Kanu Nnennaya, Behrens Axel
Mammalian Genetics Laboratory, Cancer Research UK, London Research Institute, Lincoln's Inn Fields Laboratories, 44 Lincoln's Inn Fields, London, UK.
EMBO J. 2007 Jun 20;26(12):2933-41. doi: 10.1038/sj.emboj.7601733. Epub 2007 May 24.
The checkpoint kinase ATM (ataxia telangiectasia mutated) transduces genomic stress signals to halt cell cycle progression and promote DNA repair in response to DNA damage. Here, we report the characterisation of an essential cofactor for ATM, ATMIN (ATM INteracting protein). ATMIN interacts with ATM through a C-terminal motif, which is also present in Nijmegen breakage syndrome (NBS)1. ATMIN and ATM co-localised in response to ATM activation by chloroquine and hypotonic stress, but not after induction of double-strand breaks by ionising radiation (IR). ATM/ATMIN complex disruption by IR was attenuated in cells with impaired NBS1 function, suggesting competition of NBS1 and ATMIN for ATM binding. ATMIN protein levels were reduced in ataxia telangiectasia cells and ATM protein levels were low in primary murine fibroblasts lacking ATMIN, indicating reciprocal stabilisation. Whereas phosphorylation of Smc1, Chk2 and p53 was normal after IR in ATMIN-deficient cells, basal ATM activity and ATM activation by hypotonic stress and inhibition of DNA replication was impaired. Thus, ATMIN defines a novel NBS1-independent pathway of ATM signalling.
关卡激酶ATM（共济失调毛细血管扩张症突变基因）可转导基因组应激信号，以在DNA损伤时使细胞周期进程停滞并促进DNA修复。在此，我们报告了ATM的一种必需辅因子ATMIN（ATM相互作用蛋白）的特性。ATMIN通过一个C端基序与ATM相互作用，该基序也存在于尼曼匹克氏病（NBS）1中。在氯喹和低渗应激激活ATM后，ATMIN与ATM共定位，但在电离辐射（IR）诱导双链断裂后则不然。在NBS1功能受损的细胞中，IR对ATM/ATMIN复合物的破坏作用减弱，这表明NBS1和ATMIN竞争与ATM结合。共济失调毛细血管扩张症细胞中的ATMIN蛋白水平降低，而缺乏ATMIN的原代小鼠成纤维细胞中的ATM蛋白水平较低，这表明二者相互稳定。虽然在IR处理后，ATMIN缺陷细胞中Smc1、Chk2和p53的磷酸化正常，但基础ATM活性以及低渗应激和DNA复制抑制对ATM的激活均受损。因此，ATMIN定义了一条不依赖NBS1的新型ATM信号通路。
