Mini review8,5′-Cyclopurine-2′-deoxynucleosides in DNA: Mechanisms of formation, measurement, repair and biological effects
Introduction
DNA lesions are continuously generated by numerous mechanisms in living cells. The type of DNA damage called “oxidatively induced damage to DNA” in living cells is caused by free radicals, especially by the highly reactive hydroxyl radical (OH), generated by endogenous sources as well as exogenous sources such as ionizing radiation, carcinogenic compounds, redox-cycling drugs, etc. [1]. This type of DNA damage appears to play an important role in mutagenesis, carcinogenesis and aging [2]. Hydroxyl radical reacts with organic compounds near or at diffusion-controlled rates [1], [3]. In the case of reaction with DNA, OH adds to double bonds of heterocyclic bases, and abstracts an H atom from the methyl group of thymine and from each of the C–H bonds of 2′-deoxyribose, generating numerous sugar and base radicals [3], [4], [5], [6]. Further reactions of these radicals create a plethora of modifications in DNA including base and sugar lesions, single and double strand breaks, base-free sites, DNA–protein cross-links and 8,5′-cyclopurine-2′-deoxynucleosides [3], [4], [5], [6]. This paper reviews the formation, measurement, repair and biological effects of 8,5′-cyclopurine-2′-deoxynucleosides that represent a concomitant damage to both the sugar and base moieties of the same purine nucleoside, thus being unique tandem lesions quite different from DNA lesions such as base and sugar lesions.
Section snippets
Intramolecular cyclization
Besides OH-induced reactions leading to DNA base and sugar modifications, one unique reaction is the attack of the C5′-centered sugar radical at the C8 of the purine ring within the same nucleoside in the absence of oxygen. Subsequent oxidation of the thus-formed N7-centered radical leads to intramolecular cyclization with the formation of a covalent bond between the C5′- and C8-positions of the purine nucleoside. This reaction was first discovered to take place in adenosine-5′-monophosphate
Measurement of 8,5′-cyclopurine-2′-deoxynucleosides in DNA by mass spectrometric techniques
For the past two decades, the measurement of 8,5′-cyclopurine-2′-deoxynucleosides in DNA was mainly achieved by using mass spectrometric techniques. A 32P-postlabeling assay for S-cdA was also described, reportedly being capable of detecting 1–5 lesions/diploid mammalian cell [45]. The advantage of the techniques that employ mass spectrometry over others is that mass analysis provides structural evidence for an analyte and that the application of mass spectrometry with isotope-dilution
Cellular repair of 8,5′-cyclopurine-2′-deoxynucleosides
Over two decades ago, it was hypothesized that 8,5′-cyclopurine-2′-deoxynucleosides may not be repaired by a DNA glycosylase-initiated base-excision repair (BER) pathway, but by the nucleotide-excision repair (NER) because of the presence of the covalent bond between the sugar and base moieties of the same nucleoside [19], [21]. The C5′–C8-covalent bond would remain intact, even if the glycosidic bond of a 8,5′-cyclopurine-2′-deoxynucleoside were hydrolyzed by a DNA glycosylase. In addition, R-
8,5′-Cyclopurine-2′-deoxynucleosides in vivo
The induction and identification of R- and S-diastereomers of cdG by ionizing radiation in living cells was first reported in 1987 [21]. In recent years, the presence of oxidatively induced DNA damage represented by 8,5′-cyclopurine-2′-deoxynucleosides was studied in cultured cells, and in animal and human tissues under a variety of conditions as discussed below.
Biological effects of 8,5′-cyclopurine-2′-deoxynucleosides
Unrepaired and accumulated 8,5′-cyclopurine-2′-deoxynucleosides may have deleterious consequences for living cells. Recent studies demonstrated that S-cdA is a strong block to transcription and an absolute block to DNA polymerases including DNA polymerase δ and the bypass polymerase η [55], [56], [88]. There is also evidence that S-cdA reduces transcription by blocking transcription binding factor, reducing gene expression to a great extent [89]. Three decades ago, it was hypothesized that
Conclusions
8,5′-Cyclopurine-2′-deoxynucleosides are a unique class of helix-distorting DNA lesions that represent a concomitant damage to the sugar and base moieties in a purine 2′-deoxynucleoside. Numerous studies showed the presence of these lesions at endogenous levels in vivo and their formation upon oxidative stress at levels comparable to those of other oxidatively induced DNA lesions. Because of their tandem and helix-distorting features, 8,5′-cyclopurine-2′-deoxynucleosides are subject to NER
Conflict of interest statement
The authors declare that there are no conflicts of interest.
References (96)
Oxidative damage to DNA in mammalian chromatin
Mutat. Res.
(1992)- et al.
Reactions of oxyl radicals with DNA
Free Radic. Biol. Med.
(1995) - et al.
Oxidative DNA damage and disease: induction, repair and significance
Mutat. Res.
(2004) - et al.
Cyclysation radicalaire de la desoxy-2′-adenosine en solution aqueous, sous l’effet du rayonnement gamma
Tetrahedron
(1976) - et al.
Substrate conformation in 5′-AMP-utilizing enzymes: 8,5′-cycloadenosine 5′-monophosphate
Biochem. Biophys. Res. Commun.
(1978) - et al.
Stereoselective intramolecular cyclization in irradiated nucleic acids: R- and S-8,5′-cycloadenosine in polyadenylic acid
Biochem. Biophys. Res. Commun.
(1986) - et al.
Chemical and biochemical properties of oligonucleotides that contain (5′S,6S)-cyclo-5,6-dihydro-2′-deoxyuridine and (5′S,6S)-cyclo-5,6-dihydrothymidine, two main radiation-induced degradation products of pyrimidine 2′-deoxyribonucleosides
Tetrahedron
(2000) - et al.
Identification and quantification of 8,5′-cyclo-2′-deoxyadenosine in DNA by liquid chromatography/mass spectrometry
Free Radic. Biol. Med.
(2001) - et al.
A 32P-postlabeling assay for the oxidative DNA lesion 8,5′-cyclo-2′-deoxyadenosine in mammalian tissues: evidence that four type II I-compounds are dinucleotides containing the lesion in the 3′ nucleotide
J. Biol. Chem.
(2001) - et al.
Analysis of RNA hydrolyzates by liquid chromatography–mass spectrometry
Methods Enzymol.
(1990)