Hopfner Karl-Peter
Department of Biochemistry, Gene Center, Ludwig-Maximilians-University, Munich, Germany; Center for Integrated Protein Science Munich, Gene Center, Ludwig-Maximilians-University, Munich, Germany.
Bioessays. 2014 Dec;36(12):1170-8. doi: 10.1002/bies.201400102. Epub 2014 Sep 11.
DNA double-strand breaks (DSBs) are one of the most deleterious forms of DNA damage and can result in cell inviability or chromosomal aberrations. The Mre11-Rad50-Nbs1 (MRN) ATPase-nuclease complex is a central player in the cellular response to DSBs and is implicated in the sensing and nucleolytic processing of DSBs, as well as in DSB signaling by activating the cell cycle checkpoint kinase ATM. ATP binding to Rad50 switches MRN from an open state with exposed Mre11 nuclease sites to a closed state with partially buried nuclease sites. The functional meaning of this switch remained unclear. A new study shows that ATP binding to Rad50 promotes DSB recognition, tethering, and ATM activation, while ATP hydrolysis opens the nuclease active sites to promote processing of DSBs. MRN thus emerges as functional switch that may coordinate the temporal transition from signaling to processing of DSBs.
DNA双链断裂（DSBs）是最具危害性的DNA损伤形式之一，可导致细胞无法存活或染色体畸变。Mre11-Rad50-Nbs1（MRN）ATP酶-核酸酶复合物是细胞对DSBs反应的核心参与者，参与DSBs的感知和核酸酶处理，以及通过激活细胞周期检查点激酶ATM进行DSBs信号传导。ATP与Rad50结合会使MRN从具有暴露的Mre11核酸酶位点的开放状态转变为具有部分掩埋核酸酶位点的封闭状态。这种转变的功能意义尚不清楚。一项新研究表明，ATP与Rad50结合可促进DSB识别、束缚和ATM激活，而ATP水解会打开核酸酶活性位点以促进DSBs的处理。因此，MRN成为一种功能开关，可能协调DSBs从信号传导到处理的时间转变。
