- Open Access
Generation, repair and replication of guanine oxidation products
Genes and Environment volume 39, Article number: 21 (2017)
Guanine is the most readily oxidized of the four DNA bases, and guanine oxidation products cause G:C-T:A and G:C-C:G transversions through DNA replication. 8-Oxo-7,8-dihydroguanine (8-oxoG) causes G:C-T:A transversions but not G:C-C:G transversions, and is more readily oxidized than guanine. This review covers four major findings. (i) 2,2,4-Triamino-5(2H)-oxazolone (Oz) is produced from guanine and 8-oxoG under various oxidative conditions. Guanine is incorporated opposite Oz by DNA polymerases, except REV1. (ii) Several enzymes exhibit incision activity towards Oz. (iii) Since the redox potential of GG is lower than that of G, contiguous GG sequences are more readily oxidized by a one-electron oxidant than a single guanine, and OzOz is produced from GG in double-stranded DNA. Unlike most DNA polymerases, DNA polymerase ζ efficiently extends the primer up to full-length across OzOz. (iv) In quadruplex DNA, 3′-guanine is mainly damaged by one-electron oxidation in quadruplex DNA, and this damage depends on the highest occupied molecular orbital (HOMO). The oxidation products in quadruplex DNA are different from those in single-stranded or double-stranded DNA.
Cellular DNA is constantly oxidized by various endogenous and exogenous agents, and the resulting DNA damage may increase the risk of developing cancer and other diseases . Guanine has the lowest redox potential of the four DNA bases  and is therefore the most easily oxidized.
During DNA replication, adenine incorporation opposite a guanine oxidation product induces a G:C-T:A transversion, whereas guanine incorporation opposite a guanine oxidation product causes a G:C-C:G transversion. These mutations (see references in ) are found in many important genes, and in particular at CpG sites in the p53 tumor suppressor gene and in codons 12 and 13 of the K-ras oncogene [4,5,6]. Therefore, it is important to analyze nucleotide incorporation and DNA extension for each guanine oxidation product in order to elucidate the mechanisms underlying the generation of G:C-T:A and G:C-C:G transversions.
8-Oxo-7,8-dihydroguanine (8-oxoG) (Fig. 1) is one of the most common oxidative DNA lesions and is formed under various oxidative conditions. 8-OxoG has been studied extensively, has significant biological impact, and is a ubiquitous marker of oxidatively damaged DNA [1, 7]. Structural analyses have revealed that 8-oxoG adopts either an anti or syn conformation: 8-oxoG in the anti conformation forms Watson-Crick base pairs with cytosine, while the lesion in the syn conformation utilizes the Hoogsteen edge of the lesion to form a base pair with adenine [8,9,10] (Fig. 2). Furthermore, DNA polymerases incorporate adenine in addition to cytosine opposite 8-oxoG [7, 11,12,13,14,15,16,17,18,19], and 8-oxoG induces a G:C-T:A transversion in Escherichia coli (E. coli) [20, 21] and mammalian cells [22,23,24].
Although 8-oxoG causes G:C-T:A transversions, the mechanism underlying the generation of G:C-C:G transversions cannot be explained by 8-oxoG. In addition, 8-oxoG is more readily oxidized than guanine because of its lower oxidation potential [25, 26], and thus various oxidative lesions are produced by the oxidation of 8-oxoG. Therefore, it is necessary to study both 8-oxoG and other oxidized guanine lesions in order to understand the various phenomena caused by guanine oxidation.
Guanine oxidation products causing G:C-C:G transversions form base pairs by hydrogen bonding with guanine
As previously mentioned, G:C-C:G transversion is caused by incorporation of guanine opposite an guanine oxidation product. In this section we first describe the “A-rule”. Adenine is the most common base incorporated opposite an abasic site by DNA polymerases , suggesting that, of the four natural bases, adenine forms the most hydrophobic interactions and exhibits the best spatial compatibility with an abasic site. Adenine incorporation may not necessarily require the formation of hydrogen bonds with various damaged DNA sites in template DNA. In contrast, the preferential insertion of guanine requires hydrogen bond formation , in addition to hydrophobic interactions and spatial compatibility, with the templating base. Thus, in order to reveal the lesions causing G:C-C:G transversions, it is important to investigate guanine oxidation products that form base pairs by hydrogen bonding with guanine.
Potential guanine oxidation products causing G:C-C:G transersions
2,5-Diamino-4H-imidazol-4-one (Iz) is an oxidized product of both guanine and 8-oxoG [28,29,30,31] (Fig. 1), in both single- and double-stranded DNA [32, 33]. We previously proposed that the H-bonding donor and acceptor abilities of Iz are similar to those of cytosine [30, 34] (Fig. 3a), and reported that the calculated stabilization energy of the Iz:G base pair is similar to that of the C:G base pair  (Fig. 3b). Melting temperature measurements revealed that the Iz:G base pair is more stable than Iz:A, Iz:C, and Iz:T . Moreover, previous reports indicated that Iz mainly causes G:C-C:G transversions in vitro and in vivo [34, 36].
Iz is slowly hydrolyzed to 2,2,4-triamino-5(2H)-oxazolone (Oz) (Fig. 1) in neutral aqueous solution, and its half-life is 147 min under physiological conditions . Additionally, 2–6 molecules of Oz are detected per 107 guanine bases in liver DNA , and it was recently shown that the amount of Oz is significantly increased in the presence of 5-methylcytosine . Thus, the biological influence of Oz in DNA replication is likely larger than that of Iz.
Klenow fragment exo− incorporates adenine opposite Oz in vitro , and Oz causes G:C-T:A transversions in E. coli . In contrast, in our in vitro reaction system, Klenow fragment exo− incorporates either adenine or guanine opposite Oz . Moreover, we revealed that DNA polymerases α, β, δ, and ε each incorporate only guanine opposite Oz; DNA polymerases γ, κ, and Sulfolobus solfataricus DNA polymerase IV, in addition to Klenow fragment exo−, each incorporate guanine and adenine; DNA polymerase η incorporates guanine, adenine and cytosine; DNA polymerases ζ and ι each incorporate guanine, adenine, cytosine and thymine; and REV1 incorporates cytosine [12, 40, 41]. These analyses indicate that DNA polymerases, except REV1, incorporate guanine opposite Oz [12, 40, 41]. We predicted that Oz can form a stable base pair with guanine, and that this Oz:G base pair has two hydrogen bonds and is planar (Fig. 3c) [12, 42]. We recently performed thermal denaturation experiments and reported that the Oz:G base pair is more thermodynamically stable than Oz:A, Oz:C, and Oz:T .
In addition, DNA polymerases α, β, γ, δ, ε, η, κ, and ζ each elongate the primer to full length across Oz [12, 40, 41]. Thus, Oz appears to be an oxidized lesion related to the induction of G:C-C:G transversions. In particular, DNA polymerase ζ elongates beyond Oz with almost the same efficiency as beyond G , but not beyond tetrahydrofuran (THF; a chemically stable abasic site analog), 8-oxoG, or O 6-methylguanine [18, 44]. These data indicate that DNA polymerase ζ is an effective error-prone replication polymerase for Oz. Moreover, only REV1 incorporates cytosine opposite Oz, and the frequency of cytosine insertion follows the order Oz > guanidinohydantoin (Gh) > THF > 8-oxoG . Given that REV1 can interact with DNA polymerases [45,46,47,48,49], the collective results to date suggest that REV1 together with DNA polymerase ζ might prevent G:C-C:G transversions . Such systems for preventing mutation are seen in other DNA polymerases [50, 51].
Recently, other groups reported that Gh and spiroiminodihydantoin (Sp), which are oxidation products of 8-oxoG (Fig. 1) [29, 52, 53], induce G:C-T:A and G:C-C:G transversions [12, 21, 41, 54,55,56,57]. Gh can isomerize to iminoallantoin (Ia) (Fig. 1) . The efficiency of guanine incorporation opposite Gh/Ia is higher than that opposite Sp , and guanine insertion opposite Oz is more efficient compared to that opposite Gh/Ia . In addition to guanine incorporation, extension beyond Oz is more efficient than that beyond Gh/Ia or Sp [12, 41, 54]. This phenomenon is believed to depend on the stacking effect and structural distortion [51, 58], in addition to the stability of the base pair : Oz has no sp 3 carbon and is planar, whereas Gh/Ia and Sp are nonplanar due to their sp 3 carbon . Thus, we believe that Oz is a more important cause of G:C-C:G transversions than Gh/Ia or Sp.
Reaction of oligonucleotides containing oz with repair enzymes
Cells utilize a number of mechanisms to prevent mutagenic effects of the above-described types of DNA damage, and have various enzymes that repair DNA damage such as 8-oxoG [7, 60, 61].
E. coli formamidopyrimidine DNA glycosylase and endonucleases III enzymes excise Oz from double-stranded DNA oligomers [39, 62]. In addition, human NTH1 and NEIL1, which are homologues of E. coli endonucleases III and VIII, remove Oz as efficiently as they remove 5-hydroxyuracil, and their reactivity towards Oz is higher than towards 8-oxoG . Since Oz is more sensitive than 8-oxoG to treatment with piperidine, this difference in reactivity depends on the strength of the N-glycosidic bond .
We analyzed the incision activities of other repair enzymes on Oz. Chlorella virus pyrimidine dimer glycosylase, which exhibits incision activity towards cyclobutane pyrimidine dimer, reacts with Oz-containing double-stranded DNA. Its reactivity towards Oz is higher than towards 8-oxoG, indicating that reactivity is dependent on N-glycosidic bond strength, similar to human NEIL1 and NTH1 . However, this repair enzyme exhibits moderate activity towards Oz compared to its activity towards cyclobutane pyrimidine dimer .
Endonuclease IV, an apurinic/apyrimidinic endonuclease, incised Oz with an observed activity one-third to one-fourth of that towards THF , but with greater efficiency than its activity towards Gh. These results suggest that Oz may be more structurally similar to an abasic site than is Gh .
Endonuclease V, which exhibits activity towards hypoxanthine residues, is also active towards Oz. This activity is lower than that towards hypoxanthine at high concentrations of endonuclease V, but endonuclease V recognizes Oz much more efficiently than it does Gh. Endonuclease V can recognize uracil but not thymine, suggesting that the 5′-methyl group is critical for recognition by endonuclease V . As described previously , unlike the closed-ring structure of Oz (Fig. 1), Gh has a moiety protruding from the ring, similar to thymine. Thus, endonuclease V can recognize Oz but not Gh.
Human OGG1 and AP endonuclease 1 cannot excise Oz residues [63, 66], and single-strand-selective monofunctional uracil-DNA glycosylase 1 exhibits no incision activity towards Oz (data not shown). E. coli Mut Y cannot act on Oz:G and Oz:A lesions (data not shown). Oz is a weak substrate for human nucleotide excision repair because the damaged site is less bulky than that of pyrimidine (6–4) pyrimidone photoproducts, making it difficult for XPC-RAD23B to recognize Oz .
The data available to date indicate that human NEIL1 and NTH1 are the most likely repair enzymes for Oz. However, human NEIL1, NTH1, E. coli endonucleases III, and formamidopyrimidine DNA glycosylase can all excise Oz from double-stranded DNA, regardless of the type of base opposite Oz [39, 62, 63]. If the base opposite Oz is adenine, guanine, or thymine before base excision repair, genetic information is altered in subsequent replications. Thus, there may be unknown enzymes which can remove Oz accurately from oligonucleotides in which Oz is paired to a C, just as human OGG1 can remove 8-oxoG. Alternatively, as mentioned earlier , REV1-DNA polymerase ζ may prevent G:C-C:G transversions.
Does OzOz obstruct DNA synthesis by DNA polymerases?
Contiguous guanines (GG), which exist in many important genomic regions such as the K-ras oncogene , are more readily oxidized than a single guanine due to their lower redox potential [68,69,70,71,72]. The oxidation of GG sequences under high oxidation conditions results in a contiguous oxidized guanine lesion. We previously reported that IzIz is produced by the oxidation of GG in single- and double-stranded DNA , suggesting that hydrolysis of these Iz molecules produces two contiguous Oz molecules (OzOz). It is expected that OzOz stalls DNA synthesis more effectively than a single Oz and thus represents more serious DNA damage than a single Oz.
Our analysis showed that DNA polymerase κ did not incorporate any nucleotide opposite OzOz . Klenow fragment exo− preferentially incorporated one adenine opposite the 3′ Oz of OzOz lesions, REV1 incorporated cytosine, and DNA polymerase β incorporated guanine . DNA polymerase α incorporated guanine, adenine and cytosine opposite the 3′ Oz of OzOz lesions, and guanine was incorporated more readily than adenine and cytosine . DNA polymerase ι slightly incorporated guanine, adenine and thymine . Whether a base is incorporated or not, these polymerases cannot elongate the primer up to full-length across OzOz .
In contrast, DNA polymerase η elongated the primer up to full-length across OzOz lesions with modest efficiency compared to across cyclobutane pyrimidine dimer lesions, with the synthesis of most DNA strands stalling at the 3′ or 5′ Oz of OzOz . In contrast, DNA polymerase ζ could efficiently elongate the primer up to full-length across OzOz , suggesting that DNA polymerase ζ is an important enzyme for translesion synthesis past both single and contiguous Oz molecules. In addition, DNA polymerase ζ incorporates all nucleotides opposite both the 3′ and 5′ Oz  and is an error-prone DNA polymerase for OzOz.
Photooxidation in quadruplex DNA
Guanine-rich sequences such as telomeres can fold into quadruplex structures [74,75,76]. In double-stranded DNA, the one-electron oxidation of guanine in contiguous guanine sequences is dependent on the localization of the highest occupied molecular orbital (HOMO) [33, 68, 69]. Unlike double-stranded DNA , the 3′-guanine of d(TGGGGT) is mainly oxidized in quadruplex DNA, and the estimated HOMO is localized on the 3′-guanine  (Fig. 4b). Given our current understanding of double-stranded DNA [33, 68, 69] and quadruplex DNA , the selective one-electron oxidation of guanine occurs at the localized HOMO regardless of the DNA structure.
In particular, the 5′-capping cation (d(TGGGGT)4 + 4 K+) is important for HOMO localization on the 3′-guanine  (Fig. 4), and two quadruplexes may stack at their 5′ ends  (d(TGGGGT)8 + 7 K+ in Fig. 4a) in water because the HOMO of this structure is localized on the 3′-guanine  (Fig. 4b).
On the other hand, the guanine oxidation products depend on the DNA structure. For example, Iz is a major product in single-stranded DNA, whereas 8-oxoG and dehydroguanidinohydantoin (Ghox) are mainly formed in quadruplex DNA . Iz, 8-oxoG, Ghox and Gh are formed in double-stranded DNA, and are also major oxidation products found in single-stranded and quadruplex DNA .
The mechanism of guanine oxidation in single-stranded, double-stranded, and quadruplex DNA may be explained as follows. One-electron oxidation of guanine generates a guanine radical cation (G•+) , followed by two degradation pathways [32, 33] (Fig. 5). In one pathway, G•+ is deprotonated at the N1 position, followed by generation of Iz. In another pathway, G•+ is hydrated and deprotonated, followed by the generation of 8-oxoG, Ghox, and Gh. There is a hydrogen bond between the N1 proton of G•+ and the O6 of guanine in quadruplex DNA (Fig. 6a), and a hydrogen bond is formed between the N1 proton of G•+ and the N3 of cytosine in double-stranded DNA (Fig. 6b). Therefore, deprotonation of G•+ is significantly inhibited in quadruplex DNA and partially inhibited in double-stranded DNA. We estimate the ease of deprotonation to follow the order: single-stranded DNA > double-stranded DNA > quadruplex DNA , and this order explains the differences in oxidation products in each type of DNA structure.
Based on the A-rule, adenine incorporation does not necessarily require hydrogen bonds with the guanine oxidation product, whereas we think that guanine incorporation requires the formation of hydrogen bonds. Therefore, to identify candidates causing G:C-C:G transversions, we searched guanine oxidation products forming base pairs that hydrogen bond with guanine. We used several DNA polymerases to determine that Oz can cause G:C-C:G transversions, in addition to Iz, Gh, and Sp. DNA polymerase ζ is a particularly effective error-prone replication polymerase for Oz. Some repair enzymes exhibit incision activity towards Oz, and thus incision of Oz prior to guanine incorporation inhibits mutations.
In double-stranded DNA, contiguous GG is more readily oxidized by a one-electron oxidant than is a single G. OzOz, an oxidation product of GG, obstructs DNA synthesis by most DNA polymerases, and only DNA polymerase ζ acts on OzOz efficiently.
The 6-mer DNA d(TGGGGT) containing contiguous GGGG is the shortest oligomer among the quadruplex-formative sequences in the presence of ions. The 3′-guanine of contiguous GGGG is mainly oxidized, and this is attributed to the HOMO. In addition, guanine oxidation products formed in quadruplex DNA are different from those in other DNA structures, likely due to the ease of deprotonation of the guanine radical cation.
- E. coli :
highest occupied molecular orbital
Kasai H. What causes human cancer? Approaches from the chemistry of DNA damage. Genes Environ. 2016;38:19.
Steenken S, Jovanovic SV. How easily oxidizable is DNA? One-electron reduction potentials of adenosine and guanosine radicals in aqueous solution. J Am Chem Soc. 1997;119:617–8.
Suzuki M, Kino K, Miyazawa H. Selectivity of bases incorporated opposite oxidative guanine damages by DNA polymerases. Radiat Biol Res Commun. 2012;47:137–164. (Japanese).
Khaled HM, Bahnassi AA, Zekri AR, Kassem HA, Mokhtar N. Correlation between p53 mutations and HPV in bilharzial bladder cancer. Urol Oncol. 2003;21(5):334–41.
Maehira F, Miyagi I, Asato T, Eguchi Y, Takei H, Nakatsuki K, Fukuoka M, Zaha F. Alterations of protein kinase C, 8-hydroxydeoxyguanosine, and K-ras oncogene in rat lungs exposed to passive smoking. Clin Chim Acta. 1999;289:133–44.
Giaretti W, Rapallo A, Geido E, Sciutto A, Merlo F, Risio M, Rossini FP. Specific K-ras2 mutations in human sporadic colorectal adenomas are associated with DNA near-diploid aneuploidy and inhibition of proliferation. Am J Pathol. 1998;153:1201–9.
Suzuki T, Kamiya H. Mutations induced by 8-hydroxyguanine (8-oxo-7,8-dihydroguanine), a representative oxidized base, in mammalian cells. Genes Environ. 2016;39:2.
Oda Y, Uesugi S, Ikehara M, Nishimura S, Kawase Y, Ishikawa H, Inoue H, Ohtsuka E. NMR studies of a DNA containing 8-hydroxydeoxyguanosine. Nucleic Acids Res. 1991;19:1407–12.
McAuley-Hecht KE, Leonard GA, Gibson NJ, Thomson JB, Watson WP, Hunter WN, Brown T. Crystal structure of a DNA duplex containing 8-hydroxydeoxyguanine-adenine base pairs. Biochemistry. 1994;33:10266–70.
Lipscomb LA, Peek ME, Morningstar ML, Verghis SM, Miller EM, Rich A, Essigmann JM, Williams LD. X-ray structure of a DNA decamer containing 7,8-dihydro-8-oxoguanine. Proc Natl Acad Sci U S A. 1995;92:719–23.
Shibutani S, Takeshita M, Grollman AP. Insertion of specific bases during DNA synthesis past the oxidation-damaged base 8-oxodG. Nature. 1991;349:431–4.
Kino K, Sugasawa K, Mizuno T, Bando T, Sugiyama H, Akita M, Miyazawa H, Hanaoka F. Eukaryotic DNA polymerases α, β and ε incorporate guanine opposite 2,2,4-triamino-5(2H)-oxazolone. Chembiochem. 2009;10:2613–6.
Zhang Y, Yuan F, Wu X, Wang M, Rechkoblit O, Taylor JS, Geacintov NE, Wang Z. Error-free and error-prone lesion bypass by human DNA polymerase κ in vitro. Nucleic Acids Res. 2000;28:4138–46.
Haracska L, Prakash L, Prakash S. Role of human DNA polymerase κ as an extender in translesion synthesis. Proc Natl Acad Sci U S A. 2002;99:16000–5.
Yuan F, Zhang Y, Rajpal DK, Wu X, Guo D, Wang M, Taylor JS, Wang Z. Specificity of DNA lesion bypass by the yeast DNA polymerase η. J Biol Chem. 2000;275:8233–9.
Carlson KD, Washington MT. Mechanism of efficient and accurate nucleotide incorporation opposite 7,8-dihydro-8-oxoguanine by Saccharomyces cerevisiae DNA polymerase η. Mol Cell Biol. 2005;25:2169–76.
Zhang Y, Yuan F, Wu X, Taylor JS, Wang Z. Response of human DNA polymerase ι to DNA lesions. Nucleic Acids Res. 2001;29:928–35.
Haracska L, Prakash S, Prakash L. Yeast DNA polymerase ζ is an efficient extender of primer ends opposite from 7,8- dihydro-8-oxoguanine and O 6-methylguanine. Mol Cell Biol. 2003;23:1453–9.
Kamiya H, Kurokawa M, Makino T, Kobayashi M, Matsuoka I. Induction of action-at-a-distance mutagenesis by 8-oxo-7,8-dihydroguanine in DNA pol λ-knockdown cells. Genes Environ. 2015;37:10.
Henderson PT, Delaney JC, Gu F, Tannenbaum SR, Essigmann JM. Oxidation of 7,8-dihydro-8-oxoguanine affords lesions that are potent sources of replication errors in vivo. Biochemistry. 2002;41:914–21.
Henderson PT, Delaney JC, Muller JG, Neeley WL, Tannenbaum SR, Burrows CJ, Essigmann JM. The hydantoin lesions formed from oxidation of 7,8-dihydro-8-oxoguanine are potent sources of replication errors in vivo. Biochemistry. 2003;42:9257–62.
Klein JC, Bleeker MJ, Saris CP, Roelen HC, Brugghe HF, van den Elst H, van der Marel GA, van Boom JH, Westra JG, Kriek E, Berns AJM. Repair and replication of plasmids with site-specific 8-oxodG and 8-AAFdG residues in normal and repair-deficient human cells. Nucleic Acids Res. 1992;20:4437–43.
Kamiya H, Miura K, Ishikawa H, Inoue H, Nishimura S, Ohtsuka E. C-ha-ras containing 8-hydroxyguanine at codon 12 induces point mutations at the modified and adjacent positions. Cancer Res. 1992;52:3483–5.
Moriya M. Single-stranded shuttle phagemid for mutagenesis studies in mammalian cells: 8-oxoguanine in DNA induces targeted G.C. T.A transversions in simian kidney cells. Proc Natl Acad Sci U S A. 1993;90:1122–6.
Yanagawa H, Ogawa Y, Ueno M. Redox ribonucleosides. Isolation and characterization of 5-hydroxyuridine, 8-hydroxyguanosine, and 8-hydroxyadenosine from Torula yeast RNA. J Biol Chem. 1992;267:13320–6.
Steenken S, Jovanovic SV, Bietti M, Bernhard K. The trap depth (in DNA) of 8-oxo-7,8-dihydro-2’deoxyguanosine as derived from electron-transfer equilibria in aqueous solution. J Am Chem Soc. 2000;122:2373–4.
Shibutani S, Takeshita M, Grollman AP. Translesional synthesis on DNA templates containing a single abasic site. A mechanistic study of the "a rule". J Biol Chem. 1997;272:13916–22.
Cadet J, Berger M, Buchko GW, Joshi PC, Raoul S, Ravanat J-L. 2,2-Diamino-4-[(3,5-di-O-acetyl-2-deoxy-β-D-erythro-pentofuranosyl)amino]-5-(2H)-oxazolone: a novel and predominant radical oxidation product of 3′,5′-di-O-acetyl-2′-deoxyguanosine. J Am Chem Soc. 1994;116:7403–4.
Luo W, Muller JG, Burrows CJ. The pH-dependent role of superoxide in riboflavin-catalyzed photooxidation of 8-oxo-7,8-dihydroguanosine. Org Lett. 2001;3:2801–4.
Kino K, Saito I, Sugiyama H. Product analysis of GG-specific photooxidation of DNA via electron transfer: 2-Aminoimidazolone as a major guanine oxidation product. J Am Chem Soc. 1998;120:7373–4.
Kino K, Miyazawa H, Sugiyama H. User-friendly synthesis and photoirradiation of a flavin-linked oligomer. Genes Environ. 2007;29:23–8.
Morikawa M, Kino K, Oyoshi T, Suzuki M, Kobayashi T, Miyazawa H. Product analysis of photooxidation in isolated quadruplex DNA; 8-oxo-7,8-dihydroguanine and its oxidation product at 3′-G are formed instead of 2,5-diamino-4H-imidazol-4-one. RSC Adv. 2013;3:25694.
Morikawa M, Kino K, Oyoshi T, Suzuki M, Kobayashi T, Miyazawa H. Analysis of guanine oxidation products in double-stranded DNA and proposed guanine oxidation pathways in single-stranded, double-stranded or quadruplex DNA. Biomol Ther. 2014;4:140–59.
Kino K, Sugiyama H. Possible cause of G-C C-G transversion mutation by guanine oxidation product, imidazolone. Chem Biol. 2001;8:369–78.
Kino K, Sugiyama H. UVR-induced G-C to C-G transversions from oxidative DNA damage. Mutat Res. 2005;571:33–42.
Neeley WL, Delaney JC, Henderson PT, Essigmann JM. In vivo bypass efficiencies and mutational signatures of the guanine oxidation products 2-aminoimidazolone and 5-guanidino-4-nitroimidazole. J Biol Chem. 2004;279:43568–73.
Matter B, Malejka-Giganti D, Csallany AS, Tretyakova N. Quantitative analysis of the oxidative DNA lesion, 2,2-diamino-4-(2-deoxy-β-D-erythro-pentofuranosyl)amino-5(2H)-oxazolone (oxazolone), in vitro and in vivo by isotope dilution-capillary HPLC-ESI-MS/MS. Nucleic Acids Res. 2006;34:5449–60.
Ming X, Matter B, Song M, Veliath E, Shanley R, Jones R, Tretyakova N. Mapping structurally defined guanine oxidation products along DNA duplexes: influence of local sequence context and endogenous cytosine methylation. J Am Chem Soc. 2014;136:4223–35.
Duarte V, Gasparutto D, Jaquinod M, Cadet J. In vitro DNA synthesis opposite oxazolone and repair of this DNA damage using modified oligonucleotides. Nucleic Acids Res. 2000;28:1555–63.
Suzuki M, Kino K, Kawada T, Morikawa M, Kobayashi T, Miyazawa H. Analysis of nucleotide insertion opposite 2,2,4-triamino-5(2H)-oxazolone by eukaryotic B- and Y-family DNA polymerases. Chem Res Toxicol. 2015;28:1307–16.
Kino K, Ito N, Sugasawa K, Sugiyama H, Hanaoka F. Translesion synthesis by human DNA polymerase η across oxidative products of guanine. Nucleic Acids Symp Ser (Oxf). 2009;(53):315-6.
Suzuki M, Kino K, Morikawa M, Kobayashi T, Komori R, Miyazawa H. Calculation of the stabilization energies of oxidatively damaged guanine base pairs with guanine. Molecules. 2012;17:6705–15.
Suzuki M, Ohtsuki K, Kino K, Kobayashi T, Morikawa M, Kobayashi T, Miyazawa H. Effects of stability of base pairs containing an oxazolone on DNA elongation. J Nucleic Acids. 2014;2014:178350.
Haracska L, Unk I, Johnson RE, Johansson E, Burgers PM, Prakash S, Prakash L. Roles of yeast DNA polymerases δ and ζ and of Rev1 in the bypass of abasic sites. Genes Dev. 2001;15:945–54.
Murakumo Y, Ogura Y, Ishii H, Numata S, Ichihara M, Croce CM, Fishel R, Takahashi M. Interactions in the error-prone postreplication repair proteins hREV1, hREV3, and hREV7. J Biol Chem. 2001;276:35644–51.
Ohashi E, Murakumo Y, Kanjo N, Akagi J, Masutani C, Hanaoka F, Ohmori H. Interaction of hREV1 with three human Y-family DNA polymerases. Genes Cells. 2004;9:523–31.
Kim MS, Machida Y, Vashisht AA, Wohlschlegel JA, Pang YP, Machida YJ. Regulation of error-prone translesion synthesis by Spartan/C1orf124. Nucleic Acids Res. 2013;41:1661–8.
Acharya N, Johnson RE, Pages V, Prakash L, Prakash S. Yeast Rev1 protein promotes complex formation of DNA polymerase ζ with Pol32 subunit of DNA polymerase δ. Proc Natl Acad Sci U S A. 2009;106:9631–6.
Kikuchi S, Hara K, Shimizu T, Sato M, Hashimoto H. Structural basis of recruitment of DNA polymerase ζ by interaction between REV1 and REV7 proteins. J Biol Chem. 2012;287:33847–52.
Kanemaru Y, Suzuki T, Sassa A, Matsumoto K, Adachi N, Honma M, Numazawa S, Nohmi T. DNA polymerase kappa protects human cells against MMC-induced genotoxicity through error-free translesion DNA synthesis. Genes Environ. 2015;37:10.
Prakash S, Prakash L. Translesion DNA synthesis in eukaryotes: a one- or two-polymerase affair. Genes Dev. 2002;16:1872–83.
Luo W, Muller JG, Rachlin EM, Burrows CJ. Characterization of hydantoin products from one-electron oxidation of 8-oxo-7,8-dihydroguanosine in a nucleoside model. Chem Res Toxicol. 2001;14:927–38.
Kino K, Morikawa M, Kobayashi T, Kobayashi T, Komori R, Sei Y, Miyazawa H. The oxidation of 8-oxo-7,8-dihydroguanine by iodine. Bioorg Med Chem Lett. 2010;20:3818–20.
Kornyushyna O, Berges AM, Muller JG, Burrows CJ. In vitro nucleotide misinsertion opposite the oxidized guanosine lesions spiroiminodihydantoin and guanidinohydantoin and DNA synthesis past the lesions using Escherichia coli DNA polymerase I (Klenow fragment). Biochemistry. 2002;41:15304–14.
Beckman J, Wang M, Blaha G, Wang J, Konigsberg WH. Substitution of ala for Tyr567 in RB69 DNA polymerase allows dAMP and dGMP to be inserted opposite Guanidinohydantoin. Biochemistry. 2010;49:8554–63.
Delaney S, Neeley WL, Delaney JC, Essigmann JM. The substrate specificity of MutY for hyperoxidized guanine lesions in vivo. Biochemistry. 2007;46:1448–55.
Alshykhly OR, Fleming AM, Burrows CJ. Guanine oxidation product 5-carboxamido-5-formamido-2-iminohydantoin induces mutations when bypassed by DNA polymerases and is a substrate for base excision repair. Chem Res Toxicol. 2015;28:1861–71.
Wu M, Yan S, Patel DJ, Geacintov NE, Broyde S. Relating repair susceptibility of carcinogen-damaged DNA with structural distortion and thermodynamic stability. Nucleic Acids Res. 2002;30:3422–32.
Suzuki M, Kino K, Morikawa M, Kobayashi T, Miyazawa H. Calculating distortions of short DNA duplexes with base pairing between an oxidatively damaged guanine and a guanine. Molecules. 2014;19:11030–44.
Matsumoto Y, Zhang QM, Takao M, Yasui A, Yonei S. Escherichia coli Nth and human hNTH1 DNA glycosylases are involved in removal of 8-oxoguanine from 8-oxoguanine/guanine mispairs in DNA. Nucleic Acids Res. 2001;29:1975–81.
Furihata C. An active alternative splicing isoform of human mitochondrial 8-oxoguanine DNA glycosylase (OGG1). Genes Environ. 2015;37:21.
Tretyakova NY, Wishnok JS, Tannenbaum SR. Peroxynitrite-induced secondary oxidative lesions at guanine nucleobases: chemical stability and recognition by the Fpg DNA repair enzyme. Chem Res Toxicol. 2000;13:658–64.
Kino K, Takao M, Miyazawa H, Hanaoka F. A DNA oligomer containing 2,2,4-triamino-5(2H)-oxazolone is incised by human NEIL1 and NTH1. Mutat Res. 2012;734:73–7.
Kino K, Suzuki M, Morikawa M, Kobayashi T, Iwai S, Miyazawa H. Chlorella virus pyrimidine dimer glycosylase and Escherichia coli endonucleases IV and V have incision activity on 2,2,4-triamino-5(2H)-oxazolone. Genes Environ. 2015;37:22.
Feng H, Dong L, Klutz AM, Aghaebrahim N, Cao W. Defining amino acid residues involved in DNA-protein interactions and revelation of 3′-exonuclease activity in endonuclease V. Biochemistry. 2005;44:11486–95.
Kino K, Sugasawa K, Sugiyama H, Miyazawa H, Hanaoka F. The base excision repair reaction of oxazolone with hOGG1. Photomed Photobiol. 2004;26:41–2.
Kino K, Sugasawa K, Miyazawa H, Hanaoka F. 2,2,4-Triamino-5(2H)-oxazolone is a weak substrate for nucleotide excision repair. J Pharm Negative Results. 2016;7:42–5.
Sugiyama H, Saito I. Theoretical studies of GG-specific photocleavage of DNA via electron transfer: significant lowering of ionization potential and 5′- localization of HOMO of stacked GG bases in B-form DNA. J Am Chem Soc. 1996;118:7063–8.
Saito I, Nakamura T, Nakatani K, Yoshioka Y, Yamaguchi K, Sugiyama H. Mapping of the hot spots for DNA damage by one-electron oxidation: efficacy of GG doublets and GGG triplets as a trap in long-range hole migration. J Am Chem Soc. 1998;120:12686–7.
Ito K, Inoue S, Yamamoto K, Kawanishi S. 8-Hydroxydeoxyguanosine formation at the 5′ site of 5′-GG-3′ sequences in double-stranded DNA by UV radiation with riboflavin. J Biol Chem. 1993;268:13221–7.
Ito K, Kawanishi S. Photoinduced hydroxylation of deoxyguanosine in DNA by pterins: sequence specificity and mechanism. Biochemistry. 1997;36:1774–81.
Choi J, Park J, Tanaka A, Park MJ, Jang YJ, Fujitsuka M, Kim SK, Majima T. Hole trapping of G-quartets in a G-quadruplex. Angew Chem Int Ed Engl. 2013;52:1134–8.
Suzuki M, Kino K, Kawada T, Oyoshi T, Morikawa M, Kobayashi T, Miyazawa H. Contiguous 2,2,4-triamino-5(2H)-oxazolone obstructs DNA synthesis by DNA polymerases α, β, η, ι, κ, REV1 and Klenow fragment exo−, but not by DNA polymerase ζ. J Biochem. 2016;159:323–9.
Phillips K, Dauter Z, Murchie AIH, Lilley DMJ, Luisi B. The crystal structure of a parallel-stranded guanine tetraplex at 0.95 a resolution. J Mol Biol. 1997;273:171–82.
Haider S, Parkinson GN, Neidle S. Crystal structure of the potassium form of an Oxytricha Nova G-quadruplex. J Mol Biol. 2002;320:189–200.
Parkinson GN, Lee MPH, S. Neidle S. Crystal structure of parallel quadruplexes from human telomeric DNA. Nature. 2002;417:876–80.
Morikawa M, Kino K, Oyoshi T, Suzuki M, Kobayashi T, Miyazawa H. Calculation of the HOMO localization of Tetrahymena and Oxytricha telomeric quadruplex DNA. Bioorg Med Chem Lett. 2015;25:3359–62.
Laughlan G, Murchie AI, Norman DG, Moore MH, Moody PC, Lilley DM, Luisi B. The high-resolution crystal structure of a parallel-stranded guanine tetraplex. Science. 1994;265:520–4.
Kino K, Suzuki M, Morikawa M, Miyazawa H. One-electron oxidation of guanine. Radiat Biol Res Commun. 2015;50:305–320. (Japanese).
Kobayashi K, Tagawa S. Direct observation of guanine radical cation deprotonation in duplex DNA using pulse radiolysis. J Am Chem Soc. N125:10213–8.
The authors would like to thank Atsushi Hakura, Eisai Co., Ltd., for giving the opportunity to prepare for this review.
These works were supported by K. Kino’s research grants from the Japan Society for the Promotion of Science (Grants-in-Aid for Scientific Research (C) 23,510,069, 17 K00558 and for Young Scientists (B) 17,710,048), from Tokushima Bunri University, from the Radiation Effects Association, from LNest Grant L-RAD award, from the Nakatomi Foundation, and from the Japan Prize Foundation. M. Suzuki and M. Morikawa were supported by a Research Fellowship from JSPS (25.10124 to M.S. and 25.10122 to M.M.).
Availability of data and materials
KK decided the concept and design of this manuscript. All five authors contributed to write this manuscript, and approved the final manuscript. The polymerase section was discussed by KK, MHS, AS, and HM. The repair section was discussed by KK and HM. The quadruplex section was discussed by KK, MM, and HM.
The authors declare that they have no competing interests.
Consent for publication
Ethics approval and consent to participate
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
About this article
Cite this article
Kino, K., Hirao-Suzuki, M., Morikawa, M. et al. Generation, repair and replication of guanine oxidation products. Genes and Environ 39, 21 (2017). https://doi.org/10.1186/s41021-017-0081-0
- G:C-C:G transversions
- 2,2,4-triamino-5(2H)-oxazolone (oz)
- Base pair
- DNA polymerase
- Contiguous oz
- Highest occupied molecular orbital (HOMO)
- Quadruplex DNA