Regulation of ATR-dependent DNA damage response by nitric oxide

• Published in: The Journal of biological chemistry 2021-01, Vol.296, p.100388-100388, Article 100388
• Main Authors: Yeo, Chay Teng, Stancill, Jennifer S., Oleson, Bryndon J., Schnuck, Jamie K., Stafford, Joshua D., Naatz, Aaron, Hansen, Polly A., Corbett, John A.
• Format: Article
• Language: English
• Subjects: Animals; Ataxia Telangiectasia Mutated Proteins - metabolism; ATR; beta-cell; Cells, Cultured; DDR; DNA Damage; Insulin-Secreting Cells - drug effects; Insulin-Secreting Cells - metabolism; metabolism; Mice; mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; Nitric oxide; Nitric Oxide - pharmacology; Nitric Oxide Synthase Type II - metabolism; oxidation; Rats; ribonucleotide reductase; Signal Transduction
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1016/j.jbc.2021.100388

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.