Dataset Information

Independent Generation and Time-Resolved Detection of 2'-Deoxyguanosin-N2-yl Radicals.

ABSTRACT: Guanine radicals are important reactive intermediates in DNA damage. Hydroxyl radical (HO^. ) has long been believed to react with 2'-deoxyguanosine (dG) generating 2'-deoxyguanosin-N1-yl radical (dG(N1-H)^. ) via addition to the nucleobase π-system and subsequent dehydration. This basic tenet was challenged by an alternative mechanism, in which the major reaction of HO^. with dG was proposed to involve hydrogen atom abstraction from the N2-amine. The 2'-deoxyguanosin-N2-yl radical (dG(N2-H)^. ) formed was proposed to rapidly tautomerize to dG(N1-H)^. . We report the first independent generation of dG(N2-H)^. in high yield via photolysis of 1. dG(N2-H)^. is directly observed upon nanosecond laser flash photolysis (LFP) of 1. The absorption spectrum of dG(N2-H)^. is corroborated by DFT studies, and anti- and syn-dG(N2-H)^. are resolved for the first time. The LFP experiments showed no evidence for tautomerization of dG(N2-H)^. to dG(N1-H)^. within hundreds of microseconds. This observation suggests that the generation of dG(N1-H)^. via dG(N2-H)^. following hydrogen atom abstraction from dG is unlikely to be a major pathway when HO^. reacts with dG.

SUBMITTER: Zheng L

PROVIDER: S-EPMC7395871 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Independent Generation and Time-Resolved Detection of 2'-Deoxyguanosin-N2-yl Radicals.

Zheng Liwei L Dai Xiaojuan X Su Hongmei H Greenberg Marc M MM

Angewandte Chemie (International ed. in English) 20200602 32

Guanine radicals are important reactive intermediates in DNA damage. Hydroxyl radical (HO. ) has long been believed to react with 2'-deoxyguanosine (dG) generating 2'-deoxyguanosin-N1-yl radical (dG(N1-H). ) via addition to the nucleobase π-system and subsequent dehydration. This basic tenet was challenged by an alternative mechanism, in which the major reaction of HO. with dG was proposed to involve hydrogen atom abstraction from the N2-amine. The 2'-deoxyguanos ...[more]

PMID: 32365264

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Project description:Ubiquitous environmental agents [e.g., polynuclear aromatic hydrocarbons (PAHs) and their nitrated derivatives (NO(2)-PAHs)] that are known to induce mammary cancer in rodents are regarded as potential human risk factors for inducing analogous human cancers. Although 6-nitrochrysene (6-NC) is less abundant than other NO(2)-PAHs in the environment, it is the most potent mammary carcinogen in the rat; its carcinogenic potency is not only higher than that of the carcinogenic PAH, benzo[a]pyrene (B[a]P), but also of the well-known carcinogenic heterocylic aromatic amine, 2-amino-1-methyl-6-phenylimidazo[4,5- b]pyridine (PhIP). Studies in rats and in vitro assays have indicated that 6-NC can be activated by simple nitroreduction leading to the formation of 6-hydroxylaminochrysene (N-OH-6-AC); this metabolite yielded N-(deoxyguanosin-8-yl)-6-aminochrysene (N-[dG-8-yl]-6-AC) and 5-(deoxyguanosin-N(2)-yl)-6-aminochrysene (5-[dG-N(2)-yl]-6-AC. These lesions are likely to cause mutations if they are not removed by cellular defense mechanisms before DNA replication occurs. However, nothing is known about the susceptibility of these adducts to nucleotide excision repair (NER), the major cellular repair system that removes bulky adducts. In order to address this issue, we synthesized the N-(dG-8-yl)-6-AC and 5-(dG- N(2)-yl)-6-AC lesions and site-specifically inserted these lesions into 135-mer DNA duplexes. These constructs were incubated with NER-competent nuclear extracts from human HeLa cells. The efficiency of repair of these lesions was ∼ 8 times less efficient than that in the case of the well-known and excellent substrate of NER, the intrastrand cross-linked cis-diaminodichloroplatinum II adduct in double-stranded DNA (cis-Pt), but similar to N(2)-dG adducts derived from the (+)-bay region diol epoxide of B[a]P [(+)-trans-B[a]P-N(2)-dG]. The results support the hypothesis that the N-(dG-8-yl)-6-AC and 5-(dG-N(2)-yl)-6-AC lesions may be slowly repaired and thus persistent in mammalian tissue which could, in part, account for the potent tumorigenic activity of 6-NC in the rat mammary gland.

Dataset Information

Independent Generation and Time-Resolved Detection of 2'-Deoxyguanosin-N2-yl Radicals.

Publications

Independent Generation and Time-Resolved Detection of 2'-Deoxyguanosin-N2-yl Radicals.

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