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DNA interstrand cross-links induced by the major oxidative adenine lesion 7,8-dihydro-8-oxoadenine

Author

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  • Aaron L. Rozelle

    (The University of Texas at Austin
    The University of Texas at Austin)

  • Young Cheun

    (The University of Texas at Austin)

  • Caroline K. Vilas

    (The University of Texas at Austin
    The University of Texas at Austin)

  • Myong-Chul Koag

    (The University of Texas at Austin)

  • Seongmin Lee

    (The University of Texas at Austin)

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.

Suggested Citation

  • Aaron L. Rozelle & Young Cheun & Caroline K. Vilas & Myong-Chul Koag & Seongmin Lee, 2021. "DNA interstrand cross-links induced by the major oxidative adenine lesion 7,8-dihydro-8-oxoadenine," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-22273-2
    DOI: 10.1038/s41467-021-22273-2
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