Abstract
The human brain requires a high rate of oxygen consumption to perform intense metabolic activities, accounting for 20% of total body oxygen consumption. This high oxygen uptake results in the generation of free radicals, including reactive oxygen species (ROS), which, at physiological levels, are beneficial to the proper functioning of fundamental cellular processes. At supraphysiological levels, however, ROS and associated lesions cause detrimental effects in brain cells, commonly observed in several neurodegenerative disorders. In this review, we focus on the impact of oxidative DNA base lesions and the role of DNA glycosylase enzymes repairing these lesions on brain function and disease. Furthermore, we discuss the role of DNA base oxidation as an epigenetic mechanism involved in brain diseases, as well as potential roles of DNA glycosylases in different epigenetic contexts. We provide a detailed overview of the impact of DNA glycosylases on brain metabolism, cognition, inflammation, tissue loss and regeneration, and age-related neurodegenerative diseases based on evidence collected from animal and human models lacking these enzymes, as well as post-mortem studies on patients with neurological disorders.
Highlights
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These studies suggest that both OGG1 and NEIL1 are important for neuroprotection upon brain ischemia, and NEIL3 is involved in expansion of the stem-cell pool, which is essential for regeneration of damaged tissue
These results suggest that OGG1, MUTYH, and NEIL1 are associated with Parkinson’s disease (PD) and may play distinct roles in the pathogenesis of the disease
Summary
Base excision repair (BER) is the major pathway for repair of non-bulky oxidative DNA damage such as SSBs and base lesions, while cyPU lesions are exclusively repaired via nucleotide excision repair (NER) [21,22]. G4 sequences are hotspots for hypoxia-induced oxidative DNA-base modifications, inducing the recruitment of BER proteins and accumulation of strand breaks in G4 promoter regions In this scenario, OGG1 and APE1 recruitment to G4-containing promoter regions coincide with increased 8-oxoG and DNA strand-break levels in G4 sites in hypoxic rat pulmonary artery endothelial cells (PAECs) [49]. The analysis of overlapping genes after enrichment via Chip-seq revealed co-occurrence of AP sites and G4 structures, as well as binding of acetylated OGG1, APE1, and acetylated APE1 in promoter regions previously shown to form G4 structures Based on these findings, in vitro data, and cell-based assays, it was proposed that OGG1 is recruited to oxidized G-rich regions, where it removes 8-oxoG, generating an AP site, possibly destabilizing and opening the DNA duplex. In addition to maintaining genome integrity through the repair of oxidative DNA damage, DNA glycosylases play key roles in gene-expression regulation in specific sequence contexts
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