Role of Retinoic Acid Receptor-γ in DNA Damage-Induced Necroptosis

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 RAR gamma has a critical role in DNA damage-induced programmed cell death, specifically in necroptosis. The loss of RAR gamma abolishes the necroptosis induced by DNA damage. In addition, cells that lack RAR gamma are less susceptible to extrinsic apoptotic pathway activated by DNA-damaging agents whereas the intrinsic apoptotic pathway is not affected. We demonstrate that RAR gamma is essential for the formation of RIPK1/RIPK3 death complex, known as Ripoptosome, in response to DNA damage. Furthermore, we show that RAR gamma plays a role in skin cancer development by using RAR gamma 1 knockout mice and human squamous cell carcinoma biopsies. Hence, our study reveals that RAR gamma is a critical component of DNA damage-induced cell death.