Stress Induced Mutagenesis, Genetic Diversification, and Cell Survival via Anastasis, the Reversal of Late Stage Apoptosis
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.
KeywordsAnnexin Versus Caspase Cascade Membrane Blebbing Nuclear Condensation Mitochondrial Fragmentation
- Dandel M, Weng Y, Siniawski H, Stepanenko A, Krabatsch T, Potapov E, Lehmkuhl HB, Knosalla C, Hetzer R (2011) Heart failure reversal by ventricular unloading in patients with chronic cardiomyopathy: criteria for weaning from ventricular assist devices. Eur Heart J 32: 1148–1160PubMedCrossRefGoogle Scholar
- Galluzzi L, Vitale I, Abrams JM, Alnemri ES, Baehrecke EH, Blagosklonny MV, Dawson TM, Dawson VL, El-Deiry WS, Fulda S et al (2012) Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012. Cell Death Differ 19:107–120PubMedCrossRefGoogle Scholar
- Kenis H, Zandbergen HR, Hofstra L, Petrov AD, Dumont EA, Blankenberg FD, Haider N, Bitsch N, Gijbels M, Verjans JW et al (2010) Annexin A5 uptake in ischemic myocardium: demonstration of reversible phosphatidylserine externalization and feasibility of radionuclide imaging. J Nucl Med 51:259–267PubMedCrossRefGoogle Scholar
- Milting H, Bartling B, Schumann H, El-Banayosy A, Wlost S, Ruter F, Darmer D, Holtz J, Korfer R, Zerkowski HR (1999) Altered levels of mRNA of apoptosis-mediating genes after mid-term mechanical ventricular support in dilative cardiomyopathy—first results of the Halle Assist Induced Recovery Study (HAIR). Thorac Cardiovasc Surg 47:48–50PubMedCrossRefGoogle Scholar
- Narula J, Pandey P, Arbustini E, Haider N, Narula N, Kolodgie FD, Dal Bello B, Semigran MJ, Bielsa-Masdeu A, Dec GW et al (1999) Apoptosis in heart failure: release of cytochrome c from mitochondria and activation of caspase-3 in human cardiomyopathy. Proc Natl Acad Sci USA 96:8144–8149PubMedCrossRefGoogle Scholar