ATR-dependent phosphorylation and activation of ATM in response to UV treatment or replication fork stalling
ATR-dependent phosphorylation and activation of ATM in response to UV treatment or replication fork stalling
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DOI：
10.1038/sj.emboj.7601446
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发表时间：
2006-12-13
期刊：
影响因子：
11.4
通讯作者：
Jeggo, Penny A.
中科院分区：
文献类型：
--
作者：
Stiff, Thomas;Walker, Sarah A.;Jeggo, Penny A.
磷脂酰肌醇3-激酶样激酶（PIKKs）、共济失调-毛细血管扩张突变（ATM）以及ATM和Rad 3相关（ATR）调节平行的损伤反应信号传导通路。据报道，ATM被DNA双链断裂（DSB）激活，而ATR被募集到DNA的单链区域。虽然这两个途径被认为是独立的功能，最近的研究表明，ATM功能的ATR上游暴露于电离辐射（IR）在S/G2。在这里，我们表明，ATM磷酸化Ser 1981，一个特征性的自磷酸化位点，是ATR依赖性和ATM独立的复制叉失速或UV处理后。与IR诱导的ATM-S1981磷酸化相反，UV诱导的ATM-S1981磷酸化不需要Nbs 1 C末端或Mre 11。ATM的ATR依赖性磷酸化激活Chk 2的ATM磷酸化，Chk 2在调节G2/M检查点阻滞中与Chk 1具有重叠功能。我们的研究结果提供了深入了解PIKK损伤反应途径之间的相互作用。
The phosphatidyl inositol 3-kinase-like kinases (PIKKs), ataxia-telangiectasia mutated (ATM) and ATM-and Rad3-related (ATR) regulate parallel damage response signalling pathways. ATM is reported to be activated by DNA double-strand breaks (DSBs), whereas ATR is recruited to single-stranded regions of DNA. Although the two pathways were considered to function independently, recent studies have demonstrated that ATM functions upstream of ATR following exposure to ionising radiation (IR) in S/G2. Here, we show that ATM phosphorylation at Ser1981, a characterised autophosphorylation site, is ATR-dependent and ATM-independent following replication fork stalling or UV treatment. In contrast to IR-induced ATM-S1981 phosphorylation, UV-induced ATM-S1981 phosphorylation does not require the Nbs1 C-terminus or Mre11. ATR-dependent phosphorylation of ATM activates ATM phosphorylation of Chk2, which has an overlapping function with Chk1 in regulating G2/M checkpoint arrest. Our findings provide insight into the interplay between the PIKK damage response pathways.