8-Oxo-deoxyguanosine: Reduce, reuse, recycle?

Abstract

Despite a variety of antioxidant defenses, cellular production of oxidants such as reactive oxygen species leads to a background level of damage to the cell. Should the balance between oxidants and antioxidants shift in favor of the former, a condition of oxidative stress arises, which leads to widespread modification of molecules such as lipids and proteins. Nucleic acids, and their precursor (deoxy)ribonucleotide pools, are particular targets; >70 damage products have been described whose presence can have important implications for cell function (1). For example, in addition to producing mutation, oxidatively modified DNA can lead to alterations in cell signaling and gene expression, promote microsatellite instability, and accelerate telomere shortening (2). As a result, oxidative stress has been implicated in a wide variety of pathological conditions, including cancer, cardiovascular disease, aging, and neurodegenerative diseases (3). The most widely studied product of DNA oxidation is 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG), along with its nucleobase equivalent 8-oxo-7,8-dihydroguanine (8-oxoGua). Well established methods are available for assessing this biomarker of oxidative stress in nuclear or mitochondrial DNA (4), as well as in extracellular matrices such as urine (5). The prevailing view is that extracellular 8-oxodG is principally a product of Nudix hydrolase and 5′-nucleotidase activities resulting from elimination of 8-oxodGTP from deoxyribonucleotide pools, whereas 8-oxoGua derives from the action of base excision repair enzymes such as human 8-oxoGua DNA glycosylase (hOGG1; Fig. 1). In a recent issue of PNAS, Hah et al. (6) used accelerator mass spectrometry, a technique with exquisite sensitivity, to experimentally examine previously difficult questions concerning the metabolic fate of 8-oxodG, using more realistic levels of substrates than were formerly feasible.