ATM phosphorylates p95/nbs1 in an S-phase checkpoint pathway
ATM phosphorylates p95/nbs1 in an S-phase checkpoint pathway
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DOI：
10.1038/35007091
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发表时间：
2000-04-06
期刊：
影响因子：
64.8
通讯作者：
Kastan, MB
中科院分区：
文献类型：
--
作者：
Lim, DS;Kim, ST;Kastan, MB
ATM基因突变引起的共济失调-毛细血管扩张症（AT）和p95/nbs 1基因突变引起的奈梅亨断裂综合征（NBS）具有多种表型异常，如染色体不稳定性、辐射敏感性和细胞周期检查点对电离辐射的反应缺陷（1-4）。ATM基因编码一种蛋白激酶，可被电离辐射或拟放射性药物激活（5，6），而p95/nbs 1是蛋白复合物的一部分，参与对DNA双链断裂的反应（3，7）。在这里，由于AT和NBS之间的相似性，我们评估了ATM和p95/nbs 1之间的功能相互作用。电离辐射激活ATM激酶和诱导NBS细胞中ATM依赖性反应表明，p95/nbs 1可能不需要电离辐射后向ATM发出信号。然而，p95/nbs 1磷酸化丝氨酸343在ATM依赖的方式在体外和体内电离辐射后。在ATM磷酸化位点突变的p95/nbs 1构建体废除了正常细胞中电离辐射诱导的S期检查点，并且未能补偿NBS细胞中的这种功能缺陷。这些观察结果将ATM和p95/nbs 1在一个共同的信号通路中联系起来，并为这两种疾病的表型相似性提供了解释。
The rare diseases ataxia-telangiectasia (AT), caused by mutations in the ATM gene, and Nijmegen breakage syndrome (NBS), with mutations in the p95/nbs1 gene, share a variety of phenotypic abnormalities such as chromosomal instability, radiation sensitivity and defects in cell-cycle checkpoints in response to ionizing radiation(1-4). The ATM gene encodes a protein kinase that is activated by ionizing radiation or radiomimetic drugs(5,6), whereas p95/nbs1 is part of a protein complex that is involved in responses to DNA double-strand breaks(3,7). Here, because of the similarities between AT and NBS, we evaluated the functional interactions between ATM and p95/nbs1. Activation of the ATM kinase by ionizing radiation and induction of ATM-dependent responses in NBS cells indicated that p95/nbs1 may not be required for signalling to ATM after ionizing radiation. However, p95/nbs1 was phosphorylated on serine 343 in an ATM-dependent manner in vitro and in vivo after ionizing radiation. A p95/nbs1 construct mutated at the ATM phosphorylation site abrogated an S-phase checkpoint induced by ionizing radiation in normal cells and failed to compensate for this functional deficiency in NBS cells. These observations link ATM and p95/nbs1 in a common signalling pathway and provide an explanation for phenotypic similarities in these two diseases.