Functional link between ataxia-telangiectasia and Nijmegen breakage syndrome gene products
Functional link between ataxia-telangiectasia and Nijmegen breakage syndrome gene products
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DOI：
10.1038/35013083
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发表时间：
2000-05
期刊：
影响因子：
64.8
通讯作者：
Song Zhao;Yi-Chinn Weng;S. F. Yuan;Yi-Tzu Lin;H. Hsu;Suh-Chin J. Lin;E. Gerbino;Mei-hua Song;M. Zdzienicka;R. Gatti;J. Shay;Y. Ziv;Y. Shiloh;E. Y. Lee
中科院分区：
文献类型：
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作者：
Song Zhao;Yi-Chinn Weng;S. F. Yuan;Yi-Tzu Lin;H. Hsu;Suh-Chin J. Lin;E. Gerbino;Mei-hua Song;M. Zdzienicka;R. Gatti;J. Shay;Y. Ziv;Y. Shiloh;E. Y. Lee
共济失调毛细血管扩张症（A-T）和奈亨断裂综合征（NBS）是一种具有癌症易感性和相似细胞表型的隐性遗传疾病。负责a -t的基因的蛋白质产物，被称为ATM，是一个以羧基端磷脂酰肌醇3-激酶样结构域为特征的激酶家族的成员。NBS1蛋白在奈亨破裂综合征患者中发生特异性突变，并与DNA修复蛋白Rad50和Mre11形成复合物。在这里，我们发现电离辐射诱导的NBS1磷酸化需要催化活性的ATM。含有ATM和NBS1的复合物存在于未处理的细胞和电离辐射处理的细胞中。我们已经确定了NBS1的两个残基，即Ser 278和Ser 343，它们在体外被ATM磷酸化，其在体内的修饰对于细胞对DNA损伤的反应至关重要。这种反应包括s期检查点激活、NBS1/Mre11/Rad50核病灶的形成和对电离辐射超敏反应的恢复。总之，这些结果表明，在两种表型重叠的遗传疾病中，DNA损伤激活的细胞周期检查点和DNA修复之间存在生化联系。
Ataxia-telangiectasia (A-T) and Nijmegen breakage syndrome (NBS) are recessive genetic disorders with susceptibility to cancer and similar cellular phenotypes. The protein product of the gene responsible for A-T, designated ATM, is a member of a family of kinases characterized by a carboxy-terminal phosphatidylinositol 3-kinase-like domain,. The NBS1 protein is specifically mutated in patients with Nijmegen breakage syndrome and forms a complex with the DNA repair proteins Rad50 and Mre11,,,. Here we show that phosphorylation of NBS1, induced by ionizing radiation, requires catalytically active ATM. Complexes containing ATM and NBS1 existin vivoin both untreated cells and cells treated with ionizing radiation. We have identified two residues of NBS1, Ser 278 and Ser 343 that are phosphorylatedin vitroby ATM and whose modificationin vivois essential for the cellular response to DNA damage. This response includes S-phase checkpoint activation, formation of the NBS1/Mre11/Rad50 nuclear foci and rescue of hypersensitivity to ionizing radiation. Together, these results demonstrate a biochemical link between cell-cycle checkpoints activated by DNA damage and DNA repair in two genetic diseases with overlapping phenotypes.