Stress induced mutagenesis, genetic diversification, and cell survival via anastasis, the reversal of late stage apoptosis

Abstract

Changes in genomic DNA are critical for evolution as they generate genetic diversity, which is the substrate for natural selection. However, most mutations are deleterious, so protective mechanisms have evolved such as apoptotic cell death, to eliminate damaged cells. Apoptosis is generally assumed to be irreversible once massive destruction of structural and functional cellular components occurs. Recent surprising studies reveal that dying cells can reverse the apoptotic process, survive, and proliferate, even after sustaining DNA damage. This process has been named anastasis. While most cells repair their damaged DNA, residual genetic alterations persist in some cells and can result in oncogenic transformation. Although proliferation of transformed cells is a negative consequence, anastasis may serve useful purposes as well. For example, such a cell survival mechanism could serve to salvage postmitotic cells, which are difficult to replace, and thereby limit permanent tissue damage due to transient stresses. The DNA mutations that persist following anastasis represent a form of stress-induced mutagenesis, increasing genetic and phenotypic diversity in response to environmental or physiological stresses that initiate apoptosis. Negative side effects of this otherwise beneficial process may include carcinogenesis and evolution of drug resistance following chemotherapy.