MINIREVIEW:
Formation, Prevention, and Repair of DNA Damage by Iron/Hydrogen Peroxide*

Ernst S. Henle and Stuart Linn Dagger

From the Division of Biochemistry and Molecular Biology, University of California, Berkeley, California 94720-3202

INTRODUCTION
The Fenton Reaction
The Generation of Reactive Species by H2O2 and Obardot 2 in the Absence of Metals
DNA Damage by Fenton Oxidants
Elimination of Fenton Oxidants
Repair of DNA Damage from Reactive Oxygen Species
Future Perspectives
FOOTNOTES
REFERENCES


INTRODUCTION

Although oxygen is a powerful oxidant, the triplet ground state of dioxygen constitutes a kinetic barrier for oxidation of biological molecules, which are mostly singlet state (1). However, the unpaired orbitals of dioxygen can sequentially accommodate single electrons to yield Obardot 2, H2O2, the very reactive ·OH, and water (Fig. 1, Reaction 1). The oxidative potential of atmospheric oxygen is maintained by the non-alignment of electron spins, and aerobic life is based upon harnessing energy via the catalytic spin pairing of triplet oxygen by the electron transport chain (2). The latter process occasionally errs, however, giving rise to Obardot 2 and other reactive oxygen species (3) that cause cellular and genetic damage (4-7). Moreover, catabolic oxidases such as xanthine oxidase, anabolic processes such as nucleoside reduction, and defense processes such as phagocytosis also produce oxygen radicals.


Fig. 1. Reactions cited in the text. Reaction 1 shows the univalent reductions of aqueous oxygen to water at pH 7. Potentials are for 1 M aqueous oxygen at pH 7 (1). The negative potential for the O2/Obardot 2 couple and the positive potential for the Obardot 2/H2O2 couple indicate that Obardot 2 is redox ambivalent and disproportionation (Reaction 2) is favorable. The large potential for ·OH reduction and its radical nature allows it to oxidize organic molecules almost indiscriminately.
[View Larger Version of this Image (26K GIF file)]

Although DNA is a biologically important target for reactive oxygen species, free Obardot 2 is relatively unreactive with DNA (8). However, Obardot 2 dismutates (via spontaneous or enzyme-catalyzed reactions) to produce H2O2 (Fig. 1, Reaction 2). Obardot 2 can also reduce and liberate Fe3+ from ferritin (9) (Fig. 1, Reaction 3) or liberate Fe2+ from iron-sulfur clusters (10) (Fig. 1, Reaction 4); subsequently very reactive oxygen species can form via the Fenton reaction (Fig. 1, Reaction 5). Thus, the cytotoxic effects of Obardot 2 (as well as of iron and H2O2) have been linked to DNA damage by way of the Fenton reaction (4, 11, 12) (Fig. 2).


Fig. 2. Cellular reactions leading to oxidative damage of DNA via the Fenton reaction. H2O2 is formed by endogenous metabolism or is available exogenously. Superoxide is produced as a by-product of O2 reduction in the electron transport chain. Superoxide dismutation and release of protein-bound iron by superoxide form H2O2 and Fe2+, respectively, which in turn can react to form ·OH-type oxidant(s). These oxidant(s) may cause DNA damage. Fe3+ produced by the Fenton reaction is thought to be reduced by available NADH, thus replenishing Fe2+. H2O2 can be depleted by catalase or by peroxidases, which utilize reduced glutathione, other thiols, cytochrome c, ascorbate, etc.
[View Larger Version of this Image (22K GIF file)]


The Fenton Reaction

Most transition metals have more than one oxidation state besides the ground state, and their valence electrons may be unpaired (13), allowing one-electron redox reactions. As such, transition metals can react with H2O2 to produce ·OH and related oxidants. In 1894, Fenton (14) described the oxidation of tartaric acid by Fe2+ and H2O2, and the stoichiometry of Fe2+ and H2O2 consumption was subsequently shown to be consistent with that of Reaction 5 (15). This review will focus on the iron-mediated Fenton reactions; those with other transition state metals are discussed elsewhere (1, 16).

Iron has five oxidation states in aqueous solution, Fe(II)-Fe(VI). Fe(II) and Fe(III) are the most common, and their reactions with oxygen and its reduced forms are well documented (1, 17). More recently, however, reactions with Fe(IV) have been implicated in biological processes and proposed to be involved in damage to cellular components (1, 16, 18-20). For example, in the case of Fe2+ chelates with ADP, ortho-phosphate, or EDTA, the oxidant formed from H2O2 behaves differently than expected for ·OH, and it has been proposed to be the ferryl radical (Fig. 1, Reaction 6). Alternately, a caged or bound ·OH, often denoted as [Fe-H2O2]2+ or [FeOOH]+, might account for the noted differences (18). This distinction might be arbitrary, however, as this bound ·OH might be an intermediate of Reactions 5 or 6 (16) and the ferryl radical itself could give rise to ·OH via Reaction 7 (1, 18).

Both Fe2+ and Fe3+ may have open orbitals that can share outer sphere electrons with ligands for iron coordination. The chemical properties of such complexes are determined by the ligands (1, 16, 18). For example, Luo et al. (21) found that in the presence of the very complex ligand, DNA, there are three kinetically distinguishable oxidants formed that cause DNA strand breakage. One of these is easily scavengable, consistent with it being a freely diffusible ·OH, whereas the other two vary in their scavenging susceptibilities, and one or both of these might be an iron(IV) species.

Therefore, after 100 years, the basic nature of the Fenton oxidant(s) is still undefined so that "·OH" may be regarded as a symbol representing the stoichiometric equivalent of the univalent oxidation agents produced by the Fenton reaction. However, it is clear that whatever the oxidant, hydroxylations and hydrogen abstractions are the two most common modifications of organic substrates by Fenton oxidants (17, 22, 23).

It is noteworthy that H2O2 can also react with Fe3+ to form Obardot 2, presumably via Reaction 8 (24), and that if H2O2 is in excess, the Fe2+ which is thus formed can subsequently generate reactive oxygen species via the Fenton reaction.


The Generation of Reactive Species by H2O2 and Obardot 2 in the Absence of Metals

H2O2 and Obardot 2 may participate in the production of singlet oxygen and peroxynitrite. The generation of these species may be concurrent with reactions involving iron, and under some circumstances they might be important contributors to H2O2 toxicity (25, 26).

Singlet dioxygen is not spin-restricted from oxidizing organic compounds as is triplet state oxygen (1) and was once proposed to be the product of dioxygen-producing reactions involving either H2O2 or Obardot 2 (27). However, it now appears that singlet oxygen is not generated via Fenton/Haber-Weiss chemistry. Instead, for example, OCl- produced by the reaction of Cl- with H2O2 (Fig. 1, Reaction 9) might react with H2O2 to generate singlet oxygen (Fig. 1, Reaction 10). Reaction 9 is facilitated by chloroperoxidases, which generate singlet oxygen from H2O2 and chloride in vitro (28), and singlet oxygen is produced in neutrophils, which contain abundant H2O2 and chloroperoxidases (29).1

Obardot 2 reacts rapidly with nitric oxide (Fig. 1, Reaction 11) to form peroxynitrite anion (26) (Reaction 11), the protonated form of which, peroxynitrous acid (pKa = 6.7), reacts well with biological molecules. Alternatively, ONOO- might form singlet oxygen from H2O2 (30). Consequently, NO· production by nitric oxide synthase may render cells vulnerable to superoxide-mediated damage (31).


DNA Damage by Fenton Oxidants

A substantial portion of H2O2 lethality involves DNA damage by oxidants generated from iron-mediated Fenton reactions (4, 12). It would appear that NADH can drive the process by replenishing Fe2+ from Fe3+ in bacteria and in vitro (4). Moreover, NADH enhances iron-DNA association (32).

A large portion of H2O2-dependent DNA damage appears not to be due to diffusible hydroxyl radicals (4, 21, 33). Instead, DNA-damaging Fenton oxidants are produced on Fe2+ atoms associated with DNA, and it would appear that the location of iron binding may determine the substrate and nature of attack. There appear to be at least two distinguishable classes of iron-mediated Fenton oxidants of DNA (4, 21). Type I oxidants are moderately sensitive to H2O2 and ethanol and appear to cleave DNA preferentially within the sequences RTGR, TATTY, and CTTR (the bold, underscored nucleotides are the sites of cleavage); Type II oxidants, on the other hand, make preferential cleavages in the sequence NGGG.2 The distinguishing characteristics of these radicals may be predominantly due to localization of the iron that gives rise to them. However, it may be that the sites of nicking are not necessarily the iron-binding sites. The NGGG sites in particular may be sinks for radical electrons, which are formed elsewhere on the helix and travel through the base stack (34). Whether there are differences in the spectrum of base damages by the two types of oxidants has not been reported.

Damage by Fenton oxidants may occur at the DNA bases or sugars. Sugar damage is initiated by hydrogen abstraction from one of the deoxyribose carbons, and the predominant consequence is eventual strand breakage and base release (35, 36). In approximately half of these alterations, a 5'-phosphate end group is located 3' to the cleavage, a 3'-phosphoglycolate is located 5' to the cleavage, and a base propenal is released, which subsequently decomposes to the free base and malondialdehyde (37, 38). The majority of other sugar damages yield 5'- and 3'-phosphomonoesters flanking a one-nucleoside gap. Some sugar alterations, such as the gamma -lactone, do not give this product immediately but do so after adequate time or treatment (35).

Another alteration at the sugar moiety is a beta  to alpha  inversion at the 1'-carbon, which disrupts the B-DNA structure (39). Simultaneous alteration of a sugar and base moiety of a DNA nucleoside to yield 5'-8-cyclodeoxyribopurines has been reported after ionizing radiation (40), and 5'-8-cyclodeoxyguanosine was observed as a product of dGMP subjected to Fe2+ and H2O2, although it has not been shown to occur for H2O2-mediated damage of DNA (22).

Radical attack on the bases results primarily in OH addition to the electron-rich double bonds, particularly the purine N-7-C-8 bond and the pyrimidine 5,6 bond (22, 23).3 Hydrogen abstraction from thymine-methyl groups also occurs (35).3 In general, radical attack on the base moieties of DNA does not give rise to altered sugars or strand breaks except when base modifications labilize the N-glycosyl bond, allowing the formation of baseless sites that are subject to beta -elimination (41). Attack at the DNA bases leads to as many as 50 base alterations (22, 23, 42-44).3 The spectrum of damages due to iron/H2O2 is quite similar to (but is not congruent with) that caused by ionizing radiation (22, 23).3

One source of the difference between products formed by Fenton oxidants versus ionizing radiation could be the participation of iron ions directly in product formation. DNA-bound iron may interact with nascent DNA radicals and thereby qualitatively and quantitatively alter the products (45). In the absence of O2, Fe3+ can react with reducing DNA radicals (Fig. 1, Reaction 12). In the presence of O2, DNA peroxyl radicals are formed, which can react with Fe2+ (Fig. 1, Reactions 13 and 14). These reactions affect the product spectrum and thereby obfuscate identification of the initial oxidants through product analyses.

Among the oxidized purines, formamidopyrimidines and 7,8-dihydro-8-oxoguanine (8-oxo-Gua)4 have received widespread study, whereas among the pyrimidines, thymine glycol and its spontaneous hydrolysis products have been actively studied, most likely because of the ubiquitous presence of enzymes for the excision of all of these products (see below). 8-oxo-Gua is also the object of much study because of its highly mutagenic nature (it base pairs relatively well with adenine) (46) and the relative ease of its isolation and quantitation.

Another type of DNA damage mediated by iron in vivo is DNA-protein cross-links, e.g. thymine-tyrosine (47). DNA interstrand cross-links have not been shown to be formed by oxygen radicals.


Elimination of Fenton Oxidants

The fidelity of the metabolic redox reactions (2) and the sequestering of iron in ferritin and transferrin (9, 48) generally minimize the burden from reactive oxygen species. Moreover, compartmentalization of free iron and superoxide and the impediment for iron binding to DNA by histones (49) diminish the occurrence of Fenton reactions on DNA.

Active oxygen species produced by iron/H2O2 are also removed by superoxide dismutases (SODs) (Reaction 1), catalases (Fig. 1, Reaction 15), and peroxidases that catalyze the reduction of H2O2 by organic reductants (RH) such as glutathione, ascorbate, and cytochrome c (Fig. 1, Reaction 16). The major source of protection would appear to be SOD. Mammalian cells produce a mitochondrial Mn-SOD, a cytoplasmic Cu,Zn-SOD that is also found in peroxysomes (50), and an extracellular Cu,Zn-SOD (51). Fe-SOD is additionally found in some bacteria and in chloroplasts (52). Since superoxide dismutation forms H2O2, the detoxifying effect of SOD is most likely a result of preventing the accumulation of free Fe2+ (Reactions 2 and 3) and peroxynitrite production (Reaction 11).

Catalase does not appear to be nearly so important as SOD, judging from the weak phenotypes of cells that lack it (4) and persons with acatalasemia (53). In mammalian cells catalase is largely contained in peroxysomes (54) and to a lesser extent it is secreted (55). Escherichia coli contains two catalases, one regulated by stationary phase and the other by H2O2 exposure (56).

In eukaryotes, glutathione peroxidases are found in the mitochondria, cytoplasm, and peroxysomes (50). These enzymes, especially the selenium glutathione peroxidase, are more effective in removing H2O2 than catalase (52). Peroxidases are less specific than catalase and can also reduce organic hydroperoxides that can react in Fenton-like reactions. Oxidized glutathione is reduced by NADPH-dependent glutathione reductase, an auxiliary enzyme for this antioxidant function.

The relative levels of SOD, catalase, and glutathione peroxidase are important. For instance, an increase in SOD would deplete the cell of superoxide but would increase H2O2 production, which might be deleterious unless sufficient catalase and/or glutathione peroxidase were available. Likewise, excess glutathione peroxidase could unnecessarily deplete glutathione and/or NADPH reserves even though sufficient catalase was present (52, 57).

Eukaryotes also contain a thiol-specific antioxidant enzyme that acts as a thiol-dependent peroxidase, at least at low H2O2 concentrations (~50 µM) (58). At high concentrations of H2O2 (~10 mM), thiol-specific antioxidant enzyme is reported to protect DNA against damage by thiol/metal-catalyzed oxidation (59); however, this protection does not appear to be mediated by the peroxidase activity.

The only effective means of detoxification of ·OH is to scavenge it non-enzymatically. Histones and the compact structure of chromatin protect the DNA by this means (60). As yet, an enzymatic apparatus for singlet oxygen removal has not been detected; rather the cell appears to employ scavengers such as carotenoids (61).

Raising NADH levels exacerbates H2O2 toxicity in E. coli (4), and NADH increases iron/H2O2-mediated DNA damage in vitro (22, 23). However, NADPH is at least an order of magnitude slower in reducing Fe3+ and competes very effectively with NADH for iron binding (32). It may therefore be important that in E. coli an Obardot 2 challenge induces glucose-6-phosphate dehydrogenase and hence raises NADPH levels (62) and that a H2O2 challenge increases the ratio of NADPH to NADH.5 Moreover, in mammalian cells DNA strand breaks result in the depletion of nuclear NAD+ (and NADH) by forming poly(ADP)-ribose (63). Finally, E. coli aconitase is inactivated by superoxide (64), thus shutting down the Krebs cycle and NADH production.


Repair of DNA Damage from Reactive Oxygen Species

Direct Restitution

Direct enzymatic reversion of any oxidative DNA damage product has not been described. However, under some conditions, carbon-centered radicals formed on the DNA backbone by ·OH attack may be restituted to undamaged DNA by hydrogen donation from a sulfhydryl (65). O2, H2O2, and iron may interfere in this "chemical restitution," and sulfhydryls may in fact exacerbate DNA damage by iron/H2O2 (66).

Once DNA nucleoside damage is manifested, enzymatic mechanisms are necessary to correct the alteration. The damage must be recognized, removed, and replaced with normal nucleotides, and DNA ligase must seal all strand breaks (67).

Base Excision Repair

Base excision repair is manifested through a DNA glycosylase, which recognizes the damaged base and cleaves its glycosylic bond (68, 69). An enzyme recognizing hydroxymethyluracil is present in eukaryotes (70) but apparently not in bacteria (71). Its role would appear to be to avoid mutations due to the formation of hydroxymethyluracil upon oxidation of 5-methylcytosine in DNA. Most organisms appear to contain formamidopyrimidine (FAPy) glycosylases (Fpg protein) and several pyrimidine hydrate DNA glycosylases (e.g. E. coli endonucleases III and VIII). The former recognizes formamidopyrimidines and 8-oxopurines. The latter recognizes thymine glycols, pyrimidine hydrates, and their degradation products. Saccharomyces cerevisiae is exceptional in having an enzyme that recognizes both pyrimidine hydrates and formamidopyrimidines but not 8-oxo-Gua (72). These enzymes also catalyze a beta -lyase activity that cleaves a 3'-phosphodiester of a baseless sugar (AP site), leaving a nick with an unsaturated sugar at the 3' terminus and a 5'-phosphomonoester group (Fig. 1, Reaction 17). The function, if any, of the beta -lyase activities is unknown.

In addition, DNA deoxyribosephosphodiesterase (drPase) activities exist that utilize hydrolytic mechanisms for removing 5' or 3' sugar residues or sugar fragments such as glycolyate residues. Moreover, ubiquitous class II AP endonucleases initiate sugar removal by hydrolyzing the 5'-phosphodiester bond of an AP site (Fig. 1, Reaction 18). The resulting 5'-terminal deoxyribose phosphate is a substrate for the drPase or beta -lyase activity of the DNA glycosylases. Once the baseless sugars or sugar fragments are removed, the small gap is filled, most likely by DNA polymerase I in bacteria or DNA polymerase beta  in higher eukaryotes and then sealed by DNA ligase.

A mismatch repair DNA glycosylase in E. coli (MutY) (46) and in human cells (73) is an adenine DNA glycosylase that removes adenine when it is paired to 8-oxo-Gua. After the adenine is replaced by cytosine, the 8-oxo-Gua is then excised by the Fpg protein, which does not act on 8-oxo-Gua:A mismatches.

Nucleotide Excision Repair

This process is catalyzed by large enzyme complexes that ultimately result in the excision of an oligonucleotide of roughly 13 nucleotides in procaryotes or 28 nucleotides in eukaryotes (69). Undoubtedly a subset of oxidative damage is removed by this pathway. A unique pathway for repair of 8-oxo-Gua lesions has been reported in human cell extracts in which an 8-oxo-Gua endonuclease recognizes the lesion and makes incisions immediately 3' and 5' to it to form a 1-nucleotide gap (74).

Exonucleases also take part in nucleotide excision repair in the capacity of nick translation, removal of unpaired damaged termini, or in the removal of abnormal 3' termini such as phosphomonoesters or phosphoglycolates (75, 76).

Recombinational Repair

Double strand breaks and DNA-protein cross-links formed by oxygen radicals are repaired either by homologous recombination or by non-homologous end joining. In homologous recombination, double strand breaks are initially processed by degrading the 5'-ends to reveal 3'-OH single strand overhangs. These single strands associate with undamaged homologous DNA, which acts as a scaffold and template for resynthesis of the 5'-degraded ends from the 3'-OH overhangs (77). In mammalian cells, double strand breaks are predominantly repaired by non-homologous end joining (illegitimate recombination), and it seems that this mode of repair is mediated by the V(D)J system, which rejoins blunt double strand breaks (78). Since homologous DNA does not act as a scaffold, nucleotides may be lost and ends from different molecules may be joined resulting in gross chromosomal rearrangements.


Future Perspectives

By being mutagenic, reactive oxygen species have been implicated in cancer and other degenerative diseases. However, p53-dependent apoptosis seems to be mediated by reactive oxygen species (79), so these agents have diametrical effects; they cause undesirable cellular alterations but also prevent undesirable consequences of DNA damage by helping to eliminate damaged cells.

A final consideration is DNA damage to mitochondrial DNA. Clearly mitochondrial DNA is damaged by reactive oxygen species, and pyrimidine hydrate DNA glycosylases (80), AP endonuclease (81), and a recombination (82) exist in mitochondria. Whether repair of the multiple mitochondrial genomes of the cell is sufficient to prevent an accumulation of ineffective mitochondrial genomes and hence an age-related "error-catastrophe" is an active area of interest.


FOOTNOTES

*   This minireview will be reprinted in the 1997 Minireview Compendium, which will be available in December, 1997. This is the second article of five in the "Oxidative Modification of Macromolecules Minireview Series."
Dagger    To whom correspondence should be addressed: Division of Biochemistry and Molecular Biology, Barker Hall, University of California, Berkeley, CA 94720-3202. Tel.: 510-642-7583; Fax: 510-643-5035; E-mail: linn{at}mendel.berkeley.edu.
1   At low pH, HOCl can oxidize Obardot 2 or Fe2+ to form a strong oxidant, presumably ·OH (20).
2   Z. X. Han, M. S. Falk, E. S. Henle, Y. Luo, and S. Linn, unpublished observations.
3   R. Chattopadhyaya, R. Jin, Y. Luo, E. S. Henle, and S. Linn, unpublished observations.
4   The abbreviations used are: 8-oxo-Gua, 7,8-dihydro-8-oxoguanine; SOD, superoxide dismutase; AP, apurinic/apyrimidinic; drPase, DNA deoxyribosephosphodiesterase.
5   Y. Li and S. Linn, unpublished observations.

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