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

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.
Graphical Abstract
Highlights • RARγ plays a key role in DNA damage-induced cell death • RARγ is essential for RIPK1-mediated necroptosis and apoptosis following DNA damage • RARγ is required for the formation of Ripoptosome in response to DNA damage • Loss of RARγ correlates with skin cancer development
Biological Sciences; Biochemistry; Molecular Biology; Cell Biology