Genotoxic Stress Response

1. Genotoxic Stress Response In genetics, genotoxicity describes the property of chemical agents that damage the genetic information within a cell causing mutations(Genotoxicity is often confused with mutagenicity. All mutagens are genotoxic, whereas not all genotoxic substances are mutagenic.). The alteration can have direct or indirect effects on the DNA: the induction of mutations, mistimed event activation, and direct DNA damage resulting in mutations. Of course, there are exist several important defense mechanisms to response genotoxic stress. These responses are expected to be very complex, involving various cellular factors that form an extensive signal transduction network. This network includes a protein kinase cascade that connects the detection of DNA damage to the activation of transcription factors, which in turn regulate the expression of genes implicated in DNA repair, cell cycle arrest and programmed cell death (apoptosis). What's worse is heritable changes can affect either somatic cells of the organism or germ cells to be passed on to future generations. Cells prevent expression of the genotoxic mutation by either DNA repair or apoptosis, so the damage may not always be fixed leading to mutagenesis. It has long been acknowledged that exposure to certain chemicals is associated with the development of human cancers. For example, this linkage has been made between aflatoxins and liver cancer, amine dyes and bladder cancer, benzene and leukemia, vinyl chloride and hepatic cancer and smoking and lung cancer. To date, many human carcinogens have been identified, most of which are categorized as genotoxic agents, meaning that these chemicals target DNA and produce alterations in the genetic material of the host. Such environmental agents are only one source of genotoxic stress, with other sources including UV and ionizing irradiation (IR), therapeutic agents and the products of normal metabolism. As a result, human cells are constantly exposed to a variety of genotoxic stresses. To cope with the resulting damage to cellular DNA, cells have developed a repertoire of responses that ensure the normal growth and survival of the organism. A logical consequence, therefore, is that alterations in these responses may be the basis for carcinogenesis. For this reason, a better understanding of cellular responses to genotoxic stress is important in the prevention and treatment of human cancers.