Evidence that OGG1 glycosylase protects neurons against oxidative DNA damage and cell death under ischemic conditions.
7,8-Dihydro-8-oxoguanine DNA glycosylase (OGG1) is a major DNA glycosylase involved in base-excision repair (BER) of oxidative DNA damage to nuclear and mitochondrial DNA (mtDNA). We used OGG1-deficient (OGG1(-/-)) mice to examine the possible roles of OGG1 in the vulnerability of neurons to ischemic and oxidative stress. After exposure of cultured neurons to oxidative and metabolic stress levels of OGG1 in the nucleus were elevated and mitochondria exhibited fragmentation and increased levels of the mitochondrial fission protein dynamin-related protein 1 (Drp1) and reduced membrane potential. Cortical neurons isolated from OGG1(-/-) mice were more vulnerable to oxidative insults than were OGG1(+/+) neurons, and OGG1(-/-) mice developed larger cortical infarcts and behavioral deficits after permanent middle cerebral artery occlusion compared with OGG1(+/+) mice. Accumulations of oxidative DNA base lesions (8-oxoG, FapyAde, and FapyGua) were elevated in response to ischemia in both the ipsilateral and contralateral hemispheres, and to a greater extent in the contralateral cortex of OGG1(-/-) mice compared with OGG1(+/+) mice. Ischemia-induced elevation of 8-oxoG incision activity involved increased levels of a nuclear isoform OGG1, suggesting an adaptive response to oxidative nuclear DNA damage. Thus, OGG1 has a pivotal role in repairing oxidative damage to nuclear DNA under ischemic conditions, thereby reducing brain damage and improving functional outcome.
Liu
Dong
D
Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, Maryland 21224, USA.
Croteau
Deborah L
DL
Souza-Pinto
Nadja
N
Pitta
Michael
M
Tian
Jingyan
J
Wu
Christopher
C
Jiang
Haiyang
H
Mustafa
Khadija
K
Keijzers
Guido
G
Bohr
Vilhelm A
VA
Mattson
Mark P
MP
D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D015153:Blotting, Western; D002545:Brain Ischemia / Q000473:pathology* / Q000523:psychology; D016923:Cell Death / Q000502:physiology*; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D004249:DNA Damage; D045647:DNA Glycosylases / Q000235:genetics / Q000502:physiology*; D004260:DNA Repair; D004272:DNA, Mitochondrial / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D020287:In Situ Nick-End Labeling; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects; D009474:Neurons / Q000502:physiology*; D018384:Oxidative Stress / Q000502:physiology*; D020521:Stroke / Q000473:pathology / Q000523:psychology
D004272:DNA, Mitochondrial; D045647:DNA Glycosylases; C485990:Ogg1 protein, mouse