Human embryonic stem (hES) cells are highly sensitive to apoptotic stimuli such as DNA damage, which allows for rapid elimination of mutated cells during development. However, the mechanisms that maintain hES cells in the primed apoptotic state are not completely known. Key activators of apoptosis, the BH3-only proteins, are present at low levels in most cell types. In contrast, hES cells have constitutive high levels of the BH3-only protein, NOXA. We examined the importance of NOXA for enabling apoptosis in hES cells. hES cells deleted for NOXA showed remarkable protection against multiple apoptotic stimuli. NOXA was constitutively localized to the mitochondria, where it interacted with MCL1. Strikingly, inhibition of MCL1 in NOXA knockout cells was sufficient to sensitize these cells to DNA damage, and subsequently, cell death. Our study demonstrates, an essential function of constitutive high levels of NOXA in hES cells is to effectively antagonize MCL1 to permit rapid apoptosis.

中文翻译：

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NOXA的组成型高表达使人类胚胎干细胞对快速细胞死亡敏感

人类胚胎干（hES）细胞对凋亡刺激（例如DNA损伤）高度敏感，从而可以在发育过程中快速消除突变的细胞。但是，将hES细胞维持在引发凋亡状态的机制尚不完全清楚。凋亡的关键激活因子，仅BH3蛋白，在大多数细胞类型中含量较低。相反，hES细胞具有高水平的仅BH3唯一蛋白NOXA。我们研究了NOXA对使hES细胞凋亡的重要性。缺失NOXA的hES细胞显示出对多种凋亡刺激的显着保护作用。NOXA结构性地定位于线粒体，并与MCL1相互作用。令人惊讶的是，在NOXA敲除细胞中抑制MCL1足以使这些细胞对DNA损伤和随后的细胞死亡敏感。