Regulation of ATR-dependent DNA damage response by nitric oxide

Abstract

We have shown that nitric oxide limits ataxia-telangiectasia mutated signaling by inhibiting mitochondrial oxidative metabolism in a β-cell selective manner. In this study, we examined the actions of nitric oxide on a second DNA damage response transducer kinase, ataxia-telangiectasia and Rad3-related protein (ATR). In β-cells and non-β-cells, nitric oxide activates ATR signaling by inhibiting ribonucleotide reductase; however, when produced at inducible nitric oxide synthase-derived (low micromolar) levels, nitric oxide impairs ATR signaling in a β-cell selective manner. The inhibitory actions of nitric oxide are associated with impaired mitochondrial oxidative metabolism and lack of glycolytic compensation that result in a decrease in β-cell ATP. Like nitric oxide, inhibitors of mitochondrial respiration reduce ATP levels and limit ATR signaling in a β-cell selective manner. When non-β-cells are forced to utilize mitochondrial oxidative metabolism for ATP generation, their response is more like β-cells, as nitric oxide and inhibitors of mitochondrial respiration attenuate ATR signaling. These studies support a dual role for nitric oxide in regulating ATR signaling. Nitric oxide activates ATR in all cell types examined by inhibiting ribonucleotide reductase, and in a β-cell selective manner, inducible nitric oxide synthase-derived levels of nitric oxide limit ATR signaling by attenuating mitochondrial oxidative metabolism and depleting ATP.

Keywords: ATR; DDR; Nitric oxide; beta-cell; metabolism; mitochondria; oxidation; ribonucleotide reductase.