Evidence that OGG1 Glycosylase Protects Neurons against Oxidative DNA Damage and Cell Death under Ischemic Conditions

Abstract

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.

Aag-initiated base excision repair promotes ischemia reperfusion injury in liver, brain, and kidney

“…Indeed, it was shown that Parp1 has specific affinity to AP sites and 5′-dRP intermediates that are generated during BER initiated by monofunctional glycosylases (43,44), and excessive Parp1 activation is known to elicit necrotic cell death (16,18,19). Therefore, repair by Aag, a monofunctional glycosylase with an unusually broad range of substrates, may generate excessive amounts of BER intermediates and, in particular, highly toxic dRP intermediates, possibly explaining why Aag-initiated BER is toxic and Ung/Ogg1/Neil1 initiated repair is not (34)(35)(36). We previously observed that Aag −/− mice are more susceptible than WT mice to inflammation-associated colon cancer (12); this may at first appear to contradict the findings reported here.…”

“…When a panoply of damaged bases is induced, base excision by Aag, in contrast to that by Ung, Neil1, and Ogg1, may exceed the capacity for the downstream BER enzymes to complete repair, thus generating toxic BER intermediates and cell death. Consequently, when Ung, Ogg1, or Neil1 are deficient, their unrepaired substrates become subject to Aag-initiated BER such that in the Ung/Ogg1/Neil1-deficient mice, Aag has even more substrates to repair, causing increased I/R-mediated tissue damage (34)(35)(36).…”

Oxidative DNA damage in disease—Insights gained from base excision repair glycosylase‐deficient mouse models

“…When subjected to focal ischemic stroke, Ogg1 2/2 mice displayed larger cortical lesions compared to WT mice. Accumulation of the oxidative DNA lesions 8-oxoG and FapyG was significantly increased in OGG1-deficient brains, and was associated with impaired recovery from stroke in these animals [Liu et al, 2011]. In addition to models of stroke, 8-oxoG levels have also been shown to be elevated in brain areas affected by Parkinson's disease [Cardozo-Pelaez et al, 2005;Fukae et al, 2005;Nakabeppu et al, 2007].…”

Combined Exercise and Insulin-Like Growth Factor-1 Supplementation Induces Neurogenesis in Old Rats, but Do Not Attenuate Age-Associated DNA Damage

“…[1][2][3][4] It is well documented that the interaction of ROS with lipids and proteins has a significant impact on cellular function in the brain. [5][6][7][8] However, recent investigations have revealed that DNA damage/repair can contribute to the age-associated neurodegeneration.…”

“…[5][6][7][8] However, recent investigations have revealed that DNA damage/repair can contribute to the age-associated neurodegeneration. [2][3][4] Indeed, significant damage to DNA causes activation of pro-apoptotic and DNA repair proteins. Depending on the size of DNA damage and the success of repair, cells either die or survive.…”