Mordes Daniel A, Cortez David
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
Cell Cycle. 2008 Sep 15;7(18):2809-12. doi: 10.4161/cc.7.18.6689. Epub 2008 Sep 30.
The DNA damage response kinase ATR is an essential regulator of genome integrity. TopBP1 functions as a general activator of ATR. We have recently shown that TopBP1 activates ATR through its regulatory subunit ATRIP and a PIKK regulatory domain (PRD) located adjacent to its kinase domain. This mechanism of ATR activation is conserved in the S. cerevisiae ortholog Mec1. ATR is a member of the PIKK family of protein kinases that includes ATM, DNA-PKcs, mTOR and SMG1. The PRD regulates the kinase activity of other PIKKs and may serve as a site of interaction between these kinase and their respective activators. Activation of ATR by TopBP1 is maximal at low substrate concentrations and declines exponentially as substrate concentration increases. These data are consistent with a model in which TopBP1 acts to alter the conformation of ATR-ATRIP to increase the ability of ATR to bind substrates. A further understanding of the mechanism of ATR activation will likely provide insights into the regulation of related PIKKs.
DNA损伤反应激酶ATR是基因组完整性的重要调节因子。TopBP1作为ATR的一般激活剂发挥作用。我们最近发现，TopBP1通过其调节亚基ATRIP和位于其激酶结构域附近的PIKK调节结构域（PRD）激活ATR。这种ATR激活机制在酿酒酵母直系同源物Mec1中是保守的。ATR是蛋白激酶PIKK家族的成员，该家族包括ATM、DNA-PKcs、mTOR和SMG1。PRD调节其他PIKK的激酶活性，并可能作为这些激酶与其各自激活剂之间的相互作用位点。TopBP1对ATR的激活在低底物浓度下最大，并随着底物浓度的增加呈指数下降。这些数据与一个模型一致，即TopBP1作用于改变ATR-ATRIP的构象，以增加ATR结合底物的能力。对ATR激活机制的进一步理解可能会为相关PIKK的调节提供见解。
