DNA Damage Emanating From a Neutral Purine Radical Reveals the Sequence Dependent Convergence of the Direct and Indirect Effects of γ-Radiolysis

Zheng, Liwei; Greenberg, Marc M.

doi:10.1021/jacs.7b10942

Cited by 24 publications

(36 citation statements)

References 44 publications

(97 reference statements)

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“…A 5 min coupling time was used for the previously reported modified phosphoramidite. 6 Deprotection of synthesized oligonucleotides containing 1 was performed with concentrated aqueous ammonia for 16 h at room temperature, followed by concentration under reduced pressure. The oligonucleotides were purified using 20% denaturing PAGE.…”

Section: Methodsmentioning

confidence: 99%

“…Cleavage was induced either by alkali (piperidine) treatment or incubation with the BER enzyme, formamidopyrimidine glycosylase (Fpg), which cleaves DNA at many purine lesions. 6,36 8-Oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodGuo) was believed to be the major product at dG 11 , based upon its lability to Fpg and the ability of β-mercaptoethanol (BME) to prevent piperidine induced cleavage. 37 However, the structure of the modification(s) at T 12 and the final fate of dA• were undetermined.…”

Section: Introductionmentioning

confidence: 99%

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Traceless Tandem Lesion Formation in DNA from a Nitrogen-Centered Purine Radical

Zheng

Greenberg

2018

J. Am. Chem. Soc.

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Nitrogen-centered nucleoside radicals are commonly produced reactive intermediates in DNA exposed to γ-radiolysis and oxidants, but their reactivity is not well understood. Examination of the reactivity of independently generated 2'-deoxyadenosin- N6-yl radical (dA•) reveals that it is an initiator of tandem lesions, an important form of DNA damage that is a hallmark of γ-radiolysis. dA• yields O-dependent tandem lesions by abstracting a hydrogen atom from the C5-methyl group of a 5'-adjacent thymidine to form 5-(2'-deoxyuridinyl)methyl radical (T•). The subsequently formed thymidine peroxyl radical adds to the 5'-adjacent dG, ultimately producing a 5'-OxodGuo-fdU tandem lesion. Importantly, the initial hydrogen abstraction repairs dA• to form dA. Thus, the involvement of dA• in tandem lesion formation is traceless by product analysis. The tandem lesion structure, as well as the proposed mechanism, are supported by LC-MS/MS, isotopic labeling, chemical reactivity experiments, and independent generation of T•. Tandem lesion formation efficiency is dependent on the ease of ionization of the 5'-flanking sequence, and the yields are >27% in the 5'-d(GGGT) flanking sequence. The traceless involvement of dA• in tandem lesion formation may be general for nitrogen-centered radicals in nucleic acids, and presents a new pathway for forming a deleterious form of DNA damage.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Traceless Tandem Lesion Formation in DNA from a Nitrogen-Centered Purine Radical

Zheng

Greenberg

2018

J. Am. Chem. Soc.

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“…The above experiments demonstrate that it plays a comparable role in DNA damage resulting from hole transfer within poly(dA-T) sequences. 33,41…”

Section: Discussionmentioning

confidence: 99%

Independent Generation of Reactive Intermediates Leads to an Alternative Mechanism for Strand Damage Induced by Hole Transfer in Poly(dA–T) Sequences

2018

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Purine radical cations (dA and dG) are the primary hole carriers of DNA hole migration due to their favorable oxidation potential. Much less is known about the reactivity of higher energy pyrimidine radical cations. The thymidine radical cation (T) was produced at a defined position in DNA from a photochemical precursor for the first time. T initiates hole transfer to dGGG triplets in DNA. Hole localization in a dGGG sequence accounts for ∼26% of T formed under aerobic conditions in 9. Reduction to yield thymidine is also quantified. 5-Formyl-2'-deoxyuridine is formed in low yield in DNA when T is independently generated. This is inconsistent with mechanistic proposals concerning product formation from electron transfer in poly(dA-T) sequences, following hole injection by a photoexcited anthraquinone. Additional evidence that is inconsistent with the original mechanism was obtained using hole injection by a photoexcited anthraquinone in DNA. Instead of requiring the intermediacy of T, the strand damage patterns observed in those studies, in which thymidine is oxidized, are reproduced by independent generation of 2'-deoxyadenosin- N6-yl radical (dA). Tandem lesion formation by dA provides the basis for an alternative mechanism for thymidine oxidation ascribed to hole migration in poly(dA-T) sequences. Overall, these experiments indicate that the final products formed following DNA hole transfer in poly(dA-T) sequences do not result from deprotonation or hydration of T, but rather from deprotonation of the more stable dA, to form dA, which produces tandem lesions in which 5'-flanking thymidines are oxidized.

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“…Modified nucleosides received great attention because of their potential to function as anticancer and antiviral therapeutics. [1,2] Nucleosides with modified purine bases bearing reactive groups such as azide, [3,4] alkene, [5,6] alkyne, [6] aldehyde [7] or radical precursors [8][9][10] have been explored for imaging cellular DNA, bioconjugation with DNA-bound proteins, DNA damage repair, and applications in the fluorescent bioanalysis [2,11] of DNA and RNA. The 5' triphosphate or 3' phosphoroamidite of these probes were incorporated into oligonucleotides (ON) by DNA/ RNA polymerases [6,12,13] or solid-phase synthesis.…”

Section: Introductionmentioning

confidence: 99%

Purine Nucleosides with a Reactive (β‐Iodovinyl)sulfone or a (β‐Keto)sulfone Group at the C8 Position and Their Polymerase‐Catalyzed Incorporation into DNA

et al. 2022

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Iodosulfonylation of an ethynyl group attached at C8‐position of 2′‐deoxyadenosine or 2′‐deoxyguanosine A with TsNa or TsNHNH2, as tosyl source, and I2 or KI, as iodide source, provided 8‐(1‐iodo‐2‐tosylvinyl) nucleosides B with (β‐iodovinyl)sulfone group tethered to C8 position of the purine ring. Treatment of B with ammonia followed by acid‐catalyzed hydrolysis of the intermediary β‐sulfonylvinylamines C gave 8‐(β‐keto)sulfones D. The iodovinylsulfone probes B undergo nucleophilic substitution of iodide with thiols or amines, via an addition‐elimination path, to provide vinyl thioethers or vinyl amines, respectively. The 8‐(β‐keto)sulfone probes D react with electrophiles such as alkyl bromides resulting in α‐alkylation. The 5′‐triphosphate of 2′‐deoxyadenosine analog of D was incorporated by a human DNA polymerase into a double‐stranded DNA oligonucleotide possessing a one‐nucleotide gap substrate.

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DNA Damage Emanating From a Neutral Purine Radical Reveals the Sequence Dependent Convergence of the Direct and Indirect Effects of γ-Radiolysis

Cited by 24 publications

References 44 publications

Traceless Tandem Lesion Formation in DNA from a Nitrogen-Centered Purine Radical

Traceless Tandem Lesion Formation in DNA from a Nitrogen-Centered Purine Radical

Independent Generation of Reactive Intermediates Leads to an Alternative Mechanism for Strand Damage Induced by Hole Transfer in Poly(dA–T) Sequences

Purine Nucleosides with a Reactive (β‐Iodovinyl)sulfone or a (β‐Keto)sulfone Group at the C8 Position and Their Polymerase‐Catalyzed Incorporation into DNA

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