ATM activation by DNA double-strand breaks through the Mre11-Rad50-Nbs1 complex
ATM activation by DNA double-strand breaks through the Mre11-Rad50-Nbs1 complex
复制标题
DOI：
10.1126/science.1108297
复制
发表时间：
2005-04-22
期刊：
影响因子：
56.9
通讯作者：
Paull, TT
中科院分区：
文献类型：
--
作者：
Lee, JH;Paull, TT
ataxa - tetangi扩张突变（ATM）激酶通过磷酸化启动细胞周期阻滞、细胞凋亡和DNA修复的蛋白来信号哺乳动物细胞中DNA双链断裂的存在。我们发现Mre11-Rad50-Nbs1 （MRN）复合物作为ATM的双链断裂传感器，并将ATM招募到断裂的DNA分子中。失活的ATM二聚体在MRN存在下用DNA在体外激活，导致下游细胞靶点p53和Chk2磷酸化。ATM的MRN单体化不需要ATM的自磷酸化。MRN对DNA末端的解绕对于ATM刺激至关重要，这与单链DNA作为DNA损伤的进化保守信号的核心作用是一致的。
The ataxia-tetangiectasia mutated (ATM) kinase signals the presence of DNA double-strand breaks in mammalian cells by phosphorylating proteins that initiate cell-cycle arrest, apoptosis, and DNA repair. We show that the Mre11-Rad50-Nbs1 (MRN) complex acts as a double-strand break sensor for ATM and recruits ATM to broken DNA molecules. Inactive ATM dimers were activated in vitro with DNA in the presence of MRN, leading to phosphorylation of the downstream cellular targets p53 and Chk2. ATM autophosphorylation was not required for monomerization of ATM by MRN. The unwinding of DNA ends by MRN was essential for ATM stimulation, which is consistent with the central role of single-stranded DNA as an evolutionarily conserved signal for DNA damage.