The two faces of DNA oxidation in genomic and functional mosaicism during aging in human neurons

Abstract

Maintaining genomic integrity in post-mitotic neurons in the human brain is paramount because these cells must survive for an individual's entire lifespan. Due to life-long synaptic plasticity and electrochemical transmission between cells, the brain engages in an exceptionally high level of mitochondrial metabolic activity. This activity results in the generation of reactive oxygen species with 8-oxo-7,8-dihydroguanine (8-oxoG) being one of the most prevalent oxidation products in the cell. 8-oxoG is important for the maintenance and transfer of genetic information into proper gene expression: a low basal level of 8-oxoG plays an important role in epigenetic modulation of neurodevelopment and synaptic plasticity, while a dysregulated increase in 8-oxoG damages the genome leading to somatic mutations and transcription errors. The slow yet persistent accumulation of DNA damage in the background of increasing cellular 8-oxoG is associated with normal aging as well as neurological disorders such as Alzheimer's disease and Parkinson's disease. This review explores the current understanding of how 8-oxoG plays a role in brain function and genomic instability, highlighting new methods being used to advance pathological hallmarks that differentiate normal healthy aging and neurodegenerative disease.

Keywords: 8-oxo-2’-deoxoguanosine; aging; epigenetics; mutation signature; neurodegeneration; oxidative damage; single-cell ‘omics; somatic mutation.

FIGURE 1

The beneficial and detrimental sides of 8-oxoG on the genome and gene expression. (A). Oxidative stress molecules can change nucleotides by adding oxygen to the molecular structure, such as turning guanine into 8-oxoguanine (8-oxoG). This can occur to free nucleotides, which later intercalate into DNA, or via direct attack of guanosine in DNA. 8-oxoG can easily pair with cytosine, which is indistinguishable from a normal guanine-cytosine pairing. 8-oxo prefers to pair with cytosine, but sterically can form a Hoogsteen base pair with adenine. An 8-oxoG-adenine mispairing is unstable, with adenine preferring to pair with thymine. (B). The presence of 8-oxoG can indirectly promote the demethylation of nearby methylated cytosine (5-mC), via OGG1. OGG1 is the glycosylase in charge of removing 8-oxoG from DNA, but can also partner with TET1, and enhance its enzymatic activity as promoting 5-mC demethylation into forms such as 5-hmC which can promote gene expression changes via epigenetic mechanisms. (C). In a well-regulated system, the presence of 8-oxoG in the genome is efficiently removed from the DNA via the Base Excision Repair pathway. Once 8-oxoG is excised from the DNA, molecules such as APE1 continue to fix the resulting AP site by nicking the phosphate backbone and initiating polymerase-based repair. Thus, the genome is protected from permanent somatic mutational damage. 8-oxoG in such a robust repair environment is limited to having a temporary presence in DNA, which can potentially promote brief changes in OGG1- > TET methylation changes and activation in gene promoters. This can promote the gene expression changes found to be essential in many neurodevelopmental events, such as gross brain development, neuron maturation, circuit development, and synaptic function. It should be noted that in addition to BER, the NER proteins, can play a role in clearing 8-oxoG using glycosylase enzymes like OGG1 (Kumar et al., 2022). (D). In a cellular environment with excess oxidative stress, increased 8-oxoG can overwhelm repair machinery. The longer perdurance of 8-oxoG can lead to a greater chance at mispairing with adenine at a rate of ∼30%. This 8-oxoG-adenine lesion can result in the establishment of a permanent somatic mutation in the DNA. This genotoxic mutational damage can accumulate over time and lead to detrimental changes in the brain. An excess of 8-oxoG can potentially also affect OGG1 and TET-mediated cytosine methylation/demethylation balance, which results in dysregulated gene expression. Dysregulated gene expression in concert with accumulating somatic mutations to the genome is associated with age-related changes to the brain, including neuronal function and neurodegenerative disease.