Requirement of the MRN complex for ATM activation by DNA damage
Requirement of the MRN complex for ATM activation by DNA damage
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DOI：
10.1093/emboj/cdg541
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发表时间：
2003-10-15
期刊：
影响因子：
11.4
通讯作者：
Shiloh, Y
中科院分区：
文献类型：
--
作者：
Uziel, T;Lerenthal, Y;Shiloh, Y
ATM蛋白激酶是细胞对DNA双链断裂(DSB)反应的主要激活剂。作为对DSB的反应，ATM被激活，并使DNA损伤反应网络各个分支中的关键角色磷酸化。ATM缺乏导致遗传性共济失调-毛细血管扩张症(A-T)，以小脑变性、免疫缺陷、辐射敏感性、染色体不稳定和癌症易感性为特征。MRN复合体的核心是Mre11、Rad50和Nbs1蛋白，参与了DSB的初始加工。NBS1和Mre11基因亚型突变导致另外两种基因组不稳定性疾病：奈梅根断裂综合征(NBS)和A-T样病(A-TLD)。ATM和MRN在DSB响应的早期阶段的作用顺序尚不清楚。在这里，我们表明功能性MRN是ATM激活所必需的，因此也是ATM介导的通路及时激活所必需的。总而言之，这些和以前的结果指定了在DNA损伤反应途径中ATM上游和下游的MRN复合体的作用，并解释了A-T和A-TLD之间的临床相似性。
The ATM protein kinase is a primary activator of the cellular response to DNA double-strand breaks (DSBs). In response to DSBs, ATM is activated and phosphorylates key players in various branches of the DNA damage response network. ATM deficiency causes the genetic disorder ataxia-telangiectasia (A-T), characterized by cerebellar degeneration, immunodeficiency, radiation sensitivity, chromosomal instability and cancer predisposition. The MRN complex, whose core contains the Mre11, Rad50 and Nbs1 proteins, is involved in the initial processing of DSBs. Hypomorphic mutations in the NBS1 and MRE11 genes lead to two other genomic instability disorders: the Nijmegen breakage syndrome (NBS) and A-T like disease (A-TLD), respectively. The order in which ATM and MRN act in the early phase of the DSB response is unclear. Here we show that functional MRN is required for ATM activation, and consequently for timely activation of ATM-mediated pathways. Collectively, these and previous results assign to components of the MRN complex roles upstream and downstream of ATM in the DNA damage response pathway and explain the clinical resemblance between A-T and A-TLD.