Division of Chemical Biology and Medicinal Chemistry, College of Pharmacy, The University of Texas at Austin, Austin, TX, USA.
McKetta Department of Chemical Engineering, Cockrell School of Engineering, The University of Texas at Austin, Austin, TX, USA.
Nat Commun. 2021 Mar 26;12(1):1897. doi: 10.1038/s41467-021-22273-2.
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/HO/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.
DNA 的氧化损伤会产生 7,8-二氢-8-氧鸟嘌呤（oxoG）和 7,8-二氢-8-氧腺嘌呤（oxoA）这两种主要损伤。尽管这些损伤的发生率相当，但 oxoA 的生物学效应仍知之甚少。在这里，我们报告了一类涉及氧化碱基的 DNA 链间交联（ICLs）的发现。在氧化条件下，oxoA 而不是 oxoG 很容易与相反的碱基反应生成 ICLs，突出了 oxoA 潜在的烷化性质。反应性卤素物种、单电子氧化剂和髓过氧化物酶/HO/Cl 系统诱导 oxoA ICLs，表明 oxoA 介导的交联可能内源性发生。碱基类似物研究表明，C2-oxoA 与 N2-鸟嘌呤和 N3-腺嘌呤分别共价连接形成 oxoA-G 和 oxoA-A ICLs。oxoA ICLs 可能通过 oxoA 的氧化激活形成，随后由相反的碱基进行亲核攻击。我们的发现为 oxoA 介导的突变提供了新的见解，并有助于对氧化应激诱导的 ICLs 和基于 oxoA 的潜在烷化剂的研究。
