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Origin of radiation-induced genomic instability

辐射引起的基因组不稳定性的起源

基本信息

批准号：
14208068
负责人：
KOMATSU Kenshi
金额：
$ 33.86万
依托单位：
Kyoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2005
项目状态：
已结题

项目摘要

NBS1 is a responsible protein for recessive hereditary disease Nijmegen breakage syndrome, which is characterized by high sensitivity to ionizing radiation, chromosomal instability and predisposition to tumor. We demonstrated here that NBS1 regulates homologous recombination repair and the patients with defect in homologous recombination can survive, while it causes genomic instability and tumorigenesis. Present results also showed that NBS1 recruits MRE11 nuclease to sites of double strand breaks through interaction with histon H2AX. In addition to these interactions, NBS1 also binds to WRN, a protein for accelerated aging disease Werner syndrome, and FANC, a protein for recessive hereditary disease Fancony anemia, which is characterized by high sensitivity to inter-crosslinked DNA damage. Although their role in response to double strand breaks remains elusive, this repair network could contribute to genome stability after generation of DNA damage. On the basis of phenotypic resembles, Nijmegen breakage syndrome is categolized to Ataxia telangiectasia (A-T), which is mutated in ATM protein, and A-T like disorder, which is defective in MRE11. Our results also showed that NBS1 is associated with ATM and MRE11for cell cycle checkpoint but not for DNA repair via homologous recombination. Taken together, these results could shed light on a crossroad between checkpoint and DNA repair, whereas they must associated to maintain genome stability after exposure to ionizing radiation.

NBS 1是一种隐性遗传病Nijmegen断裂综合征的致病蛋白，该综合征具有对电离辐射高度敏感、染色体不稳定和易患肿瘤等特点。我们在这里证明，NBS 1调节同源重组修复，同源重组缺陷的患者可以生存，但它会导致基因组不稳定和肿瘤发生。目前的结果还表明，NBS 1通过与希斯顿H2 AX相互作用将MRE 11核酸酶募集到双链断裂位点。除了这些相互作用，NBS 1还结合WRN，一种加速老化疾病Werner综合征的蛋白质，和FANC，一种隐性遗传疾病Fancony贫血的蛋白质，其特征是对交联DNA损伤的高敏感性。虽然它们在响应双链断裂中的作用仍然难以捉摸，但这种修复网络可能有助于DNA损伤后的基因组稳定性。基于表型相似性，Nijmegen断裂综合征被分类为ATM蛋白突变的共济失调毛细血管扩张症（A-T）和MRE 11缺陷的A-T样疾病。我们的研究结果还表明，NBS 1与ATM和MRE 11通过同源重组在细胞周期检查点中相关，但在DNA修复中不相关。总之，这些结果可以揭示检查点和DNA修复之间的交叉点，而它们必须在暴露于电离辐射后保持基因组稳定性。