Abstract
Different organisms, cell types, and even similar cell lines can dramatically differ in resistance to genotoxic stress. This testifies to the wide opportunities for genetic and epigenetic regulation of stress resistance. These opportunities could be used to increase the effectiveness of cancer therapy, develop new varieties of plants and animals, and search for new pharmacological targets to enhance human radioresistance, which can be used for manned deep space expeditions. Based on the comparison of transcriptomic studies in cancer cells, in this review, we propose that there is a high diversity of genetic mechanisms of development of genotoxic stress resistance. This review focused on possibilities and limitations of the regulation of the resistance of normal cells and whole organisms to genotoxic and oxidative stress by the overexpressing of stress-response genes. Moreover, the existing experimental data on the effect of such overexpression on the resistance of cells and organisms to various genotoxic agents has been analyzed and systematized. We suggest that the recent advances in the development of multiplex and highly customizable gene overexpression technology that utilizes the mutant Cas9 protein and the abundance of available data on gene functions and their signal networks open new opportunities for research in this field.
Highlights
Genotoxic stress, including oxidative stress, causes DNA damage
The review discusses the current state of knowledge about modulation of resistance to genotoxic and oxidative stress by genes overexpression in case of normal and cancer cells, as well as whole organisms
Mechanisms for development of genotoxic and oxidative stress resistance in tumor cells are well described in a number of reviews [21–24]
Summary
Genotoxic stress, including oxidative stress, causes DNA damage. The evolutionary conservative cellular mechanisms of DNA-damage prevention and response (DNA repair, defense against reactive oxygen species, cell cycle checkpoints, and apoptosis) protect cells from mutations and tissues from acquiring malignancy [1,2]. It was suggested multiple times that gene therapy of normal tissues surrounding tumor can be used for increasing their resistance to genotoxins This can help to minimize the negative side effects of cancer treatment by chemotherapy and radiation therapy [3–5]. Signal-cascade networks of gene activation in response to various damaging agents have been elucidated Such knowledge can help in identifying potential gene targets and their combinations for transcriptional activation increasing resistance to genotoxic and oxidative stress. We expect a new round of research in the field of genetic and epigenetic regulation of resistance to genotoxic stress In this regard, the review discusses the current state of knowledge about modulation of resistance to genotoxic and oxidative stress by genes overexpression in case of normal and cancer cells, as well as whole organisms. To assess the potential of genetic regulation of stress-resistance the review discusses transcriptomic studies in cancer cells with different levels of radioresistance
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