Programming of Cell Resistance to Genotoxic and Oxidative Stress

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.

Enhanced autophagic-lysosomal activity and increased BAG3-mediated selective macroautophagy as adaptive response of neuronal cells to chronic oxidative stress

“…The adaptation to oxidative stress is a highly relevant process and some adaptive pathways focusing on antioxidant defense systems and mitochondrial and metabolic adaptations have been described to be constantly activated in neuronal cells resistant to oxidative stress as well as in AD tissue [6,26,29]. Moreover, oxidative stress resistance has been linked to failure of anticancer therapy and here a particular role of upregulated autophagy and BAG3 has been proposed in various tumor types [16,[67], [68], [69]].…”

Therapeutic targeting of cellular stress responses in cancer

“…ROS) that are highly reactive to DNA, and exposure to chemotherapy or radiation therapy. [112][113][114][115][116][117][118] Replication stress can occur even under normal physiological conditions in cancer cells because of a shortage of building blocks (histones, deoxyribonucleotide triphosphates), conflicts between concurrent activation of the massive replication and transcription machineries, as well as unusual DNA structures and topologies. 119,120 As a result of replication fork stalling, levels of exposed single-stranded DNA increase, thereby recruiting RPA (a single-stranded DNAbinding protein) to the lesion.…”

“…The threats can arise from a broad range of events and agents, including unresolved replication fork stalling during normal DNA replication, accumulation of metabolic intermediates (e.g. ROS) that are highly reactive to DNA, and exposure to chemotherapy or radiation therapy . Replication stress can occur even under normal physiological conditions in cancer cells because of a shortage of building blocks (histones, deoxyribonucleotide triphosphates), conflicts between concurrent activation of the massive replication and transcription machineries, as well as unusual DNA structures and topologies .…”

Enhanced autophagic-lysosomal activity and increased BAG3-mediated selective macroautophagy as adaptive response of neuronal cells to chronic oxidative stress

“…The adaptation to oxidative stress is a highly relevant process and some adaptive pathways focusing on antioxidant defense systems and mitochondrial and metabolic adaptations have been described to be constantly activated in neuronal cells resistant to oxidative stress as well as in AD tissue [26], [29], [6]. Moreover, oxidative stress resistance has been linked to failure of anticancer therapy and here a particular role of upregulated autophagy and BAG3 has been proposed in various tumor types [16], [65], [66], [67].…”