Elsevier

DNA Repair

Volume 7, Issue 9, 1 September 2008, Pages 1413-1425
DNA Repair

Mini review
8,5′-Cyclopurine-2′-deoxynucleosides in DNA: Mechanisms of formation, measurement, repair and biological effects

https://doi.org/10.1016/j.dnarep.2008.06.005Get rights and content

Abstract

8,5′-Cyclo-2′-deoxyadenosine (cdA) and 8,5′-cyclo-2′-deoxyguanosine (cdG) are among the major lesions formed in DNA by hydroxyl radical attack on 2′-deoxyadenosine and 2′-deoxyguanosine, respectively, followed by intramolecular cyclization between C5′ and C8. Mechanisms of formation of these unique tandem lesions were elucidated. The 8,5′-cyclization causes an unusual puckering of the sugar moiety giving rise to significant distortion in the DNA double helix. Methodologies were developed for the measurement of these lesions in DNA by mass spectrometry coupled either with gas chromatography or high performance liquid chromatography. Both techniques allowed identification and quantification of both R- and S-diastereomers of cdA and cdG in DNA in vitro and in vivo. Because of the 8,5′-covalent bond between the sugar and base moieties in the same nucleoside, cdA and cdG are repaired by nucleotide excision repair rather than by base excision repair. Thus, these lesions may play a role in diseases with defective nucleotide excision repair. Their biological effects include blocking DNA polymerases, inhibition of gene expression, transcriptional mutagenesis among others. Accumulation of cdA and cdG was observed in tissues in vivo in connection to disease and environmental conditions, suggesting an important role for these lesions in disease processes including carcinogenesis and neuronal death.

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 (radical dotOH), 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, radical dotOH 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 radical dotOH-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)

  • P.J. Brooks et al.

    The oxidative DNA lesion 8,5′-(S)-cyclo-2′-deoxyadenosine is repaired by the nucleotide excision repair pathway and blocks gene expression in mammalian cells

    J. Biol. Chem.

    (2000)
  • L. Dudycz et al.

    Susceptibility to various enzymes of the carbon-bridged (R) and (S) diastereoisomers of 8,5′-cycloadenosine and their 5′-phosphates

    FEBS Lett.

    (1979)
  • J.A. Theruvathu et al.

    The oxidatively induced DNA lesions 8,5′-cyclo-2′-deoxyadenosine and 8-hydroxy-2′-deoxyadenosine are strongly resistant to acid-induced hydrolysis of the glycosidic bond

    Mech. Ageing Dev.

    (2007)
  • Z.M. Mu et al.

    Pag, a putative tumor suppressor, interacts with the Myc Box II domain of c-Myc and selectively alters its biological function and target gene expression

    J. Biol. Chem.

    (2002)
  • B.A. Mayes et al.

    Comparative carcinogenicity in Sprague–Dawley rats of the polychlorinated biphenyl mixtures Aroclors 1016, 1242, 1254, and 1260

    Toxicol. Sci.

    (1998)
  • J.A. Mondon et al.

    Immune response of greenback flounder Rhombosolea tapirina after exposure to contaminated marine sediment and diet

    Mar. Environ. Res.

    (2000)
  • J.S. Peterson et al.

    Differential gene expression in anthracene-exposed mummichogs (Fundulus heteroclitus)

    Aquat. Toxicol.

    (2004)
  • K. Sugasawa et al.

    Xeroderma pigmentosum group C protein complex is the initiator of global genome nucleotide excision repair

    Mol. Cell.

    (1998)
  • P.J. Brooks

    DNA repair in neural cells: basic science and clinical implications

    Mutat. Res.

    (2002)
  • P.J. Brooks

    The case for 8,5′-cyclopurine-2′-deoxynucleosides as endogenous DNA lesions that cause neurodegeneration in xeroderma pigmentosum

    Neuroscience

    (2007)
  • P.J. Brooks et al.

    Do all of the neurologic diseases in patients with DNA repair gene mutations result from the accumulation of DNA damage?

    DNA Repair (Amst.)

    (2008)
  • H. de Waard et al.

    Cell type-specific hypersensitivity to oxidative damage in CSB and XPA mice

    DNA Repair (Amst.)

    (2003)
  • G. Kirkali et al.

    Oxidative DNA damage in polymorphonuclear leukocytes of patients with familial Mediterranean fever

    Free Radic. Biol. Med.

    (2008)
  • E. Mansfield et al.

    The familial Mediterranean fever protein, pyrin, associates with microtubules and colocalizes with actin filaments

    Blood

    (2001)
  • I. Kuraoka et al.

    Oxygen free radical damage to DNA. Translesion synthesis by human DNA polymerase η and resistance to exonuclease action at cyclopurine deoxynucleoside residues

    J. Biol. Chem.

    (2001)
  • C. Marietta et al.

    A single 8,5′-cyclo-2′-deoxyadenosine lesion in a TATA box prevents binding of the TATA binding protein and strongly reduces transcription in vivo

    DNA Repair (Amst.)

    (2002)
  • P.W. Doetsch

    Translesion synthesis by RNA polymerases: occurrence and biological implications for transcriptional mutagenesis

    Mutat. Res.

    (2002)
  • A. Matsuda et al.

    Synthesis of carbon-bridged 8,5-cyclo-purine nucleosides: nucleosides and nucleotides-XXIV

    Tetrahedron

    (1978)
  • B. Halliwell et al.

    Free Radicals in Biology and Medicine

    (2007)
  • E.C. Friedberg et al.

    DNA Repair and Mutagenesis

    (2005)
  • C. von Sonntag

    Free-Radical-Induced DNA Damage and Its Repair

    (2006)
  • K. Keck

    Bildung von Cyclonucleotiden bei Betrahlung wässriger Lösungen von Purinnucleotiden

    Z. Naturforsch. B

    (1968)
  • B. Pullman et al.

    Submolecular structure of the nucleic acids

    Nature

    (1961)
  • J.A. Raleigh et al.

    Radiation chemistry of nucleotides: 8,5′-cyclonucleotide formation and phosphate release initiated by hydroxyl radical attack on adenosine monophosphates

    Radiat. Res.

    (1976)
  • T.P. Haromy et al.

    Enzyme-bound conformations of nucleotide substrates. X-ray structure and absolute configuration of 8,5′-cycloadenosine monohydrate

    Biochemistry

    (1980)
  • A.F. Fuciarelli et al.

    An immunochemical probe for 8,5′-cycloadenosine-5′-monophosphate and its deoxy analog in irradiated nucleic acids

    Radiat. Res.

    (1985)
  • J.A. Raleigh et al.

    Distribution of damage in irradiated 5′-AMP: 8,5′-cyclo-AMP, 8-hydroxy-AMP, and adenine release

    Radiat. Res.

    (1985)
  • A.J. Alexander et al.

    Characterization of radiation-induced damage to polyadenylic acid using high-performance liquid chromatography/tandem mass spectrometry

    Anal. Chem.

    (1987)
  • A.F. Fuciarelli et al.

    Intramolecular cyclization in irradiated nucleic acids: correlation between high-performance liquid chromatography and an immunochemical assay for 8,5′-cycloadenosine in irradiated poly(A)

    Radiat. Res.

    (1987)
  • A.F. Fuciarelli et al.

    Interaction of nitroaromatic radiosensitizers with irradiated polyadenylic acid as measured by an indirect immunochemical assay with specificity for the 8,5′-cycloadenosine moiety

    Int. J. Radiat. Biol.

    (1987)
  • M. Dizdaroglu

    Free-radical-induced formation of an 8,5′-cyclo-2′-deoxyguanosine moiety in deoxyribonucleic acid

    Biochem. J.

    (1986)
  • M.L. Dirksen et al.

    Effect of DNA conformation on the hydroxyl radical-induced formation of 8,5′-cyclopurine-2′-deoxyribonucleoside residues in DNA

    Int. J. Radiat. Biol.

    (1988)
  • M. Dizdaroglu et al.

    Ionizing-radiation-induced damage in the DNA of cultured human cells. Identification of 8,5′-cyclo-2′-deoxyguanosine

    Biochem. J.

    (1987)
  • C. Chatgilialoglu et al.

    Model studies of DNA C5′ radicals. Selective generation and reactivity of 2′-deoxyadenosin-5′-yl radical

    J. Am. Chem. Soc.

    (2003)
  • A. Manetto et al.

    Independent generation of C5′-nucleosidyl radicals in thymidine and 2′-deoxyguanosine

    J. Org. Chem.

    (2007)
  • I.H. Goldberg

    Mechanism of neocarzinostatin action: role of DNA microstructure in determination of chemistry of bistranded oxidative damage

    Acc. Chem. Res.

    (1991)
  • A.F. Fuciarelli et al.

    Oxygen dependence of product formation in irradiated adenosine 5′-monophosphate

    Radiat. Res.

    (1988)
  • R. Zander

    The distribution space of physically dissolved oxygen in aqueous solutions of organic substances

    Z. Naturforsch. C

    (1976)
  • Cited by (0)

    View full text