权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Prediction of Radiation Sensitivity by Functional Analysis of Reeombinational Repair Genes in Human Cells

通过人体细胞重组修复基因的功能分析预测辐射敏感性

基本信息

批准号：
15310039
负责人：
MIYAGAWA Kiyoshi
金额：
$ 10.11万
依托单位：
HIROSHIMA UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

项目摘要

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.

放射敏感性与放射治疗的疗效和副作用密切相关，因此在放射治疗前预测放射敏感性具有重要意义。此外，辐射敏感性也与辐射损伤后疾病的发生有关。因此，辐射敏感性在放射医学中非常重要。然而，辐射敏感性的分子机制在很大程度上是未知的。为了解决这个问题，我们分析了与辐射敏感性相关的遗传多态性的生物学意义，通过产生缺乏DNA双链断裂修复基因的人类细胞。我们成功地产生了缺乏XRCC3的人类细胞系，XRCC3是一种参与同源重组修复的基因。XRCC3缺陷细胞显示对DNA损伤剂的超敏反应，这是同源重组和染色体断裂的缺陷。此外，在这些细胞中核内复制的频率显著增加，表明XRCC3通过阻止DNA再复制来维持染色体完整性。T241M变异已被证明与癌症风险相关。通过在XRCC 3缺陷细胞中引入该变体来检查该变异的生物学意义。令我们惊讶的是，这种变体显示出完整的重组修复活性，但失去了防止核内复制的能力。这一发现表明，241 M通过促进核内复制诱导染色体数目畸变而导致癌症风险。因此，遗传多态性通常与DNA代谢网络相关，但不一定与DNA修复活性相关。

项目成果

期刊论文数量（18）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Ishida, M.: "Mnkl is required for angiotensin II-induced protein systhesis in vascular smooth muscle cells"Circulation Research. 93(12). 1218-1224 (2003)

Ishida, M.：“Mnkl 是血管平滑肌细胞中血管紧张素 II 诱导的蛋白质合成所必需的”循环研究。

DOI：
发表时间：
期刊：
影响因子：
0
作者：
通讯作者：

XRCC3 deficienty results in a defect in recombination and increased endoreduplication in human cells.

XRCC3 缺陷会导致人类细胞重组缺陷和核内复制增加。

DOI：
发表时间：
2004
期刊：
EMBO J. 23
影响因子：
0
作者：
Yoshihara;T.
通讯作者：
T.

Gene trap mutagenesis-based forward genetic approach reveals that the tumor suppressor OVCA1 is a component of the biosynthetic pathway of diphthamide on elongation factor 2

DOI：
10.1074/jbc.m413017200
发表时间：
2005-03-18
期刊：
JOURNAL OF BIOLOGICAL CHEMISTRY
影响因子：
4.8
作者：
Nobukuni, Y;Kohno, K;Miyagawa, K
通讯作者：
Miyagawa, K

Structural basis for octameric ring formation and DNA interaction of the human homologous-pairing protein Dmc1

DOI：
10.1016/s1097-2765(04)00218-7
发表时间：
2004-05-07
期刊：
MOLECULAR CELL
影响因子：
16
作者：
Kinebuchi, T;Kagawa, W;Yokoyama, S
通讯作者：
Yokoyama, S

XRCC3 deficiency results in a defect in recombination and increased endoreduplication in human cells

DOI：
10.1038/sj.emboj.7600087
发表时间：
2004-02
期刊：
The EMBO Journal
影响因子：
0
作者：
Takashi Yoshihara;M. Ishida;A. Kinomura;M. Katsura;Takanori Tsuruga;S. Tashiro;T. Asahara;K. Miyagawa
通讯作者：
Takashi Yoshihara;M. Ishida;A. Kinomura;M. Katsura;Takanori Tsuruga;S. Tashiro;T. Asahara;K. Miyagawa