Topoisomerase II-Mediated DNA Cleavage and Mutagenesis Activated by Nitric Oxide Underlie the Inflammation-Associated Tumorigenesis

Journal of Biological Chemistry

Schreiber

et al. 2014

Background:The mechanisms that control ␤ cell fate following cytokine-and nitric oxide-induced damage remain unknown. Results: Cytokine-induced nitric oxide activates ATM and ATM-dependent caspase activation in ␤ cells. Conclusion: ATM regulates the induction of apoptosis in cytokine-treated ␤ cells. Significance: These studies define a role for DNA damage and ATM activation in nitric oxide-induced ␤ cell apoptosis.

Section: Discussionsupporting

confidence: 94%

Nitric Oxide Induces Ataxia Telangiectasia Mutated (ATM) Protein-dependent γH2AX Protein Formation in Pancreatic β Cells

Journal of Biological Chemistry

Schreiber

et al. 2014

“…Nitric oxide also stimulates the expression of genes that participate in functional recovery from cytokine-mediated damage, including the recovery of metabolic function and the repair of damaged DNA (16,45,46). These protective and damaging actions are consistent with the ability of nitric oxide to activate and inhibit DDR signaling selectively in ␤ cells (17,18,22,(38)(39)(40)(41).…”

Section: Discussionmentioning

confidence: 62%

“…We have shown that nitric oxide acts as both a positive and a negative regulator of DDR signaling in ␤ cells (15,17,18). Nitric oxide, a free radical with genotoxic properties, causes DNA damage leading to DDR activation in multiple cell types, including ␤ cells (18,22,(38)(39)(40)(41). However, under conditions where nitric oxide is present at low-micromolar levels, such as during exposure to proinflammatory cytokines, DDR signaling in ␤ cells is suppressed (17,22).…”

Section: Discussionmentioning

confidence: 99%

The Role of Metabolic Flexibility in the Regulation of the DNA Damage Response by Nitric Oxide

Molecular and Cellular Biology

Yeo

et al. 2019

In this report, we show that nitric oxide suppresses DNA damage response (DDR) signaling in the pancreatic β-cell line INS 832/13 and rat islets by inhibiting intermediary metabolism. Nitric oxide is known to inhibit complex IV of the electron transport chain and aconitase of the Krebs cycle. Non-β cells compensate by increasing glycolytic metabolism to maintain ATP levels; however, β cells lack this metabolic flexibility, resulting in a nitric oxide-dependent decrease in ATP and NAD+. Like nitric oxide, mitochondrial toxins inhibit DDR signaling in β cells by a mechanism that is associated with a decrease in ATP. Non-β cells compensate for the effects of mitochondrial toxins with an adaptive shift to glycolytic ATP generation that allows for DDR signaling. Forcing non-β cells to derive ATP via mitochondrial respiration (replacing glucose with galactose in the medium) and glucose deprivation sensitizes these cells to nitric oxide-mediated inhibition of DDR signaling. These findings indicate that metabolic flexibility is necessary to maintain DDR signaling under conditions in which mitochondrial oxidative metabolism is inhibited and support the inhibition of oxidative metabolism (decreased ATP) as one protective mechanism by which nitric oxide attenuates DDR-dependent β-cell apoptosis.

“…When DNA damage is too extensive, the DDR is also capable of removing the damaged cell by activating apoptosis. Through the induction of DNA strand breaks and DNA deamination, nitric oxide activates the DDR in multiple cell types (42)(43)(44)(45). Nitric oxide is also an effective inhibitor of apoptotic cell death by inhibiting caspase activity via S-nitrosation of the active-site cysteine (53,54).…”

Section: Discussionmentioning

confidence: 99%

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

Molecular and Cellular Biology

Naatz

et al. 2016

c Nitric oxide, produced in pancreatic ␤ cells in response to proinflammatory cytokines, plays a dual role in the regulation of ␤-cell fate. While nitric oxide induces cellular damage and impairs ␤-cell function, it also promotes ␤-cell survival through activation of protective pathways that promote ␤-cell recovery. In this study, we identify a novel mechanism in which nitric oxide prevents ␤-cell apoptosis by attenuating the DNA damage response (DDR). Nitric oxide suppresses activation of the DDR (as measured by ␥H2AX formation and the phosphorylation of KAP1 and p53) in response to multiple genotoxic agents, including camptothecin, H 2 O 2 , and nitric oxide itself, despite the presence of DNA damage. While camptothecin and H 2 O 2 both induce DDR activation, nitric oxide suppresses only camptothecin-induced apoptosis and not H 2 O 2 -induced necrosis. The ability of nitric oxide to suppress the DDR appears to be selective for pancreatic ␤ 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 ␤-cell death, these studies identify a novel role for nitric oxide as a protective molecule that promotes ␤-cell survival by suppressing DDR signaling and attenuating DNA damage-induced apoptosis.