E4F1 Is a Master Regulator of CHK1-Mediated Functions
E4F1 Is a Master Regulator of CHK1-Mediated Functions
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DOI：
10.1016/j.celrep.2015.03.019
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发表时间：
2015-04-14
期刊：
影响因子：
8.8
通讯作者：
Sauvageau, Guy
中科院分区：
文献类型：
--
作者：
Grote, David;Moison, Celine;Sauvageau, Guy
先前已经表明，多梳蛋白BMI1和E4F1在造血系统中物理和遗传地相互作用。在这里，我们报告说，E4f1是造血细胞功能和生存所必需的。E4f1缺失诱导急性骨髓衰竭，其特征在于祖细胞凋亡，而干细胞被保存。E4F1缺陷细胞积累DNA损伤，并在S期和有丝分裂的进展中显示缺陷，揭示了E4F1在细胞周期进展和基因组完整性中的作用。重要的是，我们发现E4F1与检查点激酶1（CHK1）蛋白相互作用并保护其免受降解。最后，在E4f1缺陷细胞中观察到的缺陷被Chek1的异位表达完全逆转。总而言之，我们的研究结果将E4F1归类为CHK1活性的主调节因子，确保DNA复制的高保真度，从而保护基因组稳定性。
It has been previously shown that the polycomb protein BMI1 and E4F1 interact physically and genetically in the hematopoietic system. Here, we report that E4f1 is essential for hematopoietic cell function and survival. E4f1 deletion induces acute bone marrow failure characterized by apoptosis of progenitors while stem cells are preserved. E4f1-deficient cells accumulate DNA damage and show defects in progression through S phase and mitosis, revealing a role for E4F1 in cell-cycle progression and genome integrity. Importantly, we showed that E4F1 interacts with and protects the checkpoint kinase 1 (CHK1) protein from degradation. Finally, defects observed in E4f1-deficient cells were fully reversed by ectopic expression of Chek1. Altogether, our results classify E4F1 as a master regulator of CHK1 activity that ensures high fidelity of DNA replication, thus safeguarding genome stability.