Mre11 nuclease activity has essential roles in DNA repair and genomic stability distinct from ATM activation.
Mre11 nuclease activity has essential roles in DNA repair and genomic stability distinct from ATM activation.
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DOI：
10.1016/j.cell.2008.08.015
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发表时间：
2008-10-03
期刊：
影响因子：
64.5
通讯作者：
Ferguson DO
中科院分区：
文献类型：
--
作者：
Buis J;Wu Y;Deng Y;Leddon J;Westfield G;Eckersdorff M;Sekiguchi JM;Chang S;Ferguson DO
Mre 11/Rad 50/NBS 1复合物（MRN）通过桥接DNA末端并通过激活ATM激酶启动DNA损伤信号传导来维持基因组稳定性。Mre 11具有在进化中高度保守的DNA核酸酶活性，但在哺乳动物中发挥未知的作用。为了确定Mre 11的功能，我们设计了靶向小鼠等位基因，其可以消除核酸酶活性或抑制整个MRN复合物。Mre 11核酸酶缺乏导致一系列与MRN缺乏无法区分的表型，包括早期胚胎致死性和显著的基因组不稳定性。我们确定了一个关键的作用，同源性指导双链断裂修复的核酸酶活性，并在激活ATR激酶的贡献作用。然而，在DNA损伤或端粒脱保护后，不需要核酸酶活性来激活ATM。因此，Mre 11的溶核处理是DNA修复中的一个重要功能，与ATM信号的MRN控制不同。
The Mre11/Rad50/NBS1 complex (MRN) maintains genomic stability by bridging DNA ends and initiating DNA damage signaling through activation of the ATM kinase. Mre11 possesses DNA nuclease activities that are highly conserved in evolution, but play unknown roles in mammals. To define functions of Mre11 we engineered targeted mouse alleles which either abrogate nuclease activities or inactivate the entire MRN complex. Mre11 nuclease deficiency causes a striking array of phenotypes indistinguishable from absence of MRN, including early embryonic lethality and dramatic genomic instability. We identify a crucial role for the nuclease activities in homology directed double strand break repair, and a contributing role in activating the ATR kinase. However, nuclease activities are not required to activate ATM after DNA damage or telomere deprotection. Therefore, nucleolytic processing by Mre11 is an essential function of fundamental importance in DNA repair distinct from MRN control of ATM signaling.
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影响因子：
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作者：
Grawunder, U;Zimmer, D;Lieber, MR
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