Oxidative DNA Damage And Its Processing

National Institute On Aging

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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 damage from DNA and dNTP pools and nevertheless DNA damage accrues with normal aging. Accumulating DNA damage and loss of robust DNA repair pathways with age may contribute to neurological dysfunction. In part, neurodegeneration may arise in individuals that lack BER DNA repair because in non-proliferating cells it is essential and disruption of these processes impact mitochondrial fitness which in turn compromises cellular energetics and cell survival.