Mre11-Rad50-Nbs1 complex is activated by hypertonicity.
Mre11-Rad50-Nbs1 complex is activated by hypertonicity.
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Mre11-Rad50-Nbs1 复合物由高渗性激活。
DOI：
10.1152/ajprenal.00153.2006
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发表时间：
2006
期刊：
影响因子：
--
通讯作者：
Woo,SeungKyoon
中科院分区：
文献类型：
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作者：
Sheen,MeeRie;Kim,SeungWhan;Jung,Ju-Young;Ahn,JoonYoung;Rhee,JuongG;Kwon,HMoo;Woo,SeungKyoon
当暴露在高渗条件下，细胞积累双链DNA断裂（dsb）就像暴露在电离辐射中一样。有人提出，由于核退出导致Mre11-Rad50-Nbs1 （MRN）复合物失活，导致dsb的积累，因为细胞无法修复正常细胞活动期间产生的dsb。在这项研究中，我们检测了高渗细胞中的MRN复合物。令人惊讶的是，我们发现MRN复合物在高渗性反应中留在细胞核中并保持完整。事实上，MRN复合体在切换到高渗状态4小时后以剂量依赖的方式被显著激活，如灶的形成所示。高渗性和博来霉素对ATM和MRN复合物的激活是附加的，它们的下游靶点包括γH2AX和Chk2的激活也表明细胞对DSB的反应在高渗条件下是完整的。在MRN复合物功能受损的突变细胞中，没有观察到Chk2对高张力反应的激活，证实它们处于同一途径。切换到高渗性20小时后，MRN焦点和γ - h2ax恢复到控制水平，这表明细胞通过修复DNA来适应高渗性。我们得出的结论是，细胞对DSB的反应正常，并修复高渗性引起的DNA损伤。
When exposed to hypertonic conditions, cells accumulate double-strand DNA breaks (DSBs) like they are exposed to ionizing radiation. It has been proposed that inactivation of the Mre11-Rad50-Nbs1 (MRN) complex due to nuclear exit is responsible for the accumulation of DSBs as cells fail to repair DSBs produced during normal cellular activity. In this study, we examined the MRN complex in cells switched to hypertonicity. Surprisingly, we found that the MRN complex stayed in the nucleus and remained intact in response to hypertonicity. In fact, the MRN complex was dramatically activated after 4 h of switch to hypertonicity in a dose-dependent manner as shown by formation of foci. Activation of ATM and the MRN complex by hypertonicity and bleomycin was additive as was activation of their downstream targets including γH2AX and Chk2 indicating that the cellular response to DSB was intact in hypertonic conditions. Activation of Chk2 in response to hypertonicity was not observed in mutant cells with functionally impaired MRN complex confirming that they are in the same pathway. After 20 h of a switch to hypertonicity, MRN foci and γH2AX returned to a control level, suggesting that cells adapted to hypertonicity by repairing DNA. We conclude that cells respond normally to DSB and repair the DNA damages induced by hypertonicity.