Nitric Oxide Suppresses β-Cell Apoptosis by Inhibiting the DNA Damage Response

Nitric oxide, produced in pancreatic beta cells in response to proinflammatory cytokines, plays a dual role in the regulation of beta-cell fate. While nitric oxide induces cellular damage and impairs beta-cell function, it also promotes beta-cell survival through activation of protective pathways that promote beta-cell recovery. In this study, we identify a novel mechanism in which nitric oxide prevents beta-cell apoptosis by attenuating the DNA damage response (DDR). Nitric oxide suppresses activation of the DDR (as measured by gamma H2AX formation and the phosphorylation of KAP1 and p53) in response to multiple genotoxic agents, including camptothecin, H2O2, and nitric oxide itself, despite the presence of DNA damage. While camptothecin and H2O2 both induce DDR activation, nitric oxide suppresses only camptothecin-induced apoptosis and not H2O2-induced necrosis. The ability of nitric oxide to suppress the DDR appears to be selective for pancreatic beta cells, as nitric oxide fails to inhibit DDR signaling in macrophages, hepatocytes, and fibroblasts, three additional cell types examined. While originally described as the damaging agent responsible for cytokine-induced beta-cell death, these studies identify a novel role for nitric oxide as a protective molecule that promotes beta-cell survival by suppressing DDR signaling and attenuating DNA damage-induced apoptosis.