内 広 広島大学, 原爆放射能医学研究所, 助手 (70216597)
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| Project Period (FY) |
2000 – 2001
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| Project Status |
Completed (Fiscal Year 2001)
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| Budget Amount *help |
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2001: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 2000: ¥1,900,000 (Direct Cost: ¥1,900,000)
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| Keywords | NBS / AT / NBS1 / Radiation / dsb / ATM / telomere / focus / 放射線高感受性 / 染色体不安定性 / ノックアウトマウス / Nbs1 / Atm / Ku70 / 高発癌性 / 免疫不全 |
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| Research Abstract |
The gene mutated in Nijmegen breakage syndrome, NBS1, encodes a 95-kD protein that forms a complex with RAD50 and MRE11, and the complex is involved in the initiation process of DNA double strand break repair. In mouse, complete loss of Nbs1 gene results in early embryonic lethality and ES cells inviality. Therefore, it has been suggested that human NBS patients are not null mutants but hypomorphic mutants. Consistent with this prediction, C-terminal truncated NBS1 protein was identified in NBS patients. In this study, we targeted for disruption of Nbs1 gene by replacing 3'-half of exon 3 and all exons of 4 and 5 into LacZ gene and PGKneo cassette. Our Nbs1 mutants also exhibited embryonic lethality, but the phenotypes were much milder than those reported previously. The timing of embrynic death delayed to the post-implantation stage of 8.5-9.5 dpc and the embryonic fibroblast cells were virtually viable. Analysis of embryonic fibroblasts revealed that the Nbs1 mutant allele expressed an unexpected small quantity of C-terminal Nbs1 protein, which may be analogous to the human C-terminal protein. Consistent with this result, the absence of C-terminal Nbs1 protein, by removing the PGKneo cassete, advanced the timing of embrynic death. We, therefore, concluded that the C-terminal Nbs1 protein diminished severity of lethal phenotype in mouse Nbs1 null mutants.
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