Bcl-2 facilitates recovery from DNA damage after oxidative stress.
Oxidative stress is a major factor affecting the brain during aging and neurodegenerative diseases such as Alzheimer's disease (AD). Understanding the mechanisms by which neurons can be protected from oxidative stress, therefore, is critical for the prevention and treatment of such degeneration. Previous studies have shown that bcl-2 expression is increased in neurons with DNA damage in AD and bcl-2 has an antioxidant effect. The goal of this study is to document the effects of oxidative insults on mitochondrial and nuclear DNA in PC12 cells and determine the extent to which bcl-2 prevents damage or facilitates repair. Using extralong PCR to amplify nuclear and mitochondrial DNA, the time course of DNA damage and repair was determined. Within minutes after exposure of cells to low concentrations of hydrogen peroxide and peroxynitrite, significant mitochondrial and nuclear DNA damage was evident. Mitochondrial DNA was damaged to a greater degree than nuclear DNA. Expression of bcl-2 in PC12 cells inhibited nitric oxide donor (sodium nitroprusside)- and peroxynitrite-induced cell death. Although oxidative insults caused both genomic and mitochondrial DNA damage in cells expressing bcl-2, recovery from DNA damage was accelerated in these cells. These results suggest that neuronal up-regulation of bcl-2 may facilitate DNA repair after oxidative stress.
Deng
G
G
Institute for Brain Aging and Dementia, University of California, Irvine, Irvine, California, 92697, USA.
Su
J H
JH
Ivins
K J
KJ
Van Houten
B
B
Cotman
C W
CW
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D051152:Clusterin; D003169:Complement Inactivator Proteins / Q000235:genetics; D004249:DNA Damage; D004260:DNA Repair; D004272:DNA, Mitochondrial / Q000187:drug effects / Q000378:metabolism; D004277:DNA, Single-Stranded / Q000187:drug effects / Q000378:metabolism; D006023:Glycoproteins / Q000235:genetics; D006861:Hydrogen Peroxide / Q000494:pharmacology; D018832:Molecular Chaperones; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D009566:Nitrates / Q000494:pharmacology; D020030:Nitric Oxide Donors / Q000378:metabolism; D009599:Nitroprusside / Q000494:pharmacology; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress / Q000502:physiology*; D016716:PC12 Cells; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology*; D051381:Rats; D013439:Sulfhydryl Reagents / Q000494:pharmacology; D014162:Transfection
D051152:Clusterin; D003169:Complement Inactivator Proteins; D004272:DNA, Mitochondrial; D004277:DNA, Single-Stranded; D006023:Glycoproteins; D018832:Molecular Chaperones; D009566:Nitrates; D020030:Nitric Oxide Donors; D016877:Oxidants; D019253:Proto-Oncogene Proteins c-bcl-2; D013439:Sulfhydryl Reagents; D009599:Nitroprusside; C039642:peroxynitric acid; D006861:Hydrogen Peroxide