p53 controls choice between apoptotic and non-apoptotic death following DNA damage.

DNA damage can activate apoptotic and non-apoptotic forms of cell death; however, it remains unclear what features dictate which type of cell death is activated. We report that p53 controls the choice between apoptotic and non-apoptotic death following exposure to lethal levels of DNA damage. The canonical response to DNA damage involves p53-dependent activation of cell intrinsic apoptosis, downstream of DNA damage response (DDR) activation. Decades of research suggest that DNA damage does not robustly activate cell death in the absence of p53. In contrast, we find that p53-deficient cells die at high rates following exposure to DNA damage, but exclusively using non-apoptotic types of cell death. Our experimental and computational analyses demonstrate that non-apoptotic death in p53-deficient cells has generally been missed due to use of assays that are either insensitive to cell death, or that specifically measure apoptotic cells. To characterize which subtype of non-apoptotic death is activated by DNA damage in p53-deficient cells, we used functional genetic screening, with an analysis method that enables computational inference of the drug-induced death rate, rather than the relative population size. We find in p53-deficient cells that DNA damage activates a mitochondrial respiration-dependent form of cell death called MPT-driven necrosis. This study reveals how the dual functions of p53 in regulating mitochondrial activity and the DDR combine to facilitate choice between apoptotic and non-apoptotic death following DNA damage.