miR-106b has been shown to regulate the p21 checkpoint and can, therefore, either promote cell cycle progression or cause cells to accumulate in the G1 phase. Similarly, CY5-SE miR-17 and miR-20a also can affect G1 checkpoint regulation by means of the transcription factor E2F1, and miR-34 has been shown to regulate p53. Taken together with our observations, this suggests that miRNAs may play an important role in DNA repair after radiation-induced damage. This is further supported by the fact that several of the miRNA species that are altered by radiation have potential targets that are involved in DNA repair including cyclin-dependent kinase 5, topoisomerase I, histone 2AX, and cyclindependent kinase inhibitor I, and phosphatase and tensin homolog. Since miRNAs are responding to radiation, oxidative stress, and direct DNA damage, it is logical to suggest that miRNA expression is altered by, and may regulate, pathways involved in cellular stress. This was demonstrated in one study which identified a set of hypoxia-regulated miRNA species that were induced by hypoxia in breast and other cancer cell lines causing hypoxia-inducible factor to interact with miRNA promoters. miRNA expression also appears to be responsive to pro-inflammatory signals, changes in osmolarity, cardiomyocyte stress associated with heart failure, and several species have been shown to localize to stress response elements in cells subjected to various stressors. In a recent study, the authors increased or decreased miR-521 expression and found that the levels of the DNA repair 487-39-8 protein Cockayne syndrome protein and the antioxidant manganese superoxide dismutase were altered after irradiation in prostate cancer cell lines. Furthermore, two studies have demonstrated altered susceptibility to radiation in cells overexpressing a single miRNA species. Our data suggest that both changes in intracellular oxidation/ reduction status and damage to DNA may alter miRNA transcription, however the mechanism underlying this remains unclear. Since all three agents that were tested have previously been shown to induce genetoxic and oxidative stress, this suggests to us that the miRNA response utilizes mechanisms involved in the response to other cellular stresses including both changes in intracellular oxidation/reduction status and damage to DNA. For example, many mechanisms exist that alter transcriptional activity in response to various stressors. These include well-described redox-responsive alterations
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