scholarly journals Role of Protein Phosphatase 1 and Inhibitor of Protein Phosphatase 1 in Nitric Oxide–Dependent Inhibition of the DNA Damage Response in Pancreatic β-Cells

Diabetes ◽  
2018 ◽  
Vol 67 (5) ◽  
pp. 898-910 ◽  
Author(s):  
Bryndon J. Oleson ◽  
Aaron Naatz ◽  
Sarah C. Proudfoot ◽  
Chay Teng Yeo ◽  
John A. Corbett
Keyword(s):  
Nitric Oxide ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Protein Phosphatase ◽  
Protein Phosphatase 1 ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Damage Response ◽  
Dependent Inhibition

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

2016 ◽  
Vol 36 (15) ◽  
pp. 2067-2077 ◽  
Author(s):  
Bryndon J. Oleson ◽  
Katarzyna A. Broniowska ◽  
Aaron Naatz ◽  
Neil Hogg ◽  
Vera L. Tarakanova ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Dna Damage ◽  
Cell Survival ◽  
Dna Damage Response ◽  
Cell Apoptosis ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Damage Response ◽  
Induced Apoptosis

Nitric oxide, produced in pancreatic β cells in response to proinflammatory cytokines, plays a dual role in the regulation of β-cell fate. While nitric oxide induces cellular damage and impairs β-cell function, it also promotes β-cell survival through activation of protective pathways that promote β-cell recovery. In this study, we identify a novel mechanism in which nitric oxide prevents β-cell apoptosis by attenuating the DNA damage response (DDR). Nitric oxide suppresses activation of the DDR (as measured by γH2AX 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 H2O2both 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 β 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 β-cell death, these studies identify a novel role for nitric oxide as a protective molecule that promotes β-cell survival by suppressing DDR signaling and attenuating DNA damage-induced apoptosis.

The Role of Mitochondrial Metabolism in Nitric Oxide-dependent Inhibition of the DNA Damage Response

2017 ◽  
Vol 112 ◽  
pp. 192-193
Author(s):  
Bryndon J. Oleson ◽  
Katarzyna A. Broniowska ◽  
Aaron Naatz ◽  
Chay Teng Yeo ◽  
Michael Flancher ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Mitochondrial Metabolism ◽  
Damage Response ◽  
Dependent Inhibition

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

2019 ◽  
Vol 39 (18) ◽  
Author(s):  
Bryndon J. Oleson ◽  
Katarzyna A. Broniowska ◽  
Chay Teng Yeo ◽  
Michael Flancher ◽  
Aaron Naatz ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Oxidative Metabolism ◽  
Protective Mechanism ◽  
Metabolic Flexibility ◽  
Β Cells ◽  
Β Cell ◽  
Damage Response ◽  
Mitochondrial Toxins

ABSTRACTIn 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.

scholarly journals The protein phosphatase 1 regulator PNUTS is a new component of the DNA damage response

EMBO Reports ◽  
2010 ◽  
Vol 11 (11) ◽  
pp. 868-875 ◽  
Author(s):  
Helga B Landsverk ◽  
Felipe Mora‐Bermúdez ◽  
Ole J B Landsverk ◽  
Grete Hasvold ◽  
Soheil Naderi ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Protein Phosphatase ◽  
Protein Phosphatase 1 ◽  
Damage Response

scholarly journals Id3 upregulates BrdU incorporation associated with a DNA damage response, not replication, in human pancreatic β-cells

Islets ◽  
2011 ◽  
Vol 3 (6) ◽  
pp. 358-366 ◽  
Author(s):  
Seung-Hee Lee ◽  
Ergeng Hao ◽  
Fred Levine ◽  
Pamela Itkin-Ansari
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Brdu Incorporation ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Damage Response

scholarly journals Nitric oxide donors increase PVR/CD155 DNAM-1 ligand expression in multiple myeloma cells: role of DNA damage response activation

BMC Cancer ◽  
2015 ◽  
Vol 15 (1) ◽  
Author(s):  
Cinzia Fionda ◽  
Maria Pia Abruzzese ◽  
Alessandra Zingoni ◽  
Alessandra Soriani ◽  
Biancamaria Ricci ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Multiple Myeloma ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Nitric Oxide Donors ◽  
Myeloma Cells ◽  
Damage Response ◽  
Ligand Expression ◽  
Response Activation

2118-P: Regulation of Ataxia-Telangiectasia and Rad3-Related (ATR)–Dependent DNA Damage Response by Nitric Oxide in ß-Cells

Diabetes ◽  
2020 ◽  
Vol 69 (Supplement 1) ◽  
pp. 2118-P
Author(s):  
CHAY TENG YEO ◽  
BRYNDON OLESON ◽  
JOHN A. CORBETT ◽  
JAMIE K. SCHNUCK
Keyword(s):  
Nitric Oxide ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Ataxia Telangiectasia ◽  
Damage Response
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