MRN 复合物通过招募 TOPBP1 在 ATR 激活中的作用。
A role for the MRN complex in ATR activation via TOPBP1 recruitment.
机构信息
Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305, USA.
出版信息
Mol Cell. 2013 Apr 11;50(1):116-22. doi: 10.1016/j.molcel.2013.03.006.
The MRN (MRE11-RAD50-NBS1) complex has been implicated in many aspects of the DNA damage response. It has key roles in sensing and processing DNA double-strand breaks, as well as in activation of ATM (ataxia telangiectasia mutated). We reveal a function for MRN in ATR (ATM- and RAD3-related) activation by using defined ATR-activating DNA structures in Xenopus egg extracts. Strikingly, we demonstrate that MRN is required for recruitment of TOPBP1 to an ATR-activating structure that contains a single-stranded DNA (ssDNA) and a double-stranded DNA (dsDNA) junction and that this recruitment is necessary for phosphorylation of CHK1. We also show that the 911 (RAD9-RAD1-HUS1) complex is not required for TOPBP1 recruitment but is essential for TOPBP1 function. Thus, whereas MRN is required for TOPBP1 recruitment at an ssDNA-to-dsDNA junction, 911 is required for TOPBP1 "activation." These findings provide molecular insights into how ATR is activated.
MRN（MRE11-RAD50-NBS1）复合物参与了 DNA 损伤反应的多个方面。它在感知和处理 DNA 双链断裂以及激活 ATM（共济失调毛细血管扩张突变）方面发挥着关键作用。我们在非洲爪蟾卵提取物中使用定义的 ATR 激活 DNA 结构，揭示了 MRN 在 ATR（ATM 和 RAD3 相关）激活中的作用。引人注目的是，我们证明 MRN 对于 TOPBP1 募集到包含单链 DNA（ssDNA）和双链 DNA（dsDNA）连接的 ATR 激活结构是必需的，并且这种募集对于 CHK1 的磷酸化是必需的。我们还表明，911（RAD9-RAD1-HUS1）复合物对于 TOPBP1 的募集不是必需的，但对于 TOPBP1 的功能是必需的。因此，虽然 MRN 对于 ssDNA 到 dsDNA 连接处的 TOPBP1 募集是必需的，但 911 对于 TOPBP1 的“激活”是必需的。这些发现为 ATR 如何被激活提供了分子见解。
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