Oxidative DNA base damage induced by singlet oxygen and photosensitization: recognition by repair endonucleases and mutagenicity

doi:10.1016/S0921-8777(00)00049-5

Mutation Research/DNA Repair

Volume 461, Issue 2, 16 October 2000, Pages 145-156

Mutation Research/DN...

https://doi.org/10.1016/S0921-8777(00)00049-5 Get rights and content

Abstract

We have analyzed the recognition by various repair endonucleases of DNA base modifications induced by three oxidants, viz. [4-(tert-butyldioxycarbonyl)benzyl]triethylammonium chloride (BCBT), a photochemical source of tert-butoxyl radicals, disodium salt of 1,4-etheno-2,3-benzodioxin-1,4-dipropanoic acid (NDPO₂), a chemical source of singlet oxygen, and riboflavin, a type-I photosensitizer. The base modifications induced by BCBT, which were previously shown to be mostly 7,8-dihydro-8-oxoguanine (8-oxoGua) residues, were recognized by Fpg and Ogg1 proteins, but not by endonuclease IIII, Ntg1 and Ntg2 proteins. In the case of singlet oxygen induced damage, 8-oxoGua accounted for only 35% of the base modifications recognized by Fpg protein. The remaining Fpg-sensitive modifications were not recognized by Ogg1 protein and relatively poor by endonuclease III, but they were relatively good substrates of Ntg1 and Ntg2. In the case of the damage induced by photoexcited riboflavin, the fraction of Fpg-sensitive base modifications identified as 8-oxoGua was only 23%. In contrast to the damage induced by singlet oxygen, the remaining lesions were not only recognized by Ntg1 and Ntg2 proteins and (relatively poor) by endonuclease III, but also by Ogg1 protein. The analysis of the mutations observed after transfection of modified plasmid pSV2gpt into Escherichia coli revealed that all agents induced near exclusively GC→TA and GC→CG transversions, the numbers of which were correlated with the numbers of 8-oxoGua residues and Ntg-sensitive modifications, respectively. In conclusion, both singlet oxygen and the type-I photosensitizer riboflavin induce predominantly oxidative guanine modifications other than 8-oxoGua, which most probably give rise to GC→CG transversions and in which eukaryotic cells are substrates of Ntg1 and Ntg2 proteins.

Introduction

Oxidative guanine modifications are the prevailing type of damage generated by apparently all types of reactive oxygen species (ROS), since this base has the lowest one-electron oxidation potential [1]. A highly selective generation of guanine modifications has been well-established for photosensitizers which modify DNA either via singlet oxygen (type-II photoreaction) or one-electron oxidation (type-I photoreaction) [2], [3], [4], [5]. As expected, the selectivity is less pronounced for the most reactive hydroxyl radicals, which generate relatively high amounts of single-strand breaks (SSB), sites of base loss (AP sites) and modifications of other bases as well [6], [7], [8], [9].

Among the guanine modifications, 7,8-dihydro-8-oxoguanine (8-oxoGua) is best-known, and its generation in cellular and cell-free DNA was demonstrated for virtually all types of ROS [10], [11], [12], [13]. The lesion has a distinct mutagenic potential, giving rise to GC→TA transversion [14], [15], [16]. Other guanine modifications that have been identified after reaction of DNA or isolated nucleotides with many oxidants include the imidazol-ring opened formamidopyrimidine FapyGua, the 2,2,4-triaminooxazolone Z and its precursor, the imidazolone Iz, and 4-hydroxy-8-oxo-guanine [8], [17] (Fig. 1). Until now, there is only little knowledge about the relative yields of the various guanine modifications generated by ROS. Analytical problems arise not only from the limited sensitivity of the detection methods for some of the modifications, but also from an artifactual oxidation during the sample preparation [18], [19] and from the fact that the secondary oxidation of 8-oxoGua (and possibly other oxidative guanine modifications) already becomes prominent at those levels of damage that are required for the quantification of most other types of lesions [20].

To prevent the deleterious consequences of oxidative DNA damage for the integrity of the genome, both prokaryotic and eukaryotic cells have developed specific repair mechanisms [21], [22], [23], [24]. In bacteria, the removal of oxidative guanine and adenine modifications is initiated by Fpg protein, an endonuclease which has been shown to recognize 8-oxoGua and FapyGua, besides AP sites and several other lesions (Table 1) [25], [26], [27]. Complementary, oxidative pyrimidine modifications are substrates of endonuclease III and endonuclease VIII [28], [29], [30], [31], [32]. In eukaryotic cells, 8-oxoGua and FapyGua are recognized by the Ogg1 protein, which share no sequence homology with the bacterial Fpg protein [33], [34]. Functional and also structural homologues of endonuclease III in eukaryotes are Ntg1 and Ntg2 proteins in yeast [35], [36] and Nth1 protein in mammalian cells [37], [38], [39]. Ntg1 localizes primarily to the mitochondria [35], [40]. The spectrum of substrate modifications of these eukaryotic enzymes seems to overlap largely with that of endonuclease III (Table 1). A major difference is that the purine-derived formamidopyrimidines were found to be the good substrates of Ntg1 and Ntg2 proteins, but not of endonuclease III [35], [41], [42], [43].

In the study described here, we compared the recognition by the above-mentioned enzymes of the base modifications induced by three oxidants, viz. [4-(tert-butyldioxycarbonyl)benzyl]triethylammonium chloride (BCBT), a photochemical source of tert-butoxyl radicals [44], disodium salt of 1,4-etheno-2,3-benzodioxin-1,4-dipropanoic acid (NDPO₂), which generates singlet oxygen by thermal decomposition [45], and photoexcited riboflavin, which reacts with DNA by one-electron oxidation [46]. The results not only revealed new distinct differences between the recognition spectra of the prokaryotic and eukaryotic enzymes, but also indicate that the spectrum of guanine modifications induced by the oxidants differs considerable.

Section snippets

Materials

DNA from bacteriophage PM2 (PM2 DNA) was prepared according to the method of Salditt et al. [47]. More than 97% was in the supercoiled form, as determined by the method described below. Formamidopyrimidine-DNA glycosylase (Fpg protein) from Escherichia coli was purified as described previously [25]. Endonuclease III was purified from the overproducing E. coli strain BH410 (fpg-1) [48] harboring the pNTH10 plasmid. Ogg1 protein from Saccharomyces cerevisiae was purified from E. coli BH410 (fpg-1

Recognition of AP sites

Sites of base loss (AP sites) are common substrates of all repair endonucleases and therefore are suitable reference modifications for comparisons. We used supercoiled bacteriophage PM2 partially DNA depurinated by exposure to pH 4.5 for 6 min at 70°C (AP-DNA) as a model substrate to quantify the recognition of AP sites by the various bacterial and eucaryotic repair endonucleases used in this study (Table 1) by means of a relaxation assay.

The results (Fig. 2, upper panel) indicate that

Discussion

The results presented here indicate that at least three types of oxidative guanine modifications are generated in DNA under conditions in which secondary damage of performed modifications is unlikely to play a role (induction of less than one modification per 10⁴ bp). The modifications can be distinguished by their recognition by repair endonucleases. The first modification, 8-oxoGua, is recognized by Fpg protein and its eukaryotic functional analogue Ogg1, but not by Ntg1 and Ntg2 proteins, in

Acknowledgements

This study was supported by the Deutsche Forschungsgemeinschaft (SFB 519) and by the Commissariat à l’Energie Atomique (CEA).

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Oxidative DNA base damage induced by singlet oxygen and photosensitization: recognition by repair endonucleases and mutagenicity

Abstract

Introduction

Section snippets

Materials

Recognition of AP sites

Discussion

Acknowledgements

Methods Enzymol.

J. Biol. Chem.

Free Rad. Biol. Med.

Arch. Biochem. Biophys.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Virology

Mutation Res.

Methods Enzymol.

Mutation Res.

Methods Enzymol.

Mutation Res.

How easily oxidizable is DNA? One-electron reduction potebtials of adenosine and guanosine radicals in aqueous solution

J. Am. Chem. Soc.

Comparative study of oxidation of nucleic acid components by hydroxyl radicals, singlet oxygen and superoxide anion radicals

Photochem. Photobiol.

Alteration of guanine residues during proflavine mediated photosensitization of DNA

Photochem. Photobiol.

Characterization of singlet-oxygen induced guanine residue damage after photochemical treatment of free nucleosides and DNA

Biochim. Biochphys. Acta

Modification of DNA bases by photosensitized one-electron oxidation

Int. J. Radiat. Biol.

DNA damage profiles induced by oxidizing agents

Rev. Physiol. Biochem. Pharmacol.

Oxidative damage to DNA: formation, measurement, and biological significance

Rev. Physiol. Biochem. Pharmacol.

Oxyradicals and DNA damage

Carcinogenesis

Hydroxyl free radical adduct of deoxyguanosine: sensitive detection and mechanisms of formation

Free Rad. Res. Commun.

Methylen blue plus light mediates 8-hydroxy-2′deoxyguanosine formation in DNA preferentially over strand breakage

Nucleic Acids Res.

Substrate specificity of the Escherichia coli Fpg protein (formamidopyrimidine-DNA glycosylase): excision of purine lesions in DNA produced by ionizing radiation or photosensitization

Biochemistry

Photolysis of N-hydroxypyridine-thiones, a new source of hydroxyl radicals for the direct damage of cell-free and cellular DNA

Nucleic Acids Res.

Mechanistic studies of ionizing radiation and oxidaive mutagenesis: genetic efects of a single 8-hydroxyguanine (7-hydro-8-oxoguanine) residue inserted at a unique site in a viral genome

Biochemistry

Single-stranded shuttle phage for mutagenesis studes in mammalian cells: 8-oxoguanine in DNA induces targeted GC→TA transversions in simian kidney cells

Proc. Natl. Acad. Sci. U.S.A.

Product analysis of GG-specific photooxidation via electron transfer: 2-aminoimidazolone as a major guanine oxidation product

J. Am. Chem. Soc.

Artifacts associated with the measurement of oxidized DNA bases

Environ. Health Perspect.

DNA oxidation matters: the HPLC-electrochemical detection assay of 8-oxo-deoxyguanosine and 8-oxo-guanine

Proc. Natl. Acad. Sci. U.S.A.

A repair system for 8-oxo-7 8-dihydrodeoxyguanine

Biochemistry