Kadigamuwa Chamila, Choksi Swati, Xu Qing, Cataisson Christophe, Greenbaum Steven S, Yuspa Stuart H, Liu Zheng-Gang
Laboratory of Immune Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 37 Convent Drive, Bethesda, MD 20892, USA.
Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 37 Convent Drive, Bethesda, MD 20892, USA.
iScience. 2019 Jul 26;17:74-86. doi: 10.1016/j.isci.2019.06.019. Epub 2019 Jun 18.
DNA-damaging compounds, commonly used as chemotherapeutic drugs, are known to trigger cells to undergo programmed cell death such as apoptosis and necroptosis. However, the molecular mechanism of DNA damage-induced cell death is not fully understood. Here, we report that RARγ has a critical role in DNA damage-induced programmed cell death, specifically in necroptosis. The loss of RARγ abolishes the necroptosis induced by DNA damage. In addition, cells that lack RARγ are less susceptible to extrinsic apoptotic pathway activated by DNA-damaging agents whereas the intrinsic apoptotic pathway is not affected. We demonstrate that RARγ is essential for the formation of RIPK1/RIPK3 death complex, known as Ripoptosome, in response to DNA damage. Furthermore, we show that RARγ plays a role in skin cancer development by using RARγ1 knockout mice and human squamous cell carcinoma biopsies. Hence, our study reveals that RARγ is a critical component of DNA damage-induced cell death.
DNA损伤化合物通常用作化疗药物，已知会触发细胞经历程序性细胞死亡，如凋亡和坏死性凋亡。然而，DNA损伤诱导的细胞死亡的分子机制尚未完全了解。在此，我们报告RARγ在DNA损伤诱导的程序性细胞死亡中起关键作用，特别是在坏死性凋亡中。RARγ的缺失消除了DNA损伤诱导的坏死性凋亡。此外，缺乏RARγ的细胞对DNA损伤剂激活的外源性凋亡途径不太敏感，而内源性凋亡途径不受影响。我们证明，RARγ对于响应DNA损伤形成RIPK1/RIPK3死亡复合物（即 Ripoptosome）至关重要。此外，我们通过使用RARγ1基因敲除小鼠和人类鳞状细胞癌活检表明，RARγ在皮肤癌发展中起作用。因此，我们的研究表明RARγ是DNA损伤诱导的细胞死亡的关键组成部分。
