Oxidative DNA Damage And Its Processing

National Institute On Aging

Investigators

Linked publications, trials & patents

Abstract

Oxidative lesions are removed from DNA primarily via the base excision repair (BER) pathway. BER is carried out through four enzymatic steps, but it is now clear that several other proteins modulate BER efficiency through protein-protein interactions and posttranslational modifications. We and others identified several protein interactions for the core BER enzymes. Oxidative DNA damage is implicated in brain aging, neurodegeneration and neurological diseases. Damage can be created by normal cellular metabolism, which accumulates with age, or by acute cellular stress conditions, which create bursts of oxidative damage. Thus, we are exploring mechanisms that stimulate DNA repair pathways since we believe elevated DNA repair capacity may thwart cell death and improve cellular metabolism and could limit age-associated degeneration. Brain cells have particularly high basal levels of metabolic activity and use oxidative damage repair mechanisms to remove oxidative DNA damage from DNA and dNTP pools but nevertheless DNA damage accrues with normal aging. Accumulating DNA damage and loss of robust DNA repair pathways with age contributes to tissue dysfunction, aging, and neurodegeneration. Neil1 is an important DNA glycosylase in the fight against oxidative damage. We recently found that Neil1 mice have reduced neurogenesis and resolution of neuroinflammation following IR damage. Neil1-null mice showed impaired resolution of neuroinflammation two weeks after IR treatment. These results demonstrate that DNA repair plays a vital role in neurogenesis and that unrepaired DNA lesions may perpetuate neuroinflammatory processes. Guanine oxidation is one of the most common adducts created after oxidative DNA damage. Our lab has investigated the formation and repair of 8-oxoguanine (8-oxoG) in both the nuclear and mitochondrial genomes. The BER enzyme responsible for the removal of 8-oxoG is Oxoguanine Glycosylase (OGG1). Moving forward we are investigating protein-protein interactions between OGG1 and other DNA repair proteins as well as posttranslational modification of OGG1 that can modulate its catalytic activity.