Impact of Oxidative DNA Damage and the Role of DNA Glycosylases in Neurological Dysfunction

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.

“Loss of alkyladenine DNA glycosylase alters gene expression in the developing mouse brain and leads to reduced anxiety and improved memory”

“…In addition to TDG, other DNA glycosylases can impact gene expression through different mechanisms, many of which remain though only partially understood [24][25][26]. Using human cell lines, we showed that AAG associates with actively transcribing RNA pol II and modulates expression of neurodevelopmental genes [27].…”

“…In neurons, programed generation of SSBs, through activity of thymine DNA glycosylase (TDG), has been recently proposed to be required for physiological epigenetic (re)programming and activation of transcriptional programs allowing unperturbed neuronal differentiation [22]. In addition to TDG, other DNA glycosylases can impact gene expression through different mechanisms, many of which remain though only partially understood [24-26]. Using human cell lines, we showed that AAG associates with actively transcribing RNA pol II and modulates expression of neurodevelopmental genes [27].…”

Biological Functions of the DNA Glycosylase NEIL3 and Its Role in Disease Progression Including Cancer

“…Reportedly, Fpg/Nei, NTH1, OGG1, and NEIL1/2/3 all possess the general activity of DNA glycosylases (cleaving damaged bases) and AP lyase activity, which are bifunctional [ 17 , 18 ]. Interestingly, in the presence of APE1, human NEIL3 may function mainly as a single functional enzyme, as the vigorous glycosylase and weak AP lyase activity of NEIL3 exhibit discordant properties during the repair process [ 8 , 19 ].…”