Regulation of ATR-dependent DNA damage response by nitric oxide

Area of Science:

• Cellular biology
• Biochemistry
• Molecular signaling

Background:

• Nitric oxide (NO) is known to regulate ataxia-telangiectasia mutated (ATM) signaling by affecting mitochondrial metabolism in a beta-cell selective manner.
• The role of NO in the signaling of ataxia-telangiectasia and Rad3-related protein (ATR), another key DNA damage response transducer, remains less understood.

Purpose of the Study:

• To investigate the actions of nitric oxide on ATR signaling in both beta-cells and non-beta-cells.
• To elucidate the mechanisms by which NO modulates ATR activity, particularly in the context of cellular metabolism.

Main Methods:

• Utilized cell culture models (beta-cells and non-beta-cells).
• Administered nitric oxide donors and inhibitors of mitochondrial respiration.
• Measured ATR signaling activation.
• Assessed cellular ATP levels and metabolic activity (oxidative metabolism and glycolysis).

Main Results:

• Nitric oxide activates ATR signaling in all cell types by inhibiting ribonucleotide reductase.
• At inducible nitric oxide synthase-derived levels, NO selectively impairs ATR signaling in beta-cells.
• This impairment is linked to reduced mitochondrial oxidative metabolism, insufficient glycolytic compensation, and decreased ATP levels in beta-cells.
• Inhibitors of mitochondrial respiration mimic NO's inhibitory effects on ATR signaling in a beta-cell selective manner.
• Non-beta-cells forced to rely on mitochondrial metabolism exhibit a similar sensitivity to NO and mitochondrial inhibitors regarding ATR signaling.

Conclusions:

• Nitric oxide plays a dual role in regulating ATR signaling.
• NO activates ATR globally by inhibiting ribonucleotide reductase.
• At specific concentrations, NO selectively inhibits ATR in beta-cells by compromising mitochondrial function and depleting ATP, highlighting a beta-cell specific metabolic vulnerability.