Reversal of apoptosis:an in vivo mechanism for cytoprotection and mutagenesis

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Apoptosis plays essential roles in development and homeostasis in multicellular organisms by sculpting tissues, deleting unwanted structures, and eliminating abnormal, injured or dangerous cells1. In addition, targeting apoptotic pathways is an important strategy for treatment of intractable diseases such as cancer, whereas limiting apoptosis may be beneficial for treating ischemic injury and degenerative disorders. Although loss- or gain-of-function of apoptotic regulators can artificially allow cells to survive beyond normal checkpoints, apoptosis is generally assumed to be an intrinsically irreversible process2,3. However, we recently discovered a natural reversibility of late-stage apoptosis in human and mouse cells4,5. Dying cells can reverse apoptosis and survive, despite having passed through checkpoints previously believed to be the point of no return, including caspase-3 activation and DNA damage. Simply washing away apoptotic inducers is sufficient to allow the majority of dying cells to survive and most hallmarks of apoptosis to vanish, indicating that reversal of apoptosis is an endogenous cellular mechanism. Notably, while most cells recover completely, a small fraction of cells that reverse apoptosis retain genetic alterations and undergo oncogenic transformation at a higher frequency than control cells. We propose that reversal of apoptosis may be a physiological mechanism that can serve several beneficial functions. Arrest of apoptosis at the execution stage could in principle promote survival of cells, such as neurons and heart muscle cells, which are difficult to replace. Alternatively or in addition, this recovery process, which we have named anastasis (Greek for rising to life), could promote genetic and phenotypic diversity in response to environmental or physiological stresses that initiate apoptosis. A negative side effect of this otherwise beneficial process is oncogenic transformation. We have developed and tested a biosensor to detect cells that have undergone anastasis in vivo in Drosophila melanogaster. In specific aim 1 we will test the hypothesis that anastasis functions to salvage cells that are difficult to replace, thus limiting permanent tissue damage following transient insults. We also propose to develop a similar biosensor for use in mammalian cells. In specific aim 2 we propose to initiate studies of the molecular mechanisms controlling anastasis. The proposed work has the potential to lead to a new understanding of and treatments for degenerative diseases and cancer.