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Cancersusceptibility disease Nijmegen Breakage Syndrome and the function of underlying gene.

癌症易感性疾病奈梅亨断裂综合征及其潜在基因的功能。

基本信息

批准号：
12213087
负责人：
KOMATSU Kenshi
金额：
$ 42.24万
依托单位：
KYOTO UNIVERSITY (2002-2004)Hiroshima University (2000-2001)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research on Priority Areas
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2004
项目状态：
已结题

项目摘要

Nijmegen breakage syndrome (NBS) is a human hereditary disease, characterized by high sensitivity to radiation, chromosomal instability and predisposition to cancer, and the underlying gene, NBS1, reveals to code a repair protein, which lacks both nuclease activity and DNA-binding region. We presented here that NBS1 binds Mre11/Ras50 complex, a crucial nuclease for homologous recombination, at the C-terminus. Moreover, based on the evidence that histon H2AX is phosphorylated immediately after irradiation, we showed NBS1 binds to the phosphorylated histon through FHA/BRCT domains at the N-terminus. This binding was confirmed by both IP-western and in vitro binding assay. As a result, we proposed a damage response model, in which NBS1 recognizes damaged sites and initiates homologous recombination by recruitment of Mre11/Rad50 nuclease. In fact, analysis of homologous recombination using SCneo reporter gene showed significantly decreased homologous recombination in patient cells and mouse NBS cells. Furthermore, cohesin SMC1 binding to NBS1 and consequently SMC1 phosphorylation, a dispensable modification for S-checkpoint, were repressed in the clone lacking the C-terminus and N-terminus of NBS1. Similarly, NBS1 revealed to form the multi-protein complex including BRCA1 and WRN, mutated in Werner Syndrome, after irradiation. Since the disruption of complex formation results in chromosomal instability, it must be involved in maintenance of repair fidelity and cross-talk with checkpoint.

Nijmegen断裂综合征（NBS）是一种人类遗传性疾病，具有辐射敏感性、染色体不稳定性和癌症易感性等特点，其基因NBS 1编码一种修复蛋白，但该蛋白缺乏核酸酶活性和DNA结合区。我们在这里提出，NBS 1结合Mre 11/Ras 50复合物，一个重要的核酸酶同源重组，在C-末端。此外，基于希斯顿H2 AX在照射后立即磷酸化的证据，我们表明NBS 1通过N末端的FHA/BRCT结构域与磷酸化的希斯顿结合。这种结合通过IP-蛋白质印迹和体外结合测定两者证实。因此，我们提出了一个损伤反应模型，其中NBS 1识别受损位点，并通过募集Mre 11/Rad 50核酸酶启动同源重组。事实上，使用SCneo报告基因的同源重组分析显示患者细胞和小鼠NBS细胞中的同源重组显著减少。此外，在缺乏NBS 1的C-末端和N-末端的克隆中，与NBS 1结合的粘附素SMC 1以及随后的SMC 1磷酸化（S-检查点的一种修饰）被抑制。同样，NBS 1在Werner综合征中突变后形成了包括BRCA 1和WRN的多蛋白复合物。由于复合物形成的破坏导致染色体不稳定，因此它必须参与维持修复保真度和与检查点的串扰。