title: Alzheimer's disease-associated polymorphisms in human OGG1 alter catalytic activity and sensitize cells to DNA damage.
abstract: Brain tissues from Alzheimer's disease (AD) patients show increased levels of oxidative DNA damage and 7,8-dihydro-8-oxoguanine (8-oxoG) accumulation. In humans, the base excision repair protein 8-oxoguanine-DNA glycosylase (OGG1) is the major enzyme that recognizes and excises the mutagenic DNA base lesion 8-oxoG. Recently, two polymorphisms of OGG1, A53T and A288V, have been identified in brain tissues of AD patients, but little is known about how these polymorphisms may contribute to AD. We characterized the A53T and A288V polymorphic variants and detected a significant reduction in the catalytic activity for both proteins in vitro and in cells. Additionally, the A53T polymorphism has decreased substrate binding, whereas the A288V polymorphism has reduced AP lyase activity. Both variants have decreased binding to known OGG1 binding partners PARP-1 and XRCC1. We found that OGG1(-/-) cells expressing A53T and A288V OGG1 were significantly more sensitive to DNA damage and had significantly decreased survival. Our results provide both biochemical and cellular evidence that A53T and A288V polymorphic proteins have deficiencies in catalytic and protein-binding activities that could be related to the increase in oxidative damage to DNA found in AD brains.
authors.affiliation: Laboratory of Epidemiology and Population Sciences, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224-6825, USA.
authors.forename: Kimberly D
authors.initials: KD
authors.lastname: Jacob
authors.forename: Nicole
authors.initials: N
authors.lastname: Noren Hooten
authors.forename: Takashi
authors.initials: T
authors.lastname: Tadokoro
authors.forename: Althaf
authors.initials: A
authors.lastname: Lohani
authors.forename: Janice
authors.initials: J
authors.lastname: Barnes
authors.forename: Michele K
authors.initials: MK
authors.lastname: Evans
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002384:Catalysis; D004249:DNA Damage / Q000235:genetics*; D045647:DNA Glycosylases / Q000235:genetics* / Q000378:metabolism; D004260:DNA Repair / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism; D006147:Guanine / Q000031:analogs & derivatives / Q000378:metabolism; D006801:Humans; D018384:Oxidative Stress; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011110:Polymorphism, Genetic; D011485:Protein Binding; D013379:Substrate Specificity; D000076105:X-ray Repair Cross Complementing Protein 1
chemical_list: C453560:7,8-dihydro-8-oxoguanine; D004268:DNA-Binding Proteins; D000076105:X-ray Repair Cross Complementing Protein 1; C000619371:XRCC1 protein, human; C000619352:Xrcc1 protein, mouse; D006147:Guanine; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D045647:DNA Glycosylases; C479058:oxoguanine glycosylase 1, human
keywords: 7,8-dihydro-8-oxoguanine; 8-Oxoguanine; 8-Oxoguanine-DNA glycosylase; 8-oxoG; 8-oxoguanine-DNA glycosylase; AD; Alzheimer's disease; BER; Base excision repair; DNA damage; DNA repair; Free radicals; MEF; OGG1; Oxidative stress; PAR; PARP-1; ROS; X-ray cross-complementing protein 1; XRCC1; base excision repair; mouse embryo fibroblast; poly(ADP-ribose) polymerase 1; poly(ADP-ribosyl)ation; reactive oxygen species