Abstract
Oxidative damage to DNA generates 7,8-dihydro-8-oxoguanine (oxoG) and 7,8-dihydro-8-oxoadenine (oxoA) as two major lesions. Despite the comparable prevalence of these lesions, the biological effects of oxoA remain poorly characterized. Here we report the discovery of a class of DNA interstrand cross-links (ICLs) involving oxidized nucleobases. Under oxidative conditions, oxoA, but not oxoG, readily reacts with an opposite base to produce ICLs, highlighting a latent alkylating nature of oxoA. Reactive halogen species, one-electron oxidants, and the myeloperoxidase/H2O2/Cl− system induce oxoA ICLs, suggesting that oxoA-mediated cross-links may arise endogenously. Nucleobase analog studies suggest C2-oxoA is covalently linked to N2-guanine and N3-adenine for the oxoA-G and oxoA-A ICLs, respectively. The oxoA ICLs presumably form via the oxidative activation of oxoA followed by the nucleophilic attack by an opposite base. Our findings provide insights into oxoA-mediated mutagenesis and contribute towards investigations of oxidative stress-induced ICLs and oxoA-based latent alkylating agents.
Highlights
Oxidative damage to DNA generates 7,8-dihydro-8-oxoguanine and 7,8-dihydro-8oxoadenine as two major lesions
Modeling conducted in UCSF Chimera using a crystal structure of a short DNA duplex (PDB entry 1BNA)[34] enabled our determination of DNA sequences that place the C2 of oxoA nearest the exocyclic amino groups of opposing guanine (G), adenine (A), and cytosine (C) residues (Fig. 2a)
It should be noted that this modeling approach that prioritizes proximity was a starting point for our analyses; other factors such as orbital alignment, helical distortion, and bond angles likely play a greater role in influencing the reactivity of this system
Summary
Oxidative damage to DNA generates 7,8-dihydro-8-oxoguanine (oxoG) and 7,8-dihydro-8oxoadenine (oxoA) as two major lesions. Some examples of intrastrand cross-links, which are covalently linked nucleobases on the same strand of DNA, generated by oxidizing species have been reported in the literature. These include cytosine-cytosine cross-links generated by 2-methyl-1,4-naphthoquinone, guaninethymine cross-links formed by carbonate radical anions, and similar guanine-thymine cross-links formed by hydroxyl radicals[15,16,17]. DNA ICLs generated by thymine radicals are the only example of oxidatively induced interstrand cross-linking in the literature to our knowledge[18]. The goal of the present work was to evaluate the capability of 8-oxopurines to form ICLs under oxidative conditions mimicking oxidative stress
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