Filia Is an ESC-Specific Regulator of DNA Damage Response and Safeguards Genomic Stability.
Filia Is an ESC-Specific Regulator of DNA Damage Response and Safeguards Genomic Stability.
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DOI：
10.1016/j.stem.2015.03.017
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发表时间：
2015-06-04
期刊：
影响因子：
23.9
通讯作者：
Zheng P
中科院分区：
文献类型：
--
作者：
Zhao B;Zhang WD;Duan YL;Lu YQ;Cun YX;Li CH;Guo K;Nie WH;Li L;Zhang R;Zheng P
多能干细胞（PSCs）在基于细胞的治疗中具有很大的前景，但在培养中发现的基因组不稳定性阻碍了其充分应用。更好地理解调控psc基因组稳定性的因素可能有助于解决这一问题。在这里，我们描述了Filia作为小鼠胚胎干细胞（ESCs）基因组稳定性的特异性调节因子的鉴定。基因毒性应激诱导Filia表达。Filia通过多种途径促进中心体完整性并调节DNA损伤反应（DDR），包括DDR信号传导、细胞周期检查点和损伤修复、ESC分化和凋亡。Filia缺失导致ESC基因组不稳定，诱导细胞凋亡抵抗并促进恶性转化。作为其在DDR中作用的一部分，Filia与PARP1相互作用并刺激其酶活性。Filia也组成性地驻留在中心体上，并易位到DNA损伤位点和线粒体，这与它在调节中心体完整性、损伤修复和细胞凋亡中的多方面作用是一致的。
Pluripotent stem cells (PSCs) hold great promise in cell-based therapy, but the genomic instability seen in culture hampers full application. Greater understanding of the factors that regulate genomic stability in PSCs could help address this issue. Here we describe the identification of Filia as a specific regulator of genomic stability in mouse embryonic stem cells (ESCs). Filia expression is induced by genotoxic stress. Filia promotes centrosome integrity and regulates DNA damage response (DDR) through multiple pathways, including DDR signaling, cell cycle checkpoints and damage repair, ESC differentiation and apoptosis. Filia depletion causes ESC genomic instability, induces resistance to apoptosis and promotes malignant transformation. As part of its role in the DDR, Filia interacts with PARP1 and stimulates its enzymatic activity. Filia also constitutively resides on centrosomes and translocates to DNA damage sites and mitochondria, consistent with its multifaceted roles in regulating centrosome integrity, damage repair and apoptosis.