RAD50 phosphorylation promotes ATR downstream signaling and DNA restart following replication stress
RAD50 phosphorylation promotes ATR downstream signaling and DNA restart following replication stress
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DOI：
10.1093/hmg/ddu141
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发表时间：
2014-08-15
影响因子：
3.5
通讯作者：
Lavin, Martin F.
中科院分区：
文献类型：
--
作者：
Gatei, Magtouf;Kijas, Amanda W.;Lavin, Martin F.
MRE 11/RAD 50/NBN（MRN）复合物在检测DNA双链断裂、募集和激活共济失调-毛细血管扩张突变以及处理断裂中起关键作用。该复合物的成员还充当细胞周期和其他细胞过程的下游信号传导的衔接分子。一些更有争议的结果是支持MRN在共济失调-毛细血管扩张和Rad 3相关（ATR）激活和信号传导中的作用。我们提供的证据表明，RAD 50是所需的ATR激活在哺乳动物细胞中的DNA复制应力。它又在特定位点（S635）被ATR磷酸化，这是通过Chk 1和其他下游底物进行ATR信号传导所必需的。我们发现，RAD 50磷酸化是必不可少的DNA复制重新启动，促进加载的粘附在这些网站。我们还证明了复制应激诱导的RAD 50磷酸化对细胞存活和细胞周期检查点激活具有重要的功能意义。这些结果突出了在DNA复制应激反应的各个方面的MRN复合物的成员的适配器作用的重要性。
The MRE11/RAD50/NBN (MRN) complex plays a key role in detecting DNA double-strand breaks, recruiting and activating ataxia-telangiectasia mutated and in processing the breaks. Members of this complex also act as adaptor molecules for downstream signaling to the cell cycle and other cellular processes. Somewhat more controversial are the results to support a role for MRN in the ataxia-telangiectasia and Rad3-related (ATR) activation and signaling. We provide evidence that RAD50 is required for ATR activation in mammalian cells in response to DNA replication stress. It is in turn phosphorylated at a specific site (S635) by ATR, which is required for ATR signaling through Chk1 and other downstream substrates. We find that RAD50 phosphorylation is essential for DNA replication restart by promoting loading of cohesin at these sites. We also demonstrate that replication stress-induced RAD50 phosphorylation is functionally significant for cell survival and cell cycle checkpoint activation. These results highlight the importance of the adaptor role for a member of the MRN complex in all aspects of the response to DNA replication stress.