Disruption of mRad50 causes embryonic stem cell lethality, abnormal embryonic development, and sensitivity to ionizing radiation
Disruption of mRad50 causes embryonic stem cell lethality, abnormal embryonic development, and sensitivity to ionizing radiation
复制标题
DOI：
10.1073/pnas.96.13.7376
复制
发表时间：
1999-06-22
影响因子：
11.1
通讯作者：
Petrini, JHJ
中科院分区：
文献类型：
--
作者：
Luo, GB;Yao, MS;Petrini, JHJ
Mre11/Rad50 蛋白复合物在细胞对双链断裂 (DSB) 反应的多个方面发挥作用，包括检测 DNA 损伤、激活细胞周期检查点和 DSB 修复。虽然酿酒酵母的遗传分析提供了有关这种高度保守复合物的 DSB 修复功能的见解，但人类复合物在奈梅亨断裂综合征中的含义揭示了其在细胞周期检查点功能中的作用。我们建立了 mRad50 突变小鼠来研究哺乳动物 Mre11/Rad50 蛋白复合物在 DNA 损伤反应中的作用。缺乏 mRad50 的早期胚胎细胞对电离辐射高度敏感，这与该复合物在电离辐射诱导的 DSB 修复中的作用一致。然而，mrad50 无效突变在培养的胚胎干细胞和早期发育胚胎中是致命的，表明哺乳动物 Mre11/Rad50 蛋白复合物介导正常生长细胞中对于生存至关重要的功能。
The Mre11/Rad50 protein complex functions in diverse aspects of the cellular response to double-strand breaks (DSBs), including the detection of DNA damage, the activation of cell cycle checkpoints, and DSB repair. Whereas genetic analyses in Saccharomyces cerevisiae have provided insight regarding DSB repair functions of this highly conserved complex, the implication of the human complex in Nijmegen breakage syndrome reveals its role in cell cycle checkpoint functions. We established mRad50 mutant mice to examine the role of the mammalian,Mre11/Rad50 protein complex in the DNA damage response. Early embryonic cells deficient in mRad50 are hypersensitive to ionizing radiation, consistent with a role for this complex in the repair of ionizing radiation-induced DSBs, However, the null mrad50 mutation is lethal in cultured embryonic stem cells and in early developing embryos, indicating that the mammalian,Mre11/Rad50 protein complex mediates functions in normally growing cells that are essential for viability.