Anastasis: An unexpected route to rescue dying cells, and its physiological and pathological implications. Ho Lam Tang, Ho Man Tang, Denise Montell. Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD.

   The programmed cell death process known as apoptosis (Greek for falling to death) plays critical roles in normal embryonic development and adult homeostasis. Impaired apoptosis causes cancer whereas excess apoptosis contributes to major diseases such as neurodegeneration. Apoptosis is thought to be irreversible after mitochondrial permeabilization and effector caspase activation because mitochondrial dysfunction, alone can lead to cell death and caspases cause massive destruction of structural and functional cellular components including the genome. However, this assumption has not been fully tested. Here, we report the discovery of reversal of late stage apoptosis in tissue culture cells, and we called this process anastasis (Greek for rising to life). Dying cells can reverse apoptosis, survive, and proliferate, even after they pass through critical checkpoints generally thought to be the point of no return, including mitochondrial permeabilization and caspase activation. Simply removing the apoptotic inducers by washing is sufficient to allow the vast majority of dying cells to arrest the apoptotic process and survive. Notably, while many cells recover completely, some of the cells that reverse apoptosis acquire permanent genetic alterations and undergo oncogenic transformation at a higher frequency than controls. We have developed a Drosophila anastasis biosensor to detect and track reversal of apoptosis, and identify anastasis in live Drosophila after environmental insult that induces apoptosis. We propose that anastasis could participate in various physiological and pathological conditions. For example, anastasis could be an unanticipated mechanism to protect cells that are difficult to replace, such as mature neurons in the aging brain or cardiomyocytes in adult heart cells. At the same time, the DNA mutations that persist following anastasis represent a form of stress-induced mutagenesis, which may result carcinogenesis and evolution of drug resistance following chemotherapy.