Cell Death in Response to Genotoxic Stress and DNA Damage.

PABLO LOPEZ BERGAMI; ZEEV RONAI

Apoptosis: Physiology and Pathology of Cell Death.

Cambridge University Press

Año: 2011; p. 74 - 87

Cells are subjected to multiple types of stress throughout their life cycle, including starvation, infection, and physical and chemical agents. Stressors cause transient and permanent damage. Transient damage is reflected at the level of the protein or RNA and is largely associated with the generation of reactive oxygen radicals, which directly or indirectly impact translation, folding,or conformation of proteins. In contrast to transient damage, which is expected to be cleared by existing cellular machinery that allows recognition and removal of damaged proteins, permanent damage is primarily reflected at the level of the DNA, although it could also result from damaged proteins that fail to support proper repair or cell duplication. DNA-damaging agents induce a variety of modifications that may result in improper chromosomal duplication, recombinationbetween chromosomes, gene mutations, or gene amplification, which may result in malignant transformations if not properly repaired. Damage is generated by both endogenous and exogenous sources: endogenous (spontaneous) damage is caused by agents within the cell itself(i.e., the products of normal cellular metabolism, replication, mitosis), whereas exogenous sources include ultraviolet (UV) light, ionizing radiation (IR), and environmental genotoxins (e.g., alkylating compounds, polycyclic aromatic hydrocarbons, biphenyls, and heterocyclic amines). Most cytotoxic anticancer drugs react either directly or indirectly (through reactive metabolites)with DNA or by blocking DNA-metabolizing functions, such as DNA polymerases or topoisomerases. To cope with DNA damage, two cellular strategies have evolved in multicellular organisms: (1) DNA damage is repaired or tolerated; or (2) cells harboring DNA damage are removed from the population by apoptosis or other forms of cell death. This contrasts withunicellular organisms, in which the best way to ensure survival is simply to repair any damaged DNA. Metazoans, however, are better served by having alternate strategies that enable a means of destroying irreparably damaged cells. For example, extensive damage of the DNA is likely to result in multiple genetic mutations that cannot be tolerated, therefore triggering a programmed cell death response. As a result of this flexibility, repair, growth arrest, and apoptosis are all possible cellular responses to genotoxic stress in metazoans, with the choice dependent on cell type, location, environment, and extent of damage.