Role of Retinoic Acid Receptor-γ in DNA Damage-Induced Necroptosis
Chamila Kadigamuwa,
Swati Choksi,
Qing Xu,
Christophe Cataisson,
Steven S. Greenbaum,
Stuart H. Yuspa,
Zheng-gang Liu
Affiliations
Chamila Kadigamuwa
Laboratory of Immune Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 37 Convent Drive, Bethesda, MD 20892, USA
Swati Choksi
Laboratory of Immune Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 37 Convent Drive, Bethesda, MD 20892, USA
Qing Xu
Laboratory of Immune Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 37 Convent Drive, Bethesda, MD 20892, USA
Christophe Cataisson
Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 37 Convent Drive, Bethesda, MD 20892, USA
Steven S. Greenbaum
Skin and Laser Surgery Center of Pennsylvania, 1528 Walnut Street, STE 1101, Philadelphia, PA 19102, USA
Stuart H. Yuspa
Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 37 Convent Drive, Bethesda, MD 20892, USA
Zheng-gang Liu
Laboratory of Immune Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 37 Convent Drive, Bethesda, MD 20892, USA; Corresponding author
Summary: 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. : Biological Sciences; Biochemistry; Molecular Biology; Cell Biology Subject Areas: Biological Sciences, Biochemistry, Molecular Biology, Cell Biology
