Oxidative damage to DNA preferentially gives rise to 7,8-dihydro-8-oxoguanine (oxoG) and 7,8-dihydro-8-oxoadenine (oxoA). While the biological ramifications of oxoG are thoroughly characterized, the effects of oxoA on cellular processes remain poorly understood. A number of reports indicate Fanconi anemia (FA) proteins protect cells against oxidative damage, and loss of FA proteins renders cells hypersensitive to oxidative stress and cancer transformation. This points to the formation of oxidative stress-induced ICLs but such ICLs have not been identified. We have discovered a new class of DNA interstrand cross-links (ICLs) mediated by oxoA. Under oxidative conditions mimicking oxidative stress, oxoA, but not oxoG, readily forms a covalent bond with an opposite base to produce structurally diverse ICLs. Various oxidants including reactive halogen species, one-electron oxidants, and the myeloperoxidase/H2O2/Cl– system induce oxoA ICLs, suggesting that oxoA-mediated cross-links may arise in vivo. Our mechanistic studies indicate 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. The supF-based mutation assay involving site-specific oxoA-G ICL in bacterial and human cells showed the high mutagenicity of this ICL, especially at the oxoA site of the ICL. Overall, our results reveal the latent alkylating nature of oxoA and provide new insights into oxoA- and oxoA ICL-mediated mutagenesis.

DNA interstrand cross-links induced by C8-modified adenines

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ACS Fall 2022

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