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- W2591693500 abstract "The cytokine interleukin-1 (IL-1) has been implicated as a pathogenic factor in type-1 diabetes by causing inhibition of β-cell function, DNA damage and ultimate cell death. Nitric oxide, produced by β-cells following IL-1 exposure, mediates the inhibition of oxidative metabolism and insulin secretion and induces DNA damage in β-cells. We have recently shown that nitric oxide-induced DNA damage activates the DNA damage response (DDR), a signaling network that coordinates cell fate decisions in response to DNA damage and promotes β-cell apoptosis during IL-1 exposure. Though nitric oxide causes DNA damage, in this study we identified an additional role for nitric oxide as an inhibitor of the DDR. We show that while DNA damage induced by nitric oxide results in DDR activation, this only occurs when islets or insulinoma cells are no longer endogenously producing (in response to IL-1) or exogenously exposed to (with donor compounds) micromolar levels of nitric oxide. Further, we find that nitric oxide treatment of INS 832/13 cells or rat islets completely prevents DDR activation in response to genotoxic agents such as H2O2 and camptothecin, despite persistent DNA damage. Inhibition of the DDR by nitric oxide is associated with β-cell survival, as INS 832/13 cells are protected from DNA damage-dependent apoptosis induced by camptothecin. The ability to inhibit the DDR is restricted to nitric oxide, as other forms of ROS and RNS including superoxide (generated in response to menadione), H2O2, and peroxynitrite are not capable of impairing DDR signaling. Instead, we show that superoxide scavenges nitric oxide and completely prevents its ability to both inhibit DDR signaling and protect β-cells from DNA damage-induced cell death. These findings describe a novel protective role of nitric oxide by functioning as a brake on DDR signaling, thereby attenuating DNA damage-induced apoptosis." @default.
- W2591693500 created "2017-03-16" @default.
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- W2591693500 date "2016-11-01" @default.
- W2591693500 modified "2023-09-27" @default.
- W2591693500 title "Nitric Oxide Prevents β-Cell Apoptosis Via Inhibition of the DNA Damage Response" @default.
- W2591693500 doi "https://doi.org/10.1016/j.freeradbiomed.2016.10.114" @default.
- W2591693500 hasPublicationYear "2016" @default.
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