Mutagenicity, toxicity and repair of DNA base damage induced by oxidation

Mutation Research 531 (2003) 37–80

Review

Mutagenicity, toxicity and repair of DNA base damage induced by oxidation Svein Bjelland a,∗ , Erling Seeberg b a

School of Science and Technology, Stavanger University College, PO Box 8002, N-4068 Stavanger, Norway b Centre of Molecular Biology and Neuroscience, Institute of Medical Microbiology, University of Oslo, National Hospital, N-0027 Oslo, Norway Received 7 July 2003; received in revised form 18 July 2003; accepted 22 July 2003

Abstract Oxidative DNA damage is a major cause of cell death and mutagenesis in all aerobic organisms, and several new oxidative base lesions have been identified in recent years. Improved chemistry for the synthesis of oligonucleotides with modified base residues at defined positions has allowed detailed studies of repair, replication, transcription and mutagenesis at specific lesions in vitro and in vivo. The aim of this review is to present the structure of all the various known oxidised DNA base lesions known to date and to summarise the present knowledge about the mutagenic and toxic effects of oxidised base modifications and their repair. © 2003 Elsevier B.V. All rights reserved. Keywords: Mutagenicity; Toxicity; DNA

1. Introduction Oxidative DNA damage has been recognised as a major cause of cell death and mutations in all aerobic organisms. In humans, oxidative DNA damage is also considered an important promoter of cancer and neurological disease and has been implicated in the normal process of ageing. A major fraction of the DNA damage induced by ionising radiation constitutes oxidative lesions induced by hydroxyl radicals (• OH) resulting from the radiolysis of water [1–3]. DNA oxidations are also formed spontaneously from reactive oxygen species induced as by-products in the ∗ Corresponding author. Tel.: +43-518-31884; fax: +43-518-31750. E-mail addresses: [email protected] (S. Bjelland), [email protected] (E. Seeberg).

mitochondria during respiration [4–7]. One electron transfer to molecular oxygen yields the relatively non-reactive superoxide anion radical (O2 •− ), which in turn is converted to hydrogen peroxide (H2 O2 ). The highly reactive and DNA damaging hydroxyl radical (• OH) is formed from H2 O2 by reaction with Fe2+ . Other important sources of DNA oxidations include certain cellularly generated oxidising agents and systems confined to higher life forms, such as the oxidants nitric oxide (NO• ) and especially peroxynitrite (ONOO− ) formed from NO• and O2 •− [8,9], the myeloperoxidase–H2 O2 –chloride system (H2 O2 + Cl− → HOCl + OH− [10,11]) and reactive intermediates generated by eosinophil peroxidase [12]. In the myeloperoxidase–H2 O2 –nitrite system, the hypochlorous acid (HOCl) generated in the reaction above reacts with nitrite (NO2 − ) forming the oxidising, nitrating and chlorinating species nitryl

0027-5107/$ – see front matter © 2003 Elsevier B.V. All rights reserved. doi:10.1016/j.mrfmmm.2003.07.002

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chloride (HOCl + NO2 − + H+ → NO2 Cl + H2 O [13]). In the beginning, most studies of oxidative DNA lesions and repair were focused on the formation and processing of strand breaks. However, technological advances in recent years have allowed investigations elucidating the effects of chemically defined modifications of base structures and their precursors. These are likely to be as important as strand breaks for cellular function and survival, especially under the normal conditions of endogenous oxidative stress. Repair of DNA containing oxidised bases in vivo, proceeds predominantly through the base excision repair (BER) pathway initiated by DNA glycosylases [14–20], although certain types of oxidative lesions also appear to be repaired by nucleotide excision repair (NER) and mismatch repair (MMR) [21,22]. In this report, we will focus on the biological effects of all the known types of oxidised base residues in DNA, and review their pathways for repair and contribution to the toxic and mutagenic effect of oxidations. We will not consider in any detail the conditions and mechanisms of formation of oxidative DNA damage, which has been dealt with recently in several other reviews [23,24].

2. Oxidised thymines Radiolabelling of DNA has traditionally involved incorporation of tritiated thymine residues, which opened for the detection with high sensitivity of thymine modifications in DNA. For this reason, oxidised forms of thymine were the first type of oxidative base lesions to be identified in DNA. Free radicals attack the thymine moiety at two principal sites, i.e. the 5,6-double bond and the 5-methyl group [1,2]. 2.1. Oxidised thymines formed by attack on the 5,6-double bond Free radical attack on the 5,6-double bond of thymidine followed by addition of molecular oxygen turns the planar aromatic ring structure into a non-aromatic non-planar structure generating a total number of eight different diastereomers of 5-hydroxy-6-hydroperoxy5,6-dihydrothymidine and 6-hydroxy-5-hydroperoxy5,6-dihydrothymidine. These products are rather unstable [23,25] and the presence or distribution of each

of them in DNA is not known. The hydroperoxides are converted to more stable products in reactions where they may or may not ring-open, ring-contract or ring-fragment. The following six-ring products of thymine have been detected in DNA: cis- and trans5,6-dihydro-5,6-dihydroxythymine (thymine glycol (Tg)) [26], 5,6-dihydrothymine (dHT), 5-hydroxy-5,6dihydrothymine (Th5 ) and cis- and trans-6hydroxy-5,6-dihydrothymine (Th6 ) (Fig. 1). Thymine glycol (the cis-form) has been found to be a strong blocking lesion for Escherichia coli DNA polymerase I (Klenow fragment; PolI Kf) and T4 DNA polymerase, whereas avian myeloblastosis virus (AMV) reverse transcriptase was inhibited to a lesser extent [27–30]. DNA synthesis terminates opposite the site of the lesion and the blocking effect explains the capacity to inactivate both single- and double-stranded DNA (ssDNA; dsDNA) in vivo [27,31]. However, Tg can occasionally be bypassed thus explaining its low premutational potency resulting in A:T → G:C transitions (Table 1) [32,33]. Among the recently characterised DNA polymerases catalysing translesion synthesis (TLS), some have been demonstrated to replicate across Tg in vitro. Thus, while the human replicative polymerase ␣ stalls following incorporation of cognate adenine opposite Tg (both the 5Rand 5S-isoform; Fig. 1), polymerases ␩ and ␬ are able to continue synthesis after having inserted adeTable 1 Translesion synthesis past certain oxidised bases in DNA exhibited by different DNA polymerases

E. coli PolI PolIII T4 pol Eukarya Pol ␣ Pol ␤ Pol ␦ Pol ␰ Pol ␩ Pol ␫ Pol ␬ Pol ␮

Tg

Urea

h5 U

oxo8 G

iA>G eAG

iA>G eA>G

IAC E

IC>A EA>C IA

i A e0 IA e0 ie0

Ie

IA>G EA IT>G>C EA>G IA>G EA

IA>C EA>C IC>A E IA>C E iE IC≥A>G EC>A IC>GA E IA>C E i1>A E

The opposite base(s) is(are) indicated in superscript(s): I, efficient insertion opposite the lesion; i, inefficient insertion opposite the lesion; E, efficient extension; e/e0 , inefficient/no extension.

S. Bjelland, E. Seeberg / Mutation Research 531 (2003) 37–80

O

O OH CH 3 OH H

HN O

N

O CH3 OH H OH

HN O

N dR 5S,6R

dR 5R,6S

HN O

N

CH3 OH OH H

HN O

N

O

O

N

O

CH 3 OH H H

CH 3 OH H H

HO NH 2 N

O

dR -R-Hydroxy-ureidoisobutyric acid (uba) E.coli Fpg,Nth,AlkA

dR 5-Hydroxy5,6-dihydrothymine (Th5) E.coli Nth,Nei; S.cer.Ntg1,Ntg2; S.po.Nth;hNth1

O

H H -

O3PO

C

NH N

O

OPO3

-

O

N

dR trans-6-Hydroxy5,6-dihydrothymine (tTh6) ToxB E.coli Nth

N

O HN O

CH3 OH

N

dR dR 5,6-Dihydro5-Hydroxythymine (dHT) 5-methylToxN hydantoin (hmh) MutN ToxB E.coli Nth,Nei,Fpg, E.coli Nth,Nei,Fpg; Nfo;Panth;S.cer. S.cer.Ntg1,Ntg2 Ntg1,Ntg2;hNth1, hNeil1,hNeil2;mNth1 H O C O H CH3 N HN OH dR C O OH H Formylamine (fam) N O ToxB dR T to C,C to T Methyltartronyl- E.coli Nth,Fpg urea (mtu) E.coli Nth

O O

H3C H

CH 3 H H H

HN

O OH CH 3 H OH

CH 3 H H OH

HN

O

dR dR 5R,6R 5S,6S trans-Thymine glycol (tTg) E.coli Nth

HN

N

dR cis-6-Hydroxy5,6-dihydrothymine (cTh6) ToxB E.coli Nth

cis-Thymine glycol (cTg) ToxB T to C E.coli Nth,Nei, Fpg;M.ther.Nfo; S.po.Nth;mNth1 O

O CH 3 H OH H

HN O

39

NH 2

H

C

C O N

dR N-Formyl urea (fNurea)

O

(5´S,6S)-Cyclo-5,6-dihydrothymidine (cy6dHdT) ToxB

NH 2 O

C

H N

dR Urea ToxB T to C>A,G to C E.coli Nth,Nei, Xth,Nfo,Nfi; S.cer.Ntg1,Ntg2; S.po.Nth;hNth1, hOgg1,hNER; mNth1

Fig. 1. Oxidised thymines formed by attack on the 5,6-double bond. Mutations induced by in situ lesions are shown in bold. Tox, cytotoxic (N, non; B, blocking replication); Mut, mutagenic (N, non). Tg, cTh6 and tTh6 can also be formed from 5-methylcytosine, fam from cytosine and urea from guanine.

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nine opposite the lesion. However, the error prone DNA polymerases will also inefficiently incorporate non-cognate guanine opposite Tg (Table 1) [34,35]. In addition, Tg has been shown to exert toxicity at the level of transcription by causing termination of T7 RNA polymerase in vitro [36]. Nuclear magnetic resonance (NMR) analysis has demonstrated that Tg

inserted opposite adenine induces a large localised structural change in duplex DNA with the Tg base being extrahelical [37,38]. The distortion of the DNA helix structure is thought to explain why Tg is one of the few oxidative base damages that seem to be removed by the E. coli [39,40] and human NER systems [41] (Table 2). However, it has recently been

Table 2 Proteins involved in the repair of oxidised thymines in DNA

E. coli Nth Nei Fpg Ung Mug AlkA Xth Nfo Nfi UvrABC

Tg

dHT

Th5

uba

Th6

mtu

hmh

fam

Urea

hm5 U

f5U

cy6 dHdT

+G>A>CT +G>TA>C +A

+G>ATC +G>TC>A +A

+A +A

+G>ATC

+A

+A

+A +A +A

+A

+GCAT +A

+G>A +G>A +G>A −AG +G>A +A

+A +A +A −AG +G>A +AG

−A −A −A

+ G −A

+G − A

+CGT>A +AT>CG

−A +A

+A +A +

+A

P. aerophilum Panth

+A

+G>TCA

M. thermoautotrophicum Nth +A Mig Nfo +A S. cerevisiae Ntg1 +A Ntg2 +A S. pombe Nth Mammalian hNth1 mNth1 hNeil1 mNeil1 hNeil2 hOgg1 hSmug1 rSmug1 hUng2 hMbd4 mTdg hMpg mMpg hApex1 hNER

+A +A

+A +A +GTAC +A +CTG>Ass +A

+A +CGT>A +A

+A +A

+A +A

+A +A

+A

+A

+A

+A +GACT

+A

−Ass

+C>ATG

−A

+A

+GCT>A +A

+ss>G>A

+ss>A −G + G −A +G>A −A

The opposite base(s) is(are) indicated in superscript(s): ss, ssDNA.

+A

−A +(ss)CT>G>A +Ass +G − A +G>A −A −A

S. Bjelland, E. Seeberg / Mutation Research 531 (2003) 37–80

shown that more than 80% of the Tg repair in human cell extracts was performed by short patch and 20% by long patch BER, with no evidence for NER [42]. Interestingly, Tg repair through BER and the human Nth1 DNA glycosylase appears to be stimulated by the NER factor XpG (xeroderma pigmentosum complementation group G (XPG)) [18,43]. It has been proposed that XpG is required in a poorly characterised type of transcription-coupled repair of oxidative lesions including Tg [44,45]. Mutations in the xpG or csB (Cockayne syndrome complementation group B (CSB)) genes drastically reduced global removal of Tg [46]. Results presented in another study have demonstrated that cell extracts deficient in XpG exhibit an approximate 25% reduction in Tg incision [42]. Moreover, Tg in the transcribed strand blocks transcription elongation in vitro by T7 RNA polymerase ∼50% of the time but does not block mammalian RNA polymerase II, suggesting that arrest of RNA polymerase elongation is not necessary for transcription-coupled repair of Tg [47]. Tg has been regarded as the principal lesion in the group of oxidised pyrimidines with lost aromaticity. Thus, the BER activity removing such modified bases from DNA is sometimes designated Tg DNA glycosylase. However, since the first enzyme reported to remove Tg originally was termed endonuclease III (Nth from E. coli [48–50]), gene product names relating to Nth are more common. E. coli Nth acts on both cTg and tTg and was also found to remove 5,6-dihydrothymine [51–53]; a reduced form of thymine primarily formed by radiolysis of water in the absence of molecular oxygen. dHT does not seem to promote lethality or mutations, but is nevertheless removed by other enzymes acting on Tg including endonuclease VIII from E. coli (Nei [54]; see Table 2) [55–57] and most Nth homologues in eukaryotes and certain thermophilic archaeons, as e.g. Pyrobaculum aerophilum [58] and Methanobacterium thermoautotrophicum [59]. Also the formamidopyrimidine DNA glycosylase of E. coli (Fpg/MutM) has been shown to remove dHT as well as cTg [60,61]. When a Tg or a dHT lesion is placed in close proximity to a single nucleotide gap on the opposite strand of an oligonucleotide, their ability to be excised by Nth and Nei is reduced. Thus, no excision was observed with the gap positioned one nucleotide away 5 or 3 in the opposite strand. The Nth-mediated cleavage

41

increased as the distance increased between the lesion and the opposed strand break, whereas Nei cleavage was equivalent to or less when the gap was positioned 6 nucleotides versus 3 nucleotides 3 of the lesion [62]. Interestingly, the apurinic/apyrimidinic (AP) endonuclease Nfo (endonuclease IV) of E. coli and M. thermoautotrophicum has recently been shown to incise dsDNA adjacent to a dHT and cTg residue, respectively, by a novel pathway called nucleotide incision repair (Table 2) [59,63]. In Saccharomyces cerevisiae, Tg and dHT are both removed by two different Nth homologues; Ntg1, which is induced by cell exposure to DNA damaging agents and is present both in the nucleus as well as in mitochondria, and Ntg2, a purely nuclear enzyme which is constitutively expressed [64–66]. On the other hand, Schizosaccharomyces pombe has been found to contain an Nth homologue which releases Tg but not dHT from DNA [67–69]. The mammalian Nth homologues (hNth1/mNth1 [56,70–72]) and Nei-like enzymes hNeil1/mNeil1 and hNeil2 (hNeh2) exhibit significant activity for both Tg (see Fig. 1) and dHT in DNA (Table 2) [54,73–75]. Two other six-ring products of thymine, 5-hydroxy5,6-dihydrothymine and 6-hydroxy-5,6-dihydrothymine, often designated thymine hydrates, have also been identified in DNA, but is less well characterised than Tg and dHT (Fig. 1). However, evidence has been presented to indicate that Th6 inhibits E. coli DNA polymerase I activity in vitro [76] indicating a cytotoxic effect in vivo. Studies with Th5 show that it preferentially base pairs with adenine but destabilises dsDNA disrupting pairing at the 5 -adjacent pair, which results in the inhibition of DNA synthesis across Th5 by PolI Kf (exonuclease-deficient; exo− ) [77,78]. The potential of Th5 and Th6 to be released by some DNA glycosylases has been determined (Table 2). Thus, E. coli Nth and Nei enzymes excise Th5 from ␥-irradiated DNA [79–81] whereas Nth excises Th6 (both the cis- and trans-structure) from ultraviolet (UV)-irradiated poly(dA-dT)·poly(dA-dT) [82,83]. Th5 is excised by S. cerevisiae Ntg1 and Ntg2 [64], S. pombe Nth [69] and human Nth1 [70]. Hydroxylation of thymine C5 followed by full oxidation of C6 to a carboxy group causes breakage of the N1–C6 single bond. The result is one of the two “pure” ring-opened pyrimidine products identified in DNA: methyltartronylurea (mtu) (Fig. 1). Little

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S. Bjelland, E. Seeberg / Mutation Research 531 (2003) 37–80

is known about this lesion, which has been shown to be a substrate for the E. coli Nth protein [52] (Table 2). The other “pure” ring-opened pyrimidine product is α-R-hydroxy-β-ureidoisobuturic acid (uba), formed by hydrolysis of Th5 (Fig. 1). This product appears to have coding properties although it inhibits snake venom phosphodiesterase, ␭ exonuclease and PolI Kf (exo− ) [84]. The uba is excised from DNA by the E. coli Fpg, Nth and 3-methyladenine DNA glycosylase II (AlkA) enzymes in all contexts of base pairing (Table 2) [85,86]. The only ring-contracted form of thymine shown to be present in oxidised DNA is 5-hydroxy-5-methylhydantoin (hmh) (Fig. 1), first identified in ␥-irradiated DNA by Téoule et al. [26]. It was recently found that hmh is a strong blocking lesion, although PolI Kf and Thermus aquaticus (Taq) DNA polymerase could, to a certain extent, insert dAMP and also occasionally dGMP opposite hmh, however, without further strand elongation. With DNA polymerase ␤ there was no incorporation opposite hmh [87]. The stability of hmh in DNA has been demonstrated by its presence in different ancient samples including a ≥50,000-year-old Siberian mammoth, where the ability to retrieve DNA sequences by polymerase chain reaction (PCR) from such sources was inversely correlated with the hydantoin content [88]. The hmh is excised from DNA by E. coli Nth, Nei and Fpg and S. cerevisiae Ntg1 and Ntg2 proteins (Table 2) [52,53,64,87]. Three different products—N-formyl urea (fN urea), formylamine (fam) and urea [24,89] (Fig. 1)—may be the result of extensive ring fragmentation following free radical attack on the 5,6-double bond; all first identified in ␥-irradiated DNA by Téoule et al. [26]. Of these, N-formyl urea is the least fragmented species with C4 and C5 removed from the original thymine ring [26]. To our knowledge, no published material is available on the biological implications of fN urea in DNA. The most fragmented thymine residue is formylamine, also designated formamide, consisting of only a formyl group (where C6 is oxidised) attached to N1 [26]. This lesion, which has been detected in cellular DNA following UVB exposure [90], was shown to significantly decrease the stability of DNA in an opposite base-dependent manner [91,92], although conformational changes were only observed around the mismatched site. The fam residue exists as trans and cis (ratio 3:2) isomers resulting from slow rotation

of the C–N amide bond. Both isomers are intrahelical being capable of forming one hydrogen bond to a guanine on the opposite strand [93]. This explains in vitro replication experiments with PolI Kf resulting in the insertion of guanine opposite fam, i.e. induction of T → C transitions [94]. However, in mammalian COS7 cells the lesion codes preferentially for adenine (followed by cytosine and thymine)—both alone and positioned next to an 8-hydroxyguanine (7,8-dihydro-8-oxoguanine or 8-oxoguanine; oxo8 G) residue—and since fam also can be formed from cytosine in DNA, this results in C → T transitions [95]. Also deletions are generated at fam in systems with Taq polymerase in vitro and in mammalian cells [94,95]. Both the mutagenic and replication blocking potentials of fam explain the presence in E. coli of enzymes involved in its removal from DNA (Table 2), i.e. the Nth and Fpg glycosylases [96]. Interestingly, fam has been shown to be formed before or next to (the latter position preferred) an oxo8 G, i.e. in GpT (or TpG) sequences, in short oligomers as well as in DNA. These tandem lesions are thought to arise from one single free radical initiating event and are acted upon by Nth and Fpg [97–101]. Urea (Fig. 1) is the product when fN urea loses its formyl group [26], or when the Tg moiety undergoes ring fragmentation between N3 and C4 and between N1 and C6 in the presence of OH− [102]. The urea residue, where a predominant species is extrahelical and a minor species intrahelical [103], has been found to inhibit PolI Kf and T4 DNA polymerase in vitro, with synthesis terminating one nucleotide ahead of or at the lesion site (Table 1) [27,28,33], explaining inactivation of both ss- and dsDNA in vivo [27,31]. Similar results have been obtained with human DNA polymerase ␤, AMV reverse transcriptase and a modified T7 DNA polymerase (Sequenase) [33]. In the latter study, which demonstrated low-efficiency in vitro bypass of urea and cTg by PolI Kf (exo− ), guanine was inserted more frequently opposite urea than opposite cTg, suggesting that urea, in spite of being a stronger blocking lesion, is more miscoding than cTg. The potential of urea to mispair with guanine is supported by in vivo experiments showing that urea induces T → C transitions in the E. coli lacI gene (i−d region) with a relatively high frequency [104]. In addition, urea can also be formed from guanine by hydrolysis of oxaluric acid (oxa), which is a secondary oxidation product of oxo8 G, thus giving

S. Bjelland, E. Seeberg / Mutation Research 531 (2003) 37–80

rise to G → C transversions [105]. Enzymatic activities for the release of urea (Table 2) were detected at an early stage in E. coli [106] and mammalian cells [102] and soon it became clear that they were a function of the same proteins that released Tg from DNA [48,52]. Urea is excised by E. coli Nth and Nei [55], S. cerevisiae Ntg1 and Ntg2 [66], S. pombe Nth [68] as well as by mouse [71] and human Nth1 [107] and human Ogg1 [57]. However, urea-containing DNA is also incised by E. coli Xth. Since this is a much more abundant enzyme than Nth (3500 molecules per cell versus 350 molecules per cell), it has been argued that Xth is the major repair activity for urea in E. coli [108]. In addition, E. coli Nfo also incises urea-containing DNA, and xth nfo double mutants are defective in the host cell reactivation of urea-containing phage DNA [50]. Another E. coli enzyme recognising urea is Nfi (endonuclease V), which makes an incision at the second phosphodiester bond 3 to the damaged base [109]. Similar to Tg, urea can also be repaired by the human NER system [41].

O

C OOH

HN

H

O

dR 5-(Hydroperoxymethyl)uracil (Hpm5U)

O

O

N

O

H O

dR

H

2.2. Oxidised thymines formed by attack on the methyl group In contrast to free radical attack on the thymine 5,6-double bond, attack on the 5-methyl group generates products with intact aromatic ring structure [1,2]. One such product, 5-(hydroperoxymethyl)uracil (Hpm5 U) (Fig. 2), is the most stable thymine

O

H

N

H

O

H

-

HN O

+

-H

N

H

+ H+

H

H C O

N O

N

dR 5-Carboxyuracil (c5U)

O

C O

O C OH

HN

H

dR 5-(Hydroxymethyl)uracil (hm5U) ToxN MutN E.coli Mug,AlkA,Fpg,Nth, Nei;M.ther.Mig;hSmug1, hMbd4;mTdg;rSmug1

C H

N

(5 S,6S)-Cyclo-5,6-dihydrothymidine (cy6 dHdT) (Fig. 1) has so far not been detected in DNA following exposure to reactive oxygen species. However, cy6 dHdT can be formed from thymidine by such treatment and its potential biological effects on the DNA were recently investigated by synthetic incorporation at a specific site. The lesion causes decreased melting temperature of DNA suggesting induction of local destabilisation of the helix structure, and acts as a block to PolI Kf (exo− ) and Taq DNA polymerase function in vitro. cy6 dHdT does not seem to be repaired by the BER pathway (Table 2) [110].

C OH

HN

H N

O

O

H

43

N

H

dR

dR 5-Formyluracil (f5U) ToxN,D T to C>A,G;C to T,A E.coli AlkA,Mug,Fpg,Nth,Nei,MutS; M.ther.Mig;hSmug1,hNth1,hMbd4; mNth1,mTdg;rSmug1 Fig. 2. Thymines oxidised in the methyl group. Mutations induced by in situ lesions are shown in bold; by oxidised precursors in plain text. Tox, cytotoxic (N, non; D, delaying replication); Mut, mutagenic (N, non). hm5 U can also be formed from m5 C.

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S. Bjelland, E. Seeberg / Mutation Research 531 (2003) 37–80

hydroperoxide with a half-life of 1 week estimated for the deoxynucleoside [23,25]. Hpm5 U has recently been detected in ␥-irradiated calf thymus DNA (Cadet, personal communication), but its biological implications remain obscure. It decomposes to the more stable products 5-(hydroxymethyl)uracil (hm5 U) and 5-formyluracil (f 5 U) (Fig. 2). 5-(Hydroxymethyl)uracil has been detected in cellular DNA following exposure to ionising radiation [111,112] and growth in the presence of 5-(hydroxymethyl)-2 -deoxyuridine [113]. In addition, certain Bacillus subtilis bacteriophages (SPO1) have replaced thymine with hm5 U as a normal DNA constituent [114]—suggesting essentially normal coding properties of hm5 U. Thus, some studies using either E. coli [115] or mammalian cells [116] have failed to demonstrate hm5 U-induced mutagenicity. Other studies have demonstrated mutation induction by hm5 dU when supplied to exponentially growing cells [117–119]. The latter results have been supported by NMR studies suggesting that hm5 U can base pair with both adenine and guanine in DNA inducing T → C transitions. The hm5 U:A base pair is in Watson–Crick geometry and can be stabilised by an inter-residue hydrogen bond between the hydroxymethyl group and a neighbouring 5 guanine base, whereas the hm5 U:G mispair is a wobble base pair stabilised by an intra-residue hydrogen bond between the hydroxymethyl and the O4 carbonyl groups [120]. It has also been reported that—in addition to inducing mutations—the hm5 U deoxynucleoside causes significant toxicity to cells [121]. Such toxicity has been explained by extensive enzymatic removal of incorporated hm5 U residues from DNA, since a Chinese hamster fibroblast cell line resistant to the toxic effects of hm5 dU was shown to have normal incorporation of hm5 U into DNA but no detectable DNA glycosylase activity for its removal [122]. Perhaps some of the SOS-dependent mutagenicity of hm5 U detected in E. coli [118] can also be explained by excessive repair. Another mechanism causing cellular toxicity might be to interfere with protein binding to DNA. Substitution of thymine with hm5 U has been shown to inhibit binding of the Ap-1 (c-Jun) transcription factor to its specific binding site in vitro [123]. A DNA glycosylase for excision of hm5 U from DNA was first detected in mouse cells [124] and later purified from calf thymus [125]. This enzyme was recently identified as Smug1 [126,127]. In addition, human Mbd4

and mouse Tdg enzymes also exhibit activity towards hm5 U (Table 2) [128]. E. coli AlkA and Mug as well as M. thermoautotrophicum mismatch thymine DNA glycosylase (Mig) excise hm5 U from DNA, although at slow rates (Table 2) [128–130]. It should also be noted that hm5 U can be formed, although at a very slow rate, from 5-methylcytosine (m5 C) by oxidation and deamination, potentially giving rise to G:C → A:T transitions. Consistently, base removal of hm5 U opposite G was found to be 5–60 times faster than opposite A in human cell extracts as well as by the E. coli enzymes Fpg, Nth and Nei [131,132]. The other product generated from decomposition of Hpm5 U is 5-formyluracil (Fig. 2) [133], first identified in DNA by Kasai et al. [134]. DNA polymerisation across f 5 U in vitro with PolI Kf introduces guanine as well as adenine and f 5 dUTP can be incorporated across both adenines and guanines in DNA [135,136]. In another study it was found that mispairing was dependent on the nearest neighbour base pair located at the primer terminus. When this base pair was G:C the mispairing frequency of f 5 dUTP with template guanine was one order of magnitude higher than that of dTTP at pH 7.8 [137]. However, no increase in mutagenicity was detected when f 5 dUTP was employed in gap-filling reactions of the supF gene target using the E. coli DNA polymerase III holoenzyme in vitro, followed by transformation of wild type, alkA and mutM mutY strains [138]. Similarly important, Zhang et al. [139] reported that several DNA polymerases—both proficient and deficient in proofreading activity—will direct incorporation of dCMP in addition to dAMP opposite f 5 U in DNA. These in vitro results have been confirmed by in vivo studies of Fujikawa et al. [140], who found induction of G:C → A:T, A:T → G:C and G:C → T:A mutations in the lacI gene when f 5 dUTP was introduced in permeabilised E. coli. Similar results have been obtained with f 5 dU added to wild type and different DNA repair defective strains of E. coli scoring for rpoB (RifR ) mutations (Bjelland et al., unpublished results). When mutant frequencies at position 461 in the lacZ gene were measured, using six different mutagenesis tester strains of E. coli covering all possible base substitutions [141], f 5 dU resulted in higher than control values for all strains except the one reporting G:C → C:G transversions [142]. Experiments with Chinese hamster fibroblast cells indicate that f 5 dU is more mutagenic in mammalian

S. Bjelland, E. Seeberg / Mutation Research 531 (2003) 37–80

cells than in bacteria [116], and recently it was shown that f 5 U lesions in DNA cause induction of T → G and T → A transversions in mammalian cells [143]. In conclusion, in situ f 5 U or f 5 U incorporated into DNA from the nucleotide precursor pool seem to induce all kinds of base substitutions in DNA except G:C → C:G transversions (Fig. 2). Introduction of an electron-withdrawing formyl, bromo or fluoro group into uracil changes the electrodensity of the aromatic ring structure yielding more acidic N3 imino protons, with pKa values of approximately 8. The acidic N3 hydrogen of f 5 U results in two species of f 5 U existing in a keto–enol form of equilibrium (Fig. 2). Thus, similar to the halouracils, f 5 U is substantially ionised at physiological pH [144], and X-ray diffraction analyses of oligonucleotides with f 5 U site-specifically inserted opposite guanine have recently demonstrated an ionised reversed wobble base pair probably accepted by DNA polymerases (Fig. 3) [147], which should explain the molecular basis for the T → C and G → A transitions induced by f 5 U. The keto form of f 5 U is ex-

O H

O

O 5

-

H C

H

O

H N1 2

5

H

3N

6 1

N dR

4 2

f5U

9 3

H

1

2

N

O

Br5U

H N1 2

O

dR

dR

G

H N

H N

H

N7

6 3N

6

N

N

5 4

4

O

O 5

8

H

-

Br

H

N 7

6

8 9

3

4

N

N dR

45

pected to behave like thymine, forming two hydrogen bonds to adenine yielding a “regular” Watson–Crick base pair, as concluded from X-ray diffraction data obtained from crystals of a DNA dodecamer containing f 5 U at a specific position [148]. f 5 U is removed efficiently from DNA in vitro, both opposite adenine [129,149] and guanine [137], by the E. coli AlkA protein, implying that AlkA can be involved in mutation prevention as well as fixation. The E. coli Mug protein, preferentially acting at deaminated cytosines, excises f 5 U opposite G in DNA and this is also the case for M. thermoautotrophicum Mig [128]. In addition, E. coli Nth, Fpg and Nei as well as human Nth1 and Mbd4, and mouse Nth1 and Tdg, excise f 5 U from DNA, although rather inefficiently (Table 2) [128,150–152]. The primary enzyme for f 5 U removal from DNA in mammalian cells is the Smug1 glycosylase, which excises the lesion opposite all normal bases as well as from ssDNA (Table 2) ([152,153]; Knævelsrud et al., unpublished results). The mutation frequency scored using plasmid containing f 5 U was significantly increased in the E. coli nth nei mutM alkA mutant compared to wild type and alkA strains [150]. The f 5 U:G mismatch is recognised by E. coli MutS, suggesting that f 5 U can be repaired by MMR [137]. Experiments with PolI Kf in vitro have indicated that f 5 U is a quite weak blocking lesion [136], although, is reported to delay replication [154]. Oxidation of the formyl group of f 5 U yields 5-carboxyuracil (c5 U) (Fig. 2), which has not yet been identified in DNA following treatment with reactive oxygen species. However, synthetic c5 U has been stably incorporated into DNA [155]. The free base can be formed in vivo in the following catabolic pathway: thymine → hm5 U → f 5 U → c5 U, where all steps are catalysed by thymine hydroxylase [156]. c5 dU might arise from oxidative reactions in the cellular nucleotide precursor pool [155].

G

H

Fig. 3. Postulated non-cognate base pairing of f 5 U and 5-bromouracil with guanine. Conversion of f 5 U and a halouracil from keto to ionised (anionic) form increases with pH, while favoured keto and disfavoured enol tautomeric forms are present in pH-independent equilibrium (see Fig. 2). The ionised base pair between 5-bromouracil (and 5-fluorouracil) and guanine has been demonstrated by NMR measurements [145,146] and the base pair between f 5 U and guanine by X-ray analyses [147]. Cognate base pairing with adenine is due to the keto form (not shown).

3. Oxidised cytosines The 5,6-double bond of cytosine is the only primary target for oxidation of this base. As for thymine, free radical attack on the 5,6-double bond turns the planar aromatic ring structure into a non-aromatic non-planar structure, which may or may not ring-open, ringcontract or ring-fragment thus generating different types of products [1,2,157]. Contrary to most

46

S. Bjelland, E. Seeberg / Mutation Research 531 (2003) 37–80

or dehydrate to form 5-hydroxycytosine (h5 C). However, within DNA the half-life of Cg is enhanced more than 30-fold and thus Cg is likely to have significant biological implications [159]. Another important product, 5-hydroxyuracil (h5 U), can be formed from Ug by dehydration or from h5 C by deamination. It should be noted that dehydration restores the aromatic pyrimidine ring structure, and thus makes h5 C and h5 U rather more similar to natural bases in DNA (Fig. 4).

oxidised thymines, the instability of some of the cytosine derivatives due to deamination and/or dehydration has probably delayed identification of putative DNA oxidation products significantly. 5,6-Dihydroxy5,6-dihydrocytosine (cytosine glycol (Cg)) (Fig. 4) is reported to be formed in DNA exposed to the oxidising agent OsO4 [158]. Cg is unstable in aqueous solution and will deaminate readily to form 5,6-dihydroxy-5,6-dihydrouracil (uracil glycol (Ug))

NH2 N O

NH 2 OH - H 2O N H OH H O N

N

dR Cytosine glycol (Cg) - NH3

O HN O

N

OH H OH H

HN O

N

dR trans-Uracil glycol (tUg) E.coli Nth

H

dR 5-Hydroxycytosine (h5C) ToxD C to T,G;T to C E.coli Nth,Nei, Fpg,Mug;S.cer. Ntg1,Ntg2;S.po. Nth;hNth1,hNeil1, hNeil2

H - NH 3 HN H OH O N H

N O

N

O NH2 N N

H OH H H

- H 2O OH H H OH

OH

HN O

HN

- NH3

O

N

H OH H H

dR

5-Hydroxy5,6-dihydrocytosine

O

H H OH H

dR 6-Hydroxy5,6-dihydrouracil (Uh6) E.coli Nth

dR 6-Hydroxy5,6-dihydrocytosine (Ch6) E.coli Nth

O

- NH 3

dR cis-Uracil glycol (cUg) E.coli Nth O

O

NH2 OH

dR 5-Hydroxy5,6-dihydrouracil (Uh5) E.coli Nth,Nei; S.cer.Ntg1,Ntg2

N

H NH2 O dR H H 5-Hydroxy- NH 3 HN N H H 5 uracil (h U) H H ToxD O H N O N H C to T,G,A dR dR E.coli Nth,Nei,Fpg, Ung,Mug,Nfo;S.cer. 5,6-Dihydro5,6-DihydroNtg1,Ntg2;S.po.Nth; cytosine (dHC) uracil (dHU) hNth1,hNeil1,hNeil2, ToxN hUng,hSmug1;mNth1, C to T,A mNeil1;rSmug1 E.coli Nth,Nei,Nfo; Panth;S.cer.Ntg1, Ntg2,Apn1;S.po. Nth,Uve1;hNth1, hNeil1,hNeil2

Fig. 4. Oxidised cytosines. Mutations induced by in situ lesions are shown in bold; by oxidised precursors in plain text. Tox, cytotoxic (N, non; D, delaying replication; B, blocking replication).

S. Bjelland, E. Seeberg / Mutation Research 531 (2003) 37–80

NH2

NH2 O

N O

N

O O

OH

N

H OH

O

47

HN

- NH 3 N

OH

OH

O

N

O

OH

dR

O OH H N

O

dR

NH 2

O

O

dR 5-Chlorocytosine (Cl5C)

O

Br N

N

H

H H

H

O3PO

N O N

OH H H OH

dR trans-1-Carbamoyl2-oxo-4,5-dihydroxyimidazolidine (cmiz) E.coli Nth

NH N

C

O

O

OPO3

-

(5´S,6S)-Cyclo-5,6-dihydro2´-deoxyuridine (cy6dHdU) ToxB

NH N

C

C

O

H -

O

H

H H

H

dR 5-Bromouracil (Br5U) T to C;C to T E.coli Mug; M.ther.Mig

N

dR 5-Hydroxyhydantoin (hh) E.coli Nth

H dR 5-ChloroO3PO uracil (Cl5U) E.coli Mug; O M.ther.Mig HO

O HN

O

O

Cl

HN

H

NH 2

OH

O

Cl N

N

HN

dR Alloxan (alx) E.coli Nth;hUng

Dialuric acid

N

O

HN

O

Isodialuric acid

O

O

O

H OH

N dR

dR 5,6-Dihydroxyuracil (dhU) ToxN E.coli Nth,Nei, Ung;hUng

dR 5,6-Dihydroxycytosine (dhC) E.coli Nth,Nei; S.po.Nth;hNth1

4-Amino-6-hydroxy2,5(1H,6H)pyrimidinedione

HN

O

HN

O

O

OPO3

-

(5´S,5S,6S)-5´,6-Cyclo-5-hydroxy5,6-dihydro-2´-deoxyuridine (cy 6h5dHdU) ToxB

Fig. 4. (Continued ).

Uracil glycol (Fig. 4) is a major DNA damage product induced by different oxidants and has been shown to be present at significant steady-state levels in different mammalian tissues [160]. It was first detected in ␥-irradiated DNA by Téoule et al. [161]. Ug is bypassed more efficiently than Tg in all sequence contexts examined using PolI Kf (exo− ) on three different DNA templates in vitro. Only dAMP was incorporated

opposite both lesions [61], which explains the modest mutagenicity of Tg compared to Ug; since the latter would be formed from cytosine and will be highly mutagenic in E. coli resulting in C → T transitions [162]. Ug deoxynucleoside triphosphate is a better substrate for PolI Kf (exo− ) in vitro than the corresponding Tg triphosphate regarding both insertion opposite adenine (10-fold) as well as during the following extension

48

S. Bjelland, E. Seeberg / Mutation Research 531 (2003) 37–80

reaction (100-fold) [163]. Thus, it is not surprising that efficient repair systems have evolved for this particular lesion and Ug can be removed from DNA by three different E. coli DNA glycosylases—Nth (both cUg and tUg; Fig. 4), Nei and Fpg—with quite similar efficiencies [61,164,165] (Table 3). It has also been found to be excised by S. cerevisiae Ntg1 and Ntg2 [66]. 5-Hydroxycytosine (Fig. 4) is induced in DNA to a similar extent as Ug, and their steady-state level in mammalian tissues are comparable [160]. Incubation of mouse L1210 cells with the h5 C deoxynucleoside led to the incorporation of h5 C to a level 20 times higher (43 lesions/105 cytosines) than base-line oxidation levels, without causing detectable toxicity [166]. In vitro incorporation studies with PolI Kf (exo− ) have shown that h5 dCTP can replace dCTP, but also, although to a much lesser extent, dTTP, suggesting induction of T → C transitions in vivo. TLS past h5 C in DNA by PolI Kf (exo− ) showed that dGMP was the predominant nucleotide incorporated followed by dAMP in one sequence context, whereas dCMP was preferred in another sequence context. TLS was efficient, although pause sites were observed both opposite and one nucleotide ahead of h5 C. The 5-hydroxypyrimidine dNTPs, including h5 dCTP, were more efficiently incorporated, both erroneously and non-erroneously, into DNA by PolI Kf (exo− ) than the 8-oxopurine dNTPs [167,168]. These in vitro results have been confirmed in wild type E. coli in vivo, where h5 C inserted into viral M13 DNA primarily introduced C → T transitions and to a much lesser extent C → G transversions [162,169]. Interestingly, recent in vitro results with the error prone human polymerase ␫ have shown that the enzyme efficiently inserts cognate guanine opposite h5 C in DNA where the extension reaction is unaffected, indicating an in vivo role of this polymerase in alleviating mutation induction by h5 C; thymine was inserted 10 times less frequently [170]. Recently, the presence of h5 C in DNA was shown to increase cleavage by eukaryotic DNA topoisomerase I when incorporated at the +1 position relative to the topoisomerase cleavage site [171]. The lesion has been shown to be excised from DNA by E. coli Nth (inefficiently when annealed to RNA [172]), Fpg, Nei and Mug [60,130,165,173,174], S. cerevisiae Ntg1 and Ntg2 [64,65], S. pombe Nth [69] and human Nth1, Neil1 and Neil2 enzymes [54,70,73,75,175]. It is interesting to note that hNth1

excises h5 C more efficiently when placed opposite G than A, which should prevent mutation fixation (Table 3) [176]. An observed inability of human XPA cells to repair h5 C raises the question whether the XpA protein is involved in damage recognition of this lesion [177]. 5-Hydroxyuracil (Fig. 4) is induced in DNA to a similar extent as Ug or h5 C, but its steady-state level in different mammalian tissues was found to be considerably lower than for the former lesions [160] apart from in ancient DNA, where only h5 U was detected among these three lesions [88]. In vitro incorporation studies with PolI Kf (exo− ) have shown that h5 dUTP is only inserted opposite adenine in DNA, indicating that it is non-mutagenic. Translesion bypass experiments with PolI Kf (exo− ) showed that dAMP was the predominant nucleotide incorporated opposite h5 U in one sequence context, whereas dCMP was preferred in a second sequence context, suggesting induction of both C → T transitions and C → G transversions. TLS was efficient, although pause sites were detected both opposite and one nucleotide ahead of h5 U [167]. These in vitro translesion bypass results have been partially confirmed in wild type E. coli, where h5 U inserted into viral M13 DNA exhibited high mutagenicity but caused only C → T transitions [162]. In vitro results with human polymerase ␫ showed that the enzyme inserts non-cognate thymine with a five times higher and non-cognate cytosine with a five times lower frequency than cognate guanine opposite h5 U in DNA, followed by efficient extension reactions, indicating an in vivo role in promoting C → A transversions (Table 1) [170]. h5 U is excised from DNA (Table 3) by E. coli Nth, Fpg, Nei, Ung (uracil DNA glycosylase; also by the human enzyme, see under 5,6-dihydroxyuracil (dhU) below) and Mug [130,165,173,174], S. cerevisiae Ntg1 and Ntg2 [64], S. pombe Nth [69], human and mouse Nth1 [70,71], mammalian Nei-like enzymes (Neil1/Neh1 and Neil2) [54,73–75,178] and human and rat Smug1 [152,153]. The E. coli Nfo enzyme has been shown to incise dsDNA adjacent to h5 U, by the newly discovered nucleotide incision repair pathway (Table 3, see below) [63]. Although not yet detected in natural DNA, a potential oxidation product formed by deamination and free radical attack on cytosine, 5,6-dihydrocytosine (dHC) (Fig. 4), has recently been introduced in DNA

S. Bjelland, E. Seeberg / Mutation Research 531 (2003) 37–80

49

Table 3 Proteins involved in the repair of oxidised cytosines in DNA

E. coli Nth Nei Fpg Ung Mug

Ug

dHU

Uh5

Ch6

Uh6

h5 C

h5 U

dhC

dhU

+GA +GA +GA −ssds

+GA +GA

+G +G

+G

+G

+GA +G>A +GA

+G>ATC +G>A +G>A +GA +G

+G +G

+G +G

Xth Nfo

+G +G

Mammalian hNth1 mNth1 hNeil1 mNeil1 hNeil2 hOgg1 hSmug1 rSmug1 hUng hApex1

−G +G

+G>A +GA +

+G +G

−G

±G +G

+G +G

+G +G>A

+G

+G

+G

+GA

+G>A

+G

+GCA>T

+G

+GA

+G −G −GAss

+G +GCAT +AT>G +CTGAss +G>T>A

alx

hh

cmiz

cy6 h5 dHdU

cy6 dHdU

+G

+G

+G

−G −G −G

−G −G −G

−G

M. thermoautotrophicum Mig S. cerevisiae Ntg1 Ntg2 Ogg1 Mammalian hUng

+G

+G

S. pombe Nth Uve1

E. coli Nth Nei Fpg Ung Mug AlkA

+G

+G

P. aerophilum Panth S. cerevisiae Ntg1 Ntg2 Apn1

−G

f5 C

−G −G −G +G

The opposite base(s) is(are) indicated in superscript(s): ds, dsDNA; ss, ssDNA.

+GAss +Gss +G −G

Cl5 U

Br 5 U

−G +G

−G +G

+G

+G

−GAss +G −G

50

S. Bjelland, E. Seeberg / Mutation Research 531 (2003) 37–80

by chemical synthesis [130]. In contrast to dHC, 5,6-dihydrouracil(dHU) (Fig. 4) is a stable cytosine counterpart of dHT, formed in DNA by ionising radiation under anoxic conditions [79]. When dHU was incorporated into DNA opposite guanine, NMR analysis indicated an intrahelical dHU:G wobble base pair causing minimal DNA distortion [179], which explains why the lesion seems to be non-blocking and non-lethal. DNA polymerases like PolI Kf (exo− ) and SP6 and T7 RNA polymerase efficiently insert adenine opposite dHU in vitro indicating that dHU causes C → T transitions in vivo both at the level of replication and transcription [180,181]. In vitro, human polymerase ␫ inserts non-cognate thymine half as frequently and adenine and cytosine one order of magnitude less frequently than cognate guanine opposite dHU in DNA, where efficient elongation was observed in all cases [170]. Thus, this enzyme will promote C → A transversions at the site of dHU in vivo. Experiments with ␥-irradiated DNA could not conclusively establish whether E. coli Nth enzyme excises dHU, because dHU may arise by rapid deamination of dHC following its removal from DNA [79]. However, experiments with DNA containing a dHU residue at a defined position demonstrated efficient excision of dHU (Table 3) by several DNA glycosylases including E. coli Nth and Nei, P. aerophilum Nth (Panth), S. pombe Nth and human Nth1, Neil1 and Neil2 proteins, where S. pombe Nth and human Nth1 are stimulated by human XpG protein [18,54,58,73,75,178,182–184]. Both S. cerevisiae Ntg1 and Ntg2 glycosylases remove dHU from DNA [183,185], and the broad-spectrum UV DNA endonuclease (Uve1) of S. pombe incises DNA 5 to the lesion [186]. dHU present in DNA as tandem lesions poses certain limitations for enzymatic damage removal. Thus, both E. coli Nth and S. cerevisiae Ntg1 are able to remove only one dHU in DNA containing tandem lesions, leaving behind a single dHU at either the 3 - or 5 -terminus of the cleaved fragment. S. cerevisiae Ntg2 can remove dHU remaining on the 5 -terminus of the 3 cleaved fragment, but is unable to remove dHU remaining on the 3 -terminus of the cleaved 5 fragment. In contrast, both hNth1 and E. coli Nei can remove dHU remaining on the 3 -terminus of a cleaved 5 fragment, but are unable to remove dHU remaining on the 5 -terminus of a cleaved 3 fragment [183]. Recently, a novel mode of repair termed the nucleotide incision repair pathway

was characterised using E. coli enzymes and dsDNA oligomers containing a single dHU residue inserted at a specific position. In this pathway, repair was initiated by the Nfo endonuclease, which hydrolysed the phosphodiester bond 5 to the lesion leaving a 3 OH group. DNA polymerase I could efficiently eliminate the 5 -terminal dHU residue from the nicked duplex as a mononucleotide (Table 3) [63]. Apn1 was identified as the nucleotide incision enzyme in S. cerevisiae and it was also found that human proliferating cell nuclear antigen (Pcna) stimulated flap endonuclease (Fen1) to remove the 5 -terminal dHU residue. The cytosine counterparts to the thymine hydrates are less stable than Th5 and Th6 due to deamination to uracil analogues. 6-Hydroxy-5,6-dihydrocytosine (Ch6 ) (Fig. 4) is stable at 4 ◦ C but decays at 25, 37 and 55 ◦ C with half-lives of 75, 25 and 6 h, respectively, when present in poly(dG-dC) [187]. Its deamination product 6-hydroxy-5,6-dihydrouracil (Uh6 ) (Fig. 4) is stable at 4 and 25 ◦ C and decays at 37 and 55 ◦ C with half-lives of 6 and 0.5 h, respectively, when present in poly(dA-dU) [187]. Ch6 and Uh6 are excised from DNA by E. coli Nth (Table 3) [188]; Ch6 from poly(dG-dC) in both the B and Z conformation [189]. 5-Hydroxy-5,6-dihydrouracil (Uh5 ) (Fig. 4) is a less studied product, however, has been reported to be excised from DNA by E. coli Nth and Nei and S. cerevisiae Ntg1 and Ntg2 proteins (Table 3) [64,81,190]. 5,6-Dihydroxycytosine (dhC) has been detected as a major product in oxidised DNA [191] and chromatin [192], and may also exist in its more unstable keto form (Fig. 4). It is excised from DNA by E. coli Nth and Nei, S. pombe Nth as well as hNth1 enzymes (Table 3) [69,70,81,190]. The deamination product of dhC, 5,6-dihydroxyuracil (Fig. 4), is also abundant in oxidised DNA, and it has been discussed whether it is dhU itself or its keto form (isodialuric acid) that is the species present and thus, like h5 U, excised from DNA by E. coli [173,193] and human Ung enzymes [194] (Table 3). dhU is a substrate for E. coli Nth and Nei proteins (Table 3) [81,190]. Alloxan (alx) (Fig. 4) is excised from oxidised DNA by E. coli Nth and human Ung enzymes (Table 3) [190,194]. The cytosine counterpart to the ring-contracted hmh of thymine is 5-hydroxyhydantoin (hh) (Fig. 4). Similar to hmh, the stability of hh in DNA has been demonstrated by its presence in different ancient samples including a ≥50,000-year-old Siberian mammoth, where the

S. Bjelland, E. Seeberg / Mutation Research 531 (2003) 37–80

ability to retrieve DNA sequences by PCR from such sources was inversely correlated with hh as well as hmh content [88]. The hh lesion is a substrate of E. coli Nth (Table 3) [164]. Another five-ring product is trans-1-carbamoyl-2-oxo-4,5-dihydroxyimidazolidine (cmiz) (Fig. 4), also excised from DNA by Nth (Table 3) [164]. 5-Chlorocytosine (Cl5 C) (Fig. 4) was detected in salmon sperm DNA 30 years ago [195], although the source or mechanism of its formation was not understood. However, it was recently shown to be generated in DNA in vitro by the myeloperoxidase-H2 O2 -Cl− system [11]. It is expected that Cl5 C will deaminate to 5-chlorouracil (Cl5 U) (Fig. 4), which has been detected in acid-hydrolysed DNA following exposure to HOCl at neutral pH [10]. Free Cl5 U exhibits low toxicity in spite of the fact that it is being incorporated readily into mouse liver DNA (1 in 250 nucleotides; 1% of that into mouse testes DNA) [196]. Nearly 50 years ago, Cl5 U or the corresponding deoxynucleoside was found to be incorporated into bacterial or bacteriophage DNA causing reduced cell viability and mutations [197–199], and it was later shown to induce mutations and inhibit growth in human cells [200]. Incorporation of Cl5 dU into DNA causes growth delay of mammalian cells in transit through S-phase and arrest in G2- and M-phases, indicating damage formation during the former and its subsequent repair in G2 [201]. Cl5 dU is 5–8 times more potent as an inducer of sister-chromatid exchanges (SCE) in Chinese hamster ovary cells [196,202]. When both rabbits and mice were exposed to either Cl5 dU or Br5 dU, the SCE frequencies in bone marrow cells were much higher in the different physicochemical properties and physiological distribution of Cl5 dU Cl5 dU-exposed animals [203]. The latter observations must be explained by and Br5 dU since they are both incorporated into DNA at a similar rate [201]. The mutagenic properties of these two compounds are also roughly similar [198]; exposure to Cl5 dU seems to induce fewer mutations than exposure to Br5 dU in Chinese hamster ovary cells [204], but replication past Cl5 U in DNA induces more mutations than replication past 5-bromouracil (Br5 U) [202]. It has been indicated that Cl5 U is inefficiently removed following incorporation into the DNA of Chinese hamster V79 cells [205]. However, Cl5 U can be excised from DNA by E. coli Mug and M. thermoautotrophicum Mig glycosylases (Table 3)

51

[206]. Recently, 5-bromouracil (Fig. 4), which was shown to function as a thymine analogue already 50 years ago [207], could be added to the list of cytosine base lesions. It seems to be produced in DNA in vivo by oxidants generated by eosinophils, a certain type of human phagocytes [12]. Eosinophil peroxidase released from such cells produces hypobromous acid (HOBr) from Br− and H2 O2 , which in turn halogenates 2 -deoxycytidine. The resultant Br5 dC is taken up by cells, deaminated by cytidine deaminase (or, e.g. Br5 dCMP by dCMP deaminase), and ultimately converted to Br5 dUTP, which acts as substrate for DNA polymerase to incorporate Br 5 U into cellular DNA. Br5 U/Br 5 dU can also be formed from uracil/dU by the eosinophil peroxidase-H2 O2 –Br− and myeloperoxidase–H2 O2 –Cl− –Br− systems [208,209]. In the context of base pairing, Br 5 U is chemically similar to f 5 U (Fig. 3) [144], with ability to mispair with dGTP causing A:T → G:C transitions, and as Br 5 dUTP with guanine in template causing G:C → A:T transitions [210–212]. However, NMR experiments suggest that the ionised base pair of Br 5 U and guanine is different from the f 5 U:G mispair (Fig. 3) [145,146,213]. It was also found that incorporated dGMP opposite Br 5 U in DNA is subjected to little if any correction by the 3 -exonuclease activity of T4 polymerase [211]. The mutagenicity of Br5 U/Br 5 dU in prokaryotic systems was reported 45 years ago and in mammalian cells 15 years later [198,214] (also see under Cl5 U above). Since then, Br5 dU has been much employed as a reagent for mutation induction [215]. The extensive incorporation of Br5 U that occurs [216] indicates that it is inefficiently repaired. However, it is rather easily dehalogenated to uracil, which is excised by uracil DNA glycosylase. Recently, Br 5 U was shown to be removed from DNA by E. coli Mug and M. thermoautotrophicum Mig enzymes (Table 3) [206]. (5 S,6S)-Cyclo-5,6-dihydro-2 -deoxyuridine (cy6 dHdU) (Fig. 4) has so far not been detected in DNA by treatment with oxidising agents. However, cy6 dHdU can be formed from deoxyuridine by such treatment. It has also been incorporated synthetically into DNA at a specific site and reduces the melting temperature of dsDNA suggesting induction of local destabilisation of the DNA helix [110]. It also acts as a block to PolI Kf (exo− ) and Taq DNA polymerase in vitro. Essentially the same applies to

52

S. Bjelland, E. Seeberg / Mutation Research 531 (2003) 37–80

the (5 S,5S,6S)-5 ,6-cyclo-5-hydroxy-5,6-dihydro-2 deoxyuridine (cy6 h5 dHdU) lesion and such lesions do not seem to be repaired by the BER pathway (Table 3) [110,217].

NH 2

4. Oxidised 5-methylcytosines 5-Methylcytosine is a minor (e.g. 5% of the cytosines in human DNA is methylated [218–220]) but significant component in eukaryotic DNA residing in CpG sequences throughout the genome [221]. Because enzymatic DNA methylation is considered to play an important role in gene regulation including silencing of genes, interference with m5 C integrity may result in deregulation of genes in addition to mutagenicity and cytotoxicity. The latency of several pathogenic viruses, e.g. Epstein–Barr, herpes simplex and HIV, is maintained by cytosine methylation while oxidising conditions and UV light have been shown to induce viral reactivation [222–227]. Although m5 C is a cytosine analogue and deaminates like cytosine, it is similar to thymine by exhibiting two targets of oxidative attack; the 5,6-double bond and the 5-methyl group. Thus, in the context of oxidation m5 C is a “mixture” of cytosine and thymine. For several years it has been known that the genomic CpG sequences are hot spots for mutation induction, which has primarily been ascribed to m5 C deamination to thymine which is 3–4 times faster than cytosine deamination to uracil [228,229]. One mechanism for m5 C deamination has been proposed that involves the formation of a very unstable m5 C 6-hydrate caused by oxidative attack on the 5,6-double bond. The putative m5 C 6-hydrate deaminates to Th6 (Fig. 1) followed by dehydration to thymine. Evidence for this mechanism was provided by the detection of both cTh6 and tTh6 released by E. coli Nth from UV-irradiated poly(dG-[3 H]m5 dC)·poly(dG-[3 H]m5 dC); the t1/2 of the thymine hydrates was determined to be 33.3 h at 37 ◦ C [83,230]. When poly(dG-[3 H]m5 dC)·poly(dG[3 H]m5 dC) was exposed to H2 O2 /FeCl3 /ascorbic acid or ␥-radiation, almost all Nth-excised radioactive material consisted of Tg [231]. In conclusion, because of an extremely fast hydrolytic deamination reaction, the only relatively stable lesions that are generated in DNA by oxidative attack on the m5 C 5,6-double bond are thymine products, comprising Tg, cTh6 and tTh6 (Fig. 1).

C OH

N O

NH 2

H

N

H

dR 5-(Hydroxymethyl)cytosine (hm5C) ToxN MutN

C O

N

H O

H

N

H

dR 5-Formylcytosine (f5C) C to T,A

Fig. 5. Oxidised base residues formed from m5 C only. Mutations induced by in situ lesions are shown in bold. Tox, cytotoxic (N, non); Mut, mutagenic (N, non).

Two oxidative lesions specific for m5 C are caused by attack on the 5-methyl group. The 5-(hydroxymethyl)cytosine (hm5 C) lesion (Fig. 5) has been detected in different preparations of native DNA [232,233]. In addition, it has been shown to be present in 1% yield in poly(dG-[3 H]m5 dC) [231], probably formed from 5-[methyl-3 H]methylcytosine by transmutation of 3 H to 3 He (␤-decay) as previously shown for the generation of hm5 U from thymine in [methyl-3 H]thymine-labelled DNA [111]. Little is known about the biological consequences of hm5 C in DNA, but a mammalian DNA glycosylase activity removing this product has been reported [234]. It has been argued that conversion of the hydrophobic methyl to the hydrophilic hydroxymethyl group may interfere with the binding of transcription factors to DNA thus causing changes of gene expression. It may also interfere with the conservation of the methylation pattern during replication. It has been estimated that ∼20 m5 C residues are oxidised to hm5 C per human cell per day [235]. However, the T-even bacteriophages of E. coli have cytosine replaced with hm5 C [236]—arguing against hm5 C being cytotoxic or mutagenic. Further oxidation of the 5-hydroxymethyl group of hm5 C yields 5-formylcytosine (f5 C) (Fig. 5), which was recently shown to be induced in dsDNA by Fenton-type reactions and ␥-irradiation [237]. Double-stranded oligonucleotides with f5 C inserted at a certain position and paired with A, C or T exhibit reduced thermal stability [238]. Further, mispairing with A and T was observed using PolI Kf to incorporate a single nucleotide opposite f5 C in DNA indicating the possible induction of G:C → A:T and G:C → T:A base substitutions.

S. Bjelland, E. Seeberg / Mutation Research 531 (2003) 37–80

5. Oxidised guanines Of the four nucleobases, guanine has the lowest oxidation potential and is thus generally most easily oxidised [239]. This is illustrated by the specific oxidation of guanine (to oxo8 G, see below) through long-range electron transfer induced by photoexitation of DNA intercalators, as e.g. a rhodium complex intercalator; photoreaction at the 5 -GGG-3 triplet is particularly intense followed by the 5 -GG-3 doublet [240]. Presently, about 15 oxidised forms of guanine have been shown to be generated in DNA. 8-Oxoguanine (Fig. 6) was first reported to be formed in DNA by treatment with ascorbic acid [241] and later by a variety of other oxidative treatments [23,24]. Since its discovery, it has been the most extensively studied oxidative base damage, and the stability of the lesion is indicated by the fact that it is present in significant amounts in ancient DNA [88]. Although delays in the DNA synthesis caused by oxo8 G in the template have been demonstrated in vitro with limiting concentrations of DNA polymerase [242], oxo8 G has not been shown to cause lethality or to be any significant block to DNA polymerisation in vivo [243–245]. Early in vitro primer extension results with PolI Kf have indicated that oxo8 G can base pair with all four normal bases in DNA in addition to promoting misinsertions at adjacent pyrimidines [246]. Subsequently, detailed in vitro studies have revealed that replicative and repair DNA polymerases exhibit different degrees of dAMP and dCMP incorporation opposite oxo8 G in DNA. The replicative E. coli polymerase III and mammalian polymerases ␣ and ␦ preferentially insert dAMP, whereas PolI of E. coli and mammalian polymerase ␤ insert dCMP more often than dAMP (Table 1) [242,247]. Other experiments with polymerase ␦ showed preference for incorporation of dCMP opposite oxo8 G (14% misincorporation of dAMP) although extension past A:oxo8 G predominated with Pcna as an important cofactor [248]. Nevertheless, because of poor extension, polymerase ␦ replicates rather poorly through oxo8 G. However, it was recently demonstrated that efficient TLS past oxo8 G can be obtained with a combined polymerisation with polymerase ␦ followed by extension with polymerase ␨ [249]. The latter polymerase is very inefficient at inserting nucleotides opposite oxo8 G. Human polymerase ␬ has been demonstrated

53

to efficiently insert both dAMP and dCMP opposite oxo8 G [250] with efficient extension only from the A:oxo8 G mispair [251]. The human polymerase ␫ inserts cognate cytosine most frequently followed by G and A opposite oxo8 G in DNA in vitro, in a sequence context dependent manner [170,252]. In one study it was reported that the S. cerevisiae and human polymerase ␩ efficiently bypassed oxo8 G by incorporating C and A with similar frequencies followed by G (Table 1) [253,254], whereas in another report it was found that C was incorporated much more efficiently than other bases [255]. The S. cerevisiae G template specific polymerase Rev1 inserts C very inefficiently opposite oxo8 G in DNA in vitro [256]. In contrast to all polymerases mentioned above, human polymerase ␮ efficiently bypasses oxo8 G by producing a −1 deletion, although some incorporation of A opposite oxo8 G also occurs [257]. In vivo experiments with E. coli show that oxo8 G primarily or uniquely induces G → T transversions at a frequency of 0.5–1% at the site of the lesion, consistent with mispairing with adenine [243–245]. Similar mutational responses have been obtained with mammalian systems. Replication of a double-stranded shuttle vector containing a single oxo8 G residue in HeLa cells induced targeted G → T transversions at a frequency of 1–2% [258]. When the lesion was replicated in a single-stranded shuttle vector introduced into simian COS cells the mutation frequency increased to 2.5–5% [259,260]. The oxo8 G has also been found to induce G → A transitions as well as random substitutions at the 5 flanking base in addition to the G → T transversions, when present in the c-Ha-ras gene transfected into NIH3T3 cells [261,262]. oxo8 dGTP can be used by viral, bacterial and mammalian polymerases to incorporate oxo8 dGMP into DNA—both opposite cognate cytosine and non-cognate adenine—inducing A → C transversions [168,245,263]. In vitro replication of M13mp2 vectors with SV40 origin by human HeLa cell extracts in the presence of oxo8 dGTP demonstrated a similar error rate on the leading and lagging strand, where inhibition of exonucleolytic proofreading suggested that most oxo8 G:A mispairs are proofread on both strands [264]. The oxo8 G exists in equilibrium between the keto and enol forms (Fig. 6), where the 6,8-diketo tautomer predominates in dsDNA in solution. When paired with cytosine, oxo8 G adopts the normal anti conformation about the

54

S. Bjelland, E. Seeberg / Mutation Research 531 (2003) 37–80

O HN O

HO

O

dR Cyanuric acid (cya) ToxN G to T>C,A hMpg

HN NH

O NH

N O

H

N

O

N

5-Iminoimidazolidine-2,4-dione

O

O

NH

NH

dR

HN

O

N

HN

O dR Spiroiminodihydantoin (sdh) ToxB G to T>C,A E.coli Fpg,Nei,Nth

2,4,6-Trioxo-[1,3,5]-triazinane1-carboxamidine

O

NH

OH H2N

N

N

HN

O N

C

N

NH

dR

H2N

N

O

O

C

H 2N

HN

H

C dR O O Oxaluric acid (oxa) ToxN,B G to T>C,A E.coli Fpg,Nth

NH N

O C

N

N dR

dR 7,8-Dihydro-8-oxoguanine (oxo8G) ToxN G to T>A;A to C E.coli Fpg,Nei,MutY,UvrABC;L.lac.Fpg;D.rad.Fpg; T.ther.Fpg;M.ther.Nth,Nfo;Mjogg;Afogg;S.cer.Ogg1, Ntg1,Msh2/6;S.po.Myh;Atfpg1,Atogg1;D.mel.Ogg1, RpS3;hOgg1,hNeil1,hNeil2,hMpg,hMyh,hMMR,hNER, Wrn/Ku;mOgg1,mNeil1,mMyh,mMMR;rOgg1

O N H2N

OH NH O

N

N

dR 5-Hydroxy-8-oxoguanine - CO2 + H2O

N

O

H2N HN

N dR

Iminoallantoin

O

+ H+

C

- H+

NH2

O NH H2N

C

NH O

N

N

H dR Guanidinohydantoin (gh) ToxB G to T>C E.coli Fpg,Nei,Nth

Fig. 6. The oxo8 G and its oxidation products. Mutations induced by in situ lesions are shown in bold; by oxidised precursors in plain text. Tox, cytotoxic (N, non; B, blocking replication).

S. Bjelland, E. Seeberg / Mutation Research 531 (2003) 37–80

H H H H

N7

8

N

N H

O

6 4

1N

3

H

2

dR N A (anti )

N H

3N

5

4

N7

9N

H O 5

5

H

1

N

N 7

6

4 3N

6

8

dR O oxo8G (syn )

H

H H

2

6

5

9

N H

N1

2

dR O C (anti )

O 8 9

H N1

N N dR H N oxo8G (anti ) 2

3

4

H

Fig. 7. Base pairing properties of oxo8 G residues in DNA.

N-glycosylic bond forming a stable Watson–Crick base pair with three hydrogen bonds. When paired with adenine, oxo8 G adopts the syn conformation about the N-glycosylic bond forming a stable Hoogsteen mispair containing two hydrogen bonds (Fig. 7; for a review see [265]), which establishes the structural basis for oxo8 G mutagenicity. However, in addition to the G → T and A → C transversions induced by in situ oxo8 G and oxo8 dGTP, respectively, reports as cited above have described other base substitutions

55

such as G → A transitions [261,262]. This could suggest that oxo8 G might mispair with other bases than adenine, such as thymine, depending on both sequence context and cell type, and further work is needed to substantiate these notions. The presence of oxo8 G in DNA has been shown to increase DNA breakage induced by eukaryotic DNA topoisomerase I, dependent on its position relative to the topoisomerase I cleavage site [171], but not by topoisomerase II [266]. In view of the high abundance and mutagenic effects of oxo8 G, it is not surprising that elaborate systems have evolved to remove it from and counteract its introduction into DNA. Although oxo8 G has been shown to be acted upon by the UvrABC endonuclease of E. coli [267], there is no doubt that the three components MutT, MutM and MutY, termed the GO system, are the major factors involved in protecting the cells against mutagenic effects of this lesion [3,268]. MutT prevents incorporation of oxo8 G from the nucleotide pool by hydrolysing any oxo8 dGTP to oxo8 dGMP thus suppressing A → C transversions (Scheme 1) [269]. Another protein in E. coli, Orf135, has also been shown to exhibit MutT-like activity (Scheme 1) [270]. MutT might also be involved in preventing oxo8 G incorporation into RNA, since it hydrolyses oxo8 GTP as well as oxo8 dGTP [271]. Fpg (MutM) removes oxo8 G from oxo8 G:C base pairs, and only to a very limited extent from an oxo8 G:A base pair (Table 4) [272–277]. This discrimination is necessary to prevent mutation fixation. Fpg-mediated

Scheme 1. Substrate specificity of nucleotide pool sanitisation enzymes for oxidised base precursors capable of being incorporated into DNA or RNA. Substrates are shown in bold; species demonstrated to not being hydrolysed are shown in plain text.

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S. Bjelland, E. Seeberg / Mutation Research 531 (2003) 37–80

Table 4 Proteins involved in the repair of oxidised guanines in DNA oxo8 G E. coli Nth Nei Fpg MutY UvrABC

−C +GAC +CT>G>A −ss −AG A+ G+ T− C− +C

L. lactis Fpg

+TGC>A

D. radiodurans Fpg +C

fapyG

+C>A A+

oxz

cya

oxa

cy8R dG

cy8S dG

niz

sdh

gh

+GCAT

−C

+GCAT

−C

−C

−C

+GCAT

−C

+GCAT

−C

−C

+C

+G>AC +G>AC +(C>G)T>A A− G −

+G>AC +G>A>C +(C>G)T>A A+ G−

+C

T. thermoautotrophicum Fpg +C P. aerophilum Panth −TGCA M. jannaschii Mjogg +CT>AG M. thermoautotrophicum Nth +GCAT Nfo +GCAT A. fulgidus Afogg

+CGTA

S. cerevisiae Ntg1 Ntg2 Ogg1 Msh2/6

±G>CAT −GCAT +Cm5C>TU −AG + C A+

S. pombe Myh

A + C−

A. thaliana Atfpg1 Atogg1

+G>C>A −Tss +

D. melanogaster dOgg1 +C>T>GA RpS3 +C −GAT Mammalian hOgg1 mOgg1 rOgg1 hNeil1 mNeil1 hNeil2 hNeil3 hMpg hMyh mMyh rSmug1 MMR hNER Wrn/Ku

+C>T>GA +C +C>T>GA +CG>T>A a +ACGTss +CA +C A + G+ A + G+ −C + +C +C

+C +C +C

+C +C

+C +

+CT>GA

+

The opposite base(s) is(are) indicated in superscript(s): ss, ssDNA. In the case of MutY and homologous, excision or no excision of a normal opposite base is indicated, respectively, by + or − in superscript. a Hazra et al. [178] report low activity opposite C.

S. Bjelland, E. Seeberg / Mutation Research 531 (2003) 37–80

excision of oxo8 G from the DNA strand of RNA·DNA heteroduplexes is at least 100-fold less than from dsDNA [172]. MutY is an adenine DNA glycosylase removing erroneously incorporated adenine from oxo8 G:A mispairs [278–280]. However, the enzyme also exhibits some activity towards guanine opposite oxo8 G, possibly also preventing the formation of G:C → C:G transversions [281]. The power of the GO system to prevent mutagenesis is demonstrated by the phenotypes of the different mutT/mutM/mutY mutants. Cells mutated in either mutM or mutY are mutators specific for G → T transversions [282,283] while the mutM mutY double mutant is a hypermutator in this respect [278]. E. coli carrying mutT shows elevated levels of A → C transversions [284]. The Nth-like enzyme Nei also removes oxo8 G from DNA with low efficiency [184,285] and the fpg mutY nei triple mutant has a significantly higher spontaneous mutant frequency than the fpg mutY mutant, suggesting that Nei functions as a backup for Fpg/MutY [285]. Nei will also remove oxo8 G opposite A and G (Table 4) [184]. Genes similar to one or several of the components in the GO system have been identified in other organisms including human cells. S. cerevisiae has a glycosylase with Fpg-like activity (Ogg1) to excise oxo8 G from oxo8 G:C base pairs [286,287]—with some activity also when oxo8 G is placed opposite T (Table 4) [288,289]. Disruption of the corresponding gene causes a mutator phenotype with enhanced level of G:C → T:A transversions [290]. Sequence homologues of MutT and MutY are not present in S. cerevisiae. However, Ntg1 has been found to remove oxo8 G from DNA in some sequence contexts (Table 4) [65,291], probably preventing mutation induction by oxo8 G originating from oxo8 dGTP incorporation, whereas Msh2/Msh6-dependent MMR seems to be the major mechanism by which S. cerevisiae removes adenine from oxo8 G:A mispairs [22]. Mammalian counterparts to all GO enzymes have been identified, and the BER pathway is predominantly completed by polymerase ␤-catalysed resynthesis of a single nucleotide residue [292]. Mammalian counterparts of Fpg/MutM are homologous to yeast Ogg1 [293–300]. Human Ogg1 removes oxo8 G efficiently only from base pairs with C (Table 4) [277,295]. Similarly, eukaryotic homologues of MutY S. pombe, Myh and hMyh/mMyh [301–303], and MutT have been identified and characterised [304,305]. The human MutT

57

homologue (hMth1 [304]) exhibits much broader substrate specificity than E. coli MutT (Scheme 1) [306,307]. Although the overall mutation rate in the Mth1 defective mice was not much elevated relative to wild type, a significant increase in the frequency of G:C → T:A transversions was observed and more tumours were formed in the lungs, liver and stomach [308,309]. In addition to hMth1, another human nudix enzyme, hNudT5, has been identified and shown to be involved in the cleaning of the nucleotide pool for oxo8 dGTP precursors [310]. hNudT5 hydrolysed oxo8 dGDP to oxo8 dGMP quite efficiently whereas oxo8 dGTP was hydrolysed at low level. Expression of hNudT5 in E. coli alleviated the high spontaneous mutant frequency characteristic of the mutT mutant (Scheme 1). In order to prevent mutations, hMyh must be directed to the newly synthesised strand and not to the template strand during DNA replication. In a non-replicating system an oxo8 G:A base pair produced progeny composed of 1/3 of G:C and 2/3 of T:A when transfected into simian COS7 or human MRC5V1 cells [260]. This contrasted the results with the oxo8 G:C pair where almost no mutations were detected in the plasmid progeny. Indeed, a recent report has demonstrated co-localisation of hMyh with Pcna at the replication foci, with maximum levels of hMyh observed in the S-phase of the cell cycle, suggesting replication-coupled repair of A:oxo8 G mispairs [311]. Some other mammalian enzymes have also been reported to repair oxo8 G in DNA (Table 4), e.g. the human, but not the mouse, methylpurine DNA glycosylase (Mpg) [312], an oxo8 G endonuclease identified in HeLa cells acting on oxo8 G paired with C, T or G [313], hNeil1/mNeil1 and hNeil2 [54,73–75,175,178] and the human NER system [41]. However, the observation that human Mpg can excise oxo8 G has recently been challenged by others [314]. It has also been demonstrated that the mammalian Msh2/Msh6/Mlh1/Pms2-dependent MMR system serves as a backup in the repair of oxo8 G lesions, because both steady-state and H2 O2 -induced oxo8 G levels in DNA were higher in Msh2-defective as compared to repair-proficient cells. The DNA oxo8 G concentration was reduced in MMR-defective cells by increased expression of mth1 gene, dramatically diminishing the spontaneous mutation rate of msh2−/− mouse embryo fibroblast cells [315]. In Drosophila melanogaster, an oxo8 G DNA glycosylase/AP lyase

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activity directed towards oxo8 G:C mispairs has been demonstrated to be a function of ribosomal protein S3 (RpS3) [316]. Another Drosophila enzyme related to human Ogg1 has also been characterised [317]. The model plant organism Arabidopsis thaliana exhibits both Ogg1 and Fpg homologues (Atmmh1/Atfpg1 and Atogg1) for oxo8 G removal. Atmmh1/Atfpg1 exhibits higher activity towards oxo8 G when paired with C or G than A or T (Table 4) [318,319]. In addition to the enzymes mentioned above, several glycosylases excising oxo8 G from DNA have been characterised in other organisms: Fpg homologues in Lactococcus lactis [276], Deinococcus radiodurans [320] and Thermus thermophilus [321], and Ogg1 homologues from the hyperthermophilic archaeons Archaeoglobus fulgidus and Methanocaldococcus jannaschii (Table 4) [322,323]. The Nth homologue of M. thermoautotrophicum shows a weak oxo8 G-removing activity whereas the Nfo protein of the same organism has been shown to incise dsDNA adjacent to an oxo8 G residue; both enzymes exhibit no discrimination against different opposite bases (Table 4) [59]. Exonucleases have also been shown to digest DNA past oxo8 G lesions, i.e. PolI Kf and the human Werner exonuclease (Wrn) complexed with the Ku heterodimer [324]. Although oxo8 G is non-blocking to DNA polymerisation and to transcription in E. coli in vitro [325], evidence has emerged that a fraction of template oxo8 G causes termination of T7 RNA polymerase [36]. This rather unexpected finding was recently confirmed and extended when oxo8 G was found to be a block to transcription by RNA polymerase II in mammalian cells. Such blockage promotes a presently uncharacterised mechanism of transcription-coupled repair where XpG, transcription factor IIH (TfIIH) and CsB, but not the Ogg1 glycosylase, appear to be required [44,326]. Nullmutant mice deficient in Ogg1 accumulate oxo8 G with age and are deficient in glycosylase activity for removal of oxo8 G in vitro [327,328]. However, the mice are essentially without phenotypic abnormalities and clearly possess alternative pathways for oxo8 G removal [326]. Characterisation of csB−/− ogg1−/− double knockout mice indicate the existence of a pathway for oxo8 G removal dependent on CsB but independent on Ogg1 or transcription that cannot be measured in cell free extracts [328]. When a single G is replaced by oxo8 G in consensus binding sequences

for transcription factors Ap-1 and Sp1, it was sufficient to inhibit in vitro promoter binding; no such effect was observed with transcription factor Nf-␬B regardless of the oxo8 G position [329,330]. Because oxo8 G is more receptive to oxidative attacks than guanine itself, recent work has focused on the characterisation of oxidation products of oxo8 G in DNA. In fact, in E. coli it has been shown that the secondary products are much more mutagenic than oxo8 G [105]. Thus, peroxynitrite oxidation of oxo8 G in DNA ([ONOO− ]/[DNA] > 10) generates 2,4,6-trioxo[1,3,5]triazinane-1-carboxamidine as a major product, which, however, is unstable and hydrolyses to the cyanuric acid (cya) (Fig. 6) [331–333]. The cya nucleoside has also been shown to be the major product generated by singlet oxygen exposure of oxo8 dG [334], and when present in oligonucleotides it induces a local destabilisation of the DNA duplex structure [335]. DNA polymerase studies in vitro using PolI Kf (exo− ) suggested preferential incorporation of dAMP and some incorporation of dGMP opposite cya, suggesting capacity to induce G → T and G → C transversions in vivo. In vivo results from studies with E. coli have largely confirmed these observations by showing 65% translesion past a single cya lesion in an M13 vector, generating G → T transversions in addition to low levels of G → C and G → A mutations [105]. It has been shown that cya is a substrate for neither Fpg nor Nth enzymes of E. coli [335], however, for human Mpg (Dherin et al., unpublished results), when placed opposite cytosine and thymine (Table 4). Another major lesion induced by peroxynitrite-mediated oxidation of oxo8 G in DNA ([ONOO− ]/[DNA] < 5) is 5-iminoimidazolidine-2,4-dione, which also is unstable and hydrolyses to oxaluric acid (Fig. 6) [331–333]. Further, the major singlet oxygen-generated oxidation product of oxo8 G in ssDNA has been identified as oxa [336]. Primer extension catalysed by PolI Kf (exo− ) resulted in efficient insertion of dAMP opposite oxa, while the Taq polymerase incorporated both dAMP and dGMP, but with a lower efficiency. This contrasted with DNA polymerase ␤, which was completely inhibited by oxa in the template [337]. The in vivo results largely confirmed these observations showing 52% translesion past a single oxa lesion, mostly generating G → T transversions in addition to low levels of G → C and G → A mutations

S. Bjelland, E. Seeberg / Mutation Research 531 (2003) 37–80

[105]. The oxa is efficiently excised from DNA by the E. coli Fpg and Nth enzymes in all contexts of base pairing [337]. Using an oligonucleotide without guanines and with a single oxo8 G, Duarte et al. [338] identified the major stable oxo8 G one-electron oxidation product as guanidinohydantoin (gh). The gh was formed via 5-hydroxy-8-oxoguanine (Fig. 6) in a ∼70:30 ratio and exists in pH-dependent equilibrium with its isomer iminoallantoin ([339]; the relative abundance of the two forms in DNA is currently unknown). Another product formed from oxo8 G via 5-hydroxy-8-oxoguanine is spiroiminodihydantoin (sdh) (Fig. 6). Both lesions destabilise dsDNA much more severely (sdh more than iminoallantoin) than oxo8 G and have been shown to be removed from DNA by E. coli Fpg, Nei and/or Nth enzymes opposite all four normal bases. However, MutY was unable to remove A opposite sdh although A was removed very inefficiently opposite gh (Table 4) [340–342]. Primer extension experiments using PolI Kf (exo− ) demonstrated some incorporation of dAMP and dGMP with a 2:1 preference opposite gh or sdh and no incorporation of cognate dCMP, indicating cytotoxicity and mutagenicity in vivo [338,343]. The editing function of PolI Kf (exo+ ) was found to be more active against gh and sdh than oxo8 G [342]. After a complex sequence of reactions involving addition of O2 and H2 O as well as decarboxylation and rearrangement, a product containing an aromatic 5-membered ring structure, imidazolone (2,5-diamino-4H-imidazol-4-one (imz)) (Fig. 8), can be formed from both guanine and oxo8 G [23,344]. The imz has been identified in dsDNA following type I photooxidation [345] where its half-life is 20.4 h as compared to 16.8 h in ssDNA [346]. In vitro DNA synthesis past imz using E. coli polymerase I demonstrated specific pairing with non-cognate guanine followed by significant chain elongation. The nucleotide precursor version, dimzTP, appears non-mutagenic and is specifically incorporated opposite G in DNA. It has been argued that imz is responsible for most G:C → C:G transversions generated under oxidative conditions in vivo [344]. The imz is thought to transform into the more stable oxazolone (2,2,4-triaminooxazolone (oxz)) residue (Fig. 8) [23], which also has been detected in dsDNA [347–349] and shown to be formed from an oxo8 G residue [333]. Recently, Duarte et al. [350] performed both in vitro TLS as well as repair experiments using

59

an oligomer with oxz inserted at a specific position. Although only a small amount of full-length products was obtained, PolI Kf (exo− ) selectively incorporated dAMP, whereas Taq polymerase mostly incorporated dAMP but also some dGMP and dCMP opposite oxz in the presence of only one dNTP. In the presence of all dNTPs no significant incorporation and chain elongation was observed. With DNA polymerase ␤ no insertion or extension could be detected. Thus, although oxz delays DNA polymerase I replication, it seems to have the capacity to induce G → T transversions in E. coli. For Taq polymerase and polymerase ␤, oxz represents a blocking lesion. The in vivo mutagenesis experiments in E. coli have confirmed these observations by showing 57% translesion past a single oxz lesion, mostly generating G → T transversions in addition to low levels of G → C and G → A mutations [105]. Interestingly, both Nth and Fpg enzymes were shown to excise oxz from dsDNA oligomers with similar efficiencies regardless of the type of base in the opposite strand (Table 4) [333,350], suggesting that BER may counteract as well as promote mutagenesis. 2,6-Diamino - 4 - hydroxy - 5 - formamidopyrimidine (fapyG) (Fig. 8) is formed as one of the most abundant lesions in DNA following several types of oxidative treatments [191,192,351], and has also been detected in ancient DNA [88]. By using an oligomer with fapyG present at a defined site, Wiederholt and Greenberg [352] recently demonstrated that PolI Kf (exo− ) misincorporated adenine opposite the lesion about 5% of the time, indicating possible formation of G → T transversions in vivo. PolI Kf (exo− ) was observed to pause at the site of fapyG and one nucleotide past, however, further elongation was found to be efficient. The ability of fapyG to pair with non-cognate A during replication is also supported by that the fapyG:A mispair is thermodynamically quite stable. The fapyG is excised from DNA (Table 4) by the E. coli Fpg protein [353–355], an Fpg homologue of D. radiodurans [320] as well as the Ogg1 [356] and Ntg1 and Ntg2 glycosylases of S. cerevisiae [64,65]. Although slower than opposite oxo8 G, E. coli MutY also excises A when it is opposite fapyG [353]. In D. melanogaster, fapyG is removed from DNA by two different glycosylase functions—dOgg1 [317] and RpS3 [316]—and in human cells by Neil1 and Neil3 [73,175]. An observed inability of human XPA cells to repair fapyG raises the question whether

60

S. Bjelland, E. Seeberg / Mutation Research 531 (2003) 37–80

O N

HN H 2N

N

O

H 2N

N

HN

N

O

O N

NH

O

N

dR 8-Nitroxanthine (nitro8X)

O

O

N H 2N

HN

O N H

O2N NH

O

N

HN N

N

H

H N

N

dR Imidazolone (imz) ToxD G to C

dR 2-Aminoimidazolone

dR 2,6-Diamino-4-hydroxy5-formamidopyrimidine (fapyG) ToxD G to T E.coli Fpg,MutY;D.rad.Fpg; S.cer.Ogg1,Ntg1,Ntg2;D.mel. Ogg1,RpS3;hNeil1,hNeil3

O

H 2N H 2N

O

N

H N

dR Oxazolone (oxz) ToxD,B G to T>C,A E.coli Fpg,Nth

H

O N

NH

H

dR 5-Guanidino-4-nitroimidazole (niz) ToxB G to T,C E.coli Fpg -

N

N

HN

dR 8-Nitroguanine (nitro 8G)

N C N

O N

H H

HN

H 2N

N

HN

O

N OH dR 4-Hydroxy-4,8-dihydro8-oxoguanine

H 2N

O

O

C -

O N

N

O

N

NH2

O3PO OPO3

NH

-

5´S,8-Cyclo-2´-deoxyguanosine (cy8S dG) ToxB hNER

O3PO C H

N

O

OPO3

-

N

NH2

5´R,8-Cyclo-2´-deoxyguanosine (cy8RdG)

Fig. 8. Oxidised guanines other than oxo8 G and derivatives. Mutations induced by in situ lesions are shown in bold. Tox, cytotoxic (D, delaying replication; B, blocking replication).

the XpA protein is involved in damage recognition of this lesion [177]. A poorly characterised oxidised form of guanine with the imidazole-ring structure intact is 4-hydroxy-4,8-dihydro-8-oxoguanine (Fig. 8), identified in the oligomer d(CpApTpG) following X-ray/O2 -treatment [357]. 8-Nitroguanine (nitro8 G) (Fig. 8) was first found to be induced in DNA by peroxynitrite [358,359],

and later by the myeloperoxidase–H2 O2 –nitrite system, gaseous NO• and by activated neutrophiles in the presence of NO2 − [360–362]. The deaminated form of nitro8 G is 8-nitroxanthine (nitro8 X) (Fig. 8), which, however, is not formed from nitro8 G but in higher yield as nitro8 G by exposure of DNA or deoxyguanosine to NO2 Cl. The N-glycosylic bond of nitro8 X to deoxyribose in DNA is more labile than

S. Bjelland, E. Seeberg / Mutation Research 531 (2003) 37–80

that of nitro8 G [363]. Data does not yet exist on the biological implications of nitro8 G or nitro8 X. 5-Guanidino-4-nitroimidazole (niz) (Fig. 8) is a recently described guanine lesion specifically induced in DNA by peroxynitrite. TLS experiments show that niz is a potential DNA replication blocker when the reaction is catalysed by PolI Kf (exo− ) and calf thymus polymerase ␣ but not with human polymerase ␤. While polymerase ␤ mainly incorporated cognate C, polymerase ␣ mainly inserted non-cognate A and G, opposite niz, indicating induction of G → T and G → C transversions in vivo. PolI Kf (exo− ) introduced C > A > G opposite niz, which has been shown to be a poor substrate for E. coli Fpg (Table 4) [364]. Free radical-mediated cross-linking between the C8 position of guanine and the 5 position of 2-deoxyribose yields 5 ,8-cyclo-2 -deoxyguanosine, which exists in two diastereoisomeric forms, 5 R (cy8R dG) and 5 S (cy8S dG) (Fig. 8) [365]. The oxidative lesions cy8R dG and cy8S dG were first identified in ␥-irradiated purified DNA [366] and at the same time in DNA isolated from ␥-irradiated human cells [367]. Recently, cy8S dG was shown to be a substrate for the human NER complex when inserted site-specifically into a 7059 base pair long closed circular M13-derived plasmid [368].

6. Oxidised adenines Among the eight different oxidised forms of adenine so far detected, seven have both their pyrimidineand imidazole-ring structures intact. One of them, 4,6-diamino-5-formamidopyrimidine (fapyA), is imidazole ring-opened between C8 and N9 leaving behind an intact aromatic pyrimidine ring (Fig. 9). Many years ago, 7,8-dihydro-8-oxoadenine (8hydroxyadenine (oxo8 A)) (Fig. 9) and fapyA were identified as the two main products formed from adenine following treatment of DNA with ionising radiation [369,370]. These lesions have also been detected in the DNA of different ancient tissues [88]. The oxo8 A residue is formed by hydroxylation of adenine at the C8 position, and exists in three different forms; 8-enol (or 8-hydroxy), 8-keto (or 8-oxo) and 8-enolate. Paired with thymine in an oligomer duplex, oxo8 A exists predominantly in the keto form without changing the conformation of DNA, as determined by 1 H

61

NMR spectroscopy [371]. In vitro translesion bypass experiments with oxo8 A in DNA have shown that the lesion blocks replication transiently with a limiting, but not with an excess concentration of DNA polymerase present [372]. The oxo8 A preferentially pairs with its cognate thymine base [371,372], and exclusively so using the Taq DNA polymerase [371,373]. Mispairing with adenine and guanine occurred with PolI Kf and mammalian DNA polymerase ␤, whereas mispairing with guanine was observed with mammalian polymerase ␣ [372,373]. The higher mispairing efficiency observed for mammalian versus the E. coli polymerases in vitro could explain the significant mutation induction caused by oxo8 A in mammalian cells (A → G and A → C substitutions) and the apparent lack of detectable mutation induction in bacteria [373,374]. Correspondingly, E. coli MutT exhibits no activity for hydrolysis of oxo8 dATP as opposed to the human Mth1 protein (Scheme 1) [306,307]. The oxo8 dATP is a poor substrate for PolI Kf (exo− ) and does not exhibit mispairing ability [168]. The presence of an oxo8 A residue has been shown to increase DNA cleavage by eukaryotic DNA topoisomerase II 2–3-fold when present at the +4 position relative to the topoisomerase cleavage site [266]. The E. coli Fpg and Nei glycosylases excise oxo8 A inefficiently and the S. cerevisiae, D. melanogaster and human Ogg1 enzymes efficiently from DNA when placed opposite cytosine (Table 5) [17,273,289,317]. The syn–anti conformation of the oxo8 A:C base pair causes a local distortion of the DNA, which might explain the observed specificity of repair [375]. In addition, E. coli MutY protein can excise, although inefficiently, A from DNA when placed opposite oxo8 A [280]. Exonucleases have also been shown to digest DNA past oxo8 A lesions, i.e. E. coli Xth and human Wrn complexed with the Ku heterodimer [324]. 4,6-Diamino-5-formamidopyrimidine (Fig. 9) has been shown to be the most abundant adenine product following ␥-irradiation of DNA [376] and to be present in healthy as well as cancerous human tissues [377]. It has been suggested that fapyA residues will induce A → G transitions in E. coli following SOS induction and will be moderately efficient chain terminators for prokaryotic DNA polymerases [378,379]. However, recent in vitro TLS experiments past fapyA using PolI Kf (exo− ) have demonstrated A and G to be the most frequently incorporated bases opposite

62

S. Bjelland, E. Seeberg / Mutation Research 531 (2003) 37–80

NH 2 NH

N

N

N

O N

H

NH 2

NH 2

N dR

O N N

H

N

N H H N

H

dR Adenine N 1-oxide

dR Adenine N 6hydroxylamine

N

N

C H

O

N

N H

NH 2

O3PO N

N

N

Cl

N

dR 8-Chloroadenine (Cl 8A)

dR 4,6-Diamino-5-formamidopyrimidine (fapyA) ToxD A to T>C E.coli Fpg,Nth,Nei,DenV;D.rad. Fpg;S.cer.Ntg1,Ntg2;hNeil1

N

NH 2 -

H

N C O

N

N

H

N dR

NH 2 H H

N N

H N

HO

N

dR 2-Hydroxyadenine (h2A) NH 2 ToxN A to G,T,C;G,C to T N E.coli MutY;hMyh N

OH

H

N

N

H HN

O

dR 7,8-Dihydro-8-oxoadenine (oxo8A) ToxN A to G,C,T E.coli Fpg,Nei,MutY,Xth;S.cer.Ogg1; D.mel.Ogg1;hOgg1,Wrn/Ku NH 2

N

OH N

H

N

NH 2

N

H

N

OH CH 2

N

O

H

H OPO3

-

C -

O

N

N

N

H

H

OH H

O3PO

5´R,8-Cyclo-2´-deoxyadenosine (cy8RdA) OPO3 ToxB 5´S,8-Cyclo-2´-deoxyhNER adenosine (cy8S dA) ToxB hNER

N

N

N

NH 2 -Deoxyadenosine ( dA) ToxN,D 1

E.coli Nfo

Fig. 9. Oxidised adenines. Mutations induced by in situ lesions are shown in bold; by oxidised precursors in plain text. Tox, cytotoxic (N, non; D, delaying replication; B, blocking replication).

the lesion [380], suggesting induction of A → T and A → C transversions in vivo. The fapyA lesion is excised from DNA (Table 5) by Fpg as rapidly as oxo8 G [354,355,381,382] and also by Nth, Nei and DenV (T4 endonuclease V) proteins of E. coli [81,190,383], by an Fpg homologue of D. radiodurans [320] as well as by Ntg1 and Ntg2 of S. cerevisiae [64]. The fapyA is inefficiently repaired in human cells [177], although it is excised from DNA by Neil1 in vitro [73]. 2-Hydroxyadenine (h2 A; 1,2-dihydro-2-oxoadenine or isoguanine), which like oxo8 A exists in a keto–enol

form of equilibrium (in a ratio of 9:1 in favour of the keto tautomer) (Fig. 9) [384], was first detected in DNA of human chromatin exposed to Ni(II)/H2 O2 or Co(II)/H2 O2 [385]. The lesion has also been detected in the DNA of human cancerous tissues [377] as well as in hepatic DNA of mice following exposure to whole body ␥-irradiation [386]. It is possible that most h2 A that can be detected in DNA arises through incorporation from the nucleotide pool, since the yield of h2 A is 70–80 times higher following oxidation of deoxyadenosine and dATP as compared to oxidation of

S. Bjelland, E. Seeberg / Mutation Research 531 (2003) 37–80

63

Table 5 Proteins involved in the repair of oxidised adenines in DNA

E. coli Nth Nei Fpg MutY DenV Xth Nfo

oxo8 A

fapyA

−C + +C>T A+ −G ±oxo8G

+T +T +GTA −AG A− +T

+T

D. radiodurans Fpg

−TACG +G −ATC

␣dA

cy8R dA

cy8S dA

−TA

−T

−T

−TA

−T

−T

+

+

−TA −TA +TAGC −ss

+T

S. cerevisiae Ntg1 Ntg2 Ogg1

+Cm5C −ATGUss

D. melanogaster dOgg1

+C −GAT

Mammalian hOgg1 hNeil1 hNeil2 hMyh hNER Wrn/Ku

h2 A

+C

+T +T

+T

+T

− − +GA>CT

The opposite base(s) is(are) indicated in superscript(s): ss, ssDNA. In the case of MutY and homologues, excision or no excision of a normal opposite base is indicated, respectively, by + or − in superscript.

dsDNA. Incorporation of h2 A into DNA may be prevented by the E. coli Orf135 nudix protein and hMth1 (but not E. coli MutT), which hydrolyse h2 dATP to h2 dAMP in vitro [270,306,307]. Efficient hydrolysis of h2 ATP may also prevent introduction of h2 AMP into RNA alleviating misincorporation at the level of transcription (Scheme 1). In vitro DNA polymerase studies have shown that calf thymus DNA polymerase ␣ incorporates h2 dATP opposite non-cognate cytosine in addition to cognate thymine, suggesting induction of C → T transitions in vivo. For E. coli, base pairing with cognate T was two orders of magnitude more efficient than with non-cognate G using PolI Kf (exo− ), but only 10 times more efficient with T compared to G using the ␣ (catalytic) subunit of DNA polymerase III [387,388], indicating that the replicative polymerase III is more prone to induce mutations than polymerase I. Accordingly, when h2 dATP was employed in an in vitro gap-filling reaction of supF by E. coli DNA polymerase III holoenzyme, induction of G → T transver-

sions was observed [138]. In contrast to the incorporation of h2 A from the nucleotide pool, incorporation of non-cognate dNMPs (cognate T is preferred in most cases) opposite h2 A appears to be sequence context dependent. PolI Kf (exo− ) misincorporates G in most sequence contexts followed by A and more seldom C, while calf thymus polymerase ␣ and rat polymerase ␤ misincorporate C in most sequence contexts followed by A and more seldom by G [389,390]. Thus, h2 A in DNA seems to have the ability to induce A → G transitions as well as A → T and A → C transversions [389]. E. coli MutY and human Myh have been shown to remove h2 A from dsDNA in vitro (Table 5) [303,391,392]. Another oxidised form of adenine recently reported to be present in a DNA-like structure is adenine N6 -hydroxylamine (Fig. 9), which was detected in poly(dA)·poly(dT) following peroxyl radical treatment [393]. The biological effects of such residues in DNA are presently unknown. This is also true for

64

S. Bjelland, E. Seeberg / Mutation Research 531 (2003) 37–80

malian cellular DNA in vivo [396]. Since the cy8S dA residue causes local distortion in dsDNA [397], it was not unexpected when cy8R dA and cy8S dA were found to be substrates for the human NER complex [368,398]. In the study by Kuraoka et al. [368], in vitro primer extension experiments with T7 DNA polymerase showed incorporation of a residue opposite the two isomers mostly without elongation.

8-chloroadenine (Cl8 A) (Fig. 9), which is induced in DNA by HOCl [13]. As for guanine, cross-linking between the C8 position of adenine and the 5 position of 2-deoxyribose yields 5 ,8-cyclo-2 -deoxyadenosine, first identified in DNA by Fuciarelli et al. [394]. In ␥-irradiated DNA it exists in two diastereoisomeric forms, 5 R (cy8R dA) and 5 S (cy8S dA) (Fig. 9) [395]. The lesion has also been detected in mamO

N

dR

H

N -

PO3 dR

N

NH 2

H2N

N

3´

N 5´

dR

O

H C H

N

HN

NH

H N

5´

O

O

C

HN O

H

NH N

H PO3

-

O 3´

dR

Thymine-guanine ([5-methyl]-8) dimer Guanine-thymine (8-[5-methyl]) dimer (G^T) (T^G) O

O CH 3

N

HN HO O

NH

N H dR PO3 dR

HN

N

NH 2

5´

N

dR

H

N -

PO3 dR

N

N H

O 5´

dR

N

3´

N N

H

5´

H

N -

PO3 dR

N

H C H

N

H

dR

PO3

H

NH 2

3´

3´

O NH N -

O

dR

3´

O

O HN

NH N

dR

Adenine-thymine (8-[5-methyl]) dimer (A^T)

O

N

HO PO3

dR

NH 2

Thymine-adenine ([5-methyl]-8) dimer (T^A) NH 2

N

NH H NO

Guanine-6-hydroxythymine (8-5) dimer (G^Th6)

N

H N

N 5´

NH 2

C

HN O

H

H 2N

3´

6-Hydroxythymine-guanine (5-8) dimer (Th6^G) O

O N H 3C

N 5´

O

O

N H PO3 dR

N 5´

N

dR O

Cytosine-guanine (5-8) dimer (C^G)

NH 2

3´

N

NH

H

ON 5´

N

O H

HN

NH

H

dR

N H PO3 dR

N

NH 2

3´

Dihydrouracil-guanine (5-8) dimers (dHU^G) Fig. 10. Dimeric base lesions.

S. Bjelland, E. Seeberg / Mutation Research 531 (2003) 37–80

However, slight but significant read-through activity was also observed, especially with cy8R dA. The mammalian replication polymerase ␦ in the presence of Pcna ceased DNA synthesis immediately before the lesions with no read-through activity. Human polymerase ␩ catalyses TLS on cy8R dA but not on cy8S dA. Non-cognate dAMP was preferentially incorporated opposite cy8R dA, however, elongation was only achieved following insertion of correct dTMP opposite the lesion, indicating bypass with reasonable fidelity. The 3 → 5 exonuclease function of the mammalian DNA-editing enzyme DNase III (Trex1) was blocked by cy8R dA as well as cy8S dA, whereas the exonuclease activity of T4 DNA polymerase was only blocked by cy8S dA [399]. It has also been demonstrated that cy8S dA is a strong block to gene expression in Chinese hamster ovary and human cells [398]. If present in the TATA box of the cytomegalovirus promoter, binding of the TATA binding protein is prevented causing strongly reduced transcription [400]. Present evidence indicates that BER is unable to correct cy8R dA or cy8S dA in DNA [368,398,401]. α-Deoxyadenosine (␣dA) (Fig. 9) is a major anoxic radiolysis product of adenine in DNA [402], where the stability of an ␣dA:T pair in dsDNA is similar to the stability of an A:T pair [403]. In vitro DNA polymerase I studies show that ␣dA directs misincorporation of C and A in addition to the correct T [404], suggesting induction of A:T → G:C and A:T → T:A mutations in vivo. However, transfection experiments with single-stranded M13 bacteriophage containing ␣dA resulted in no base substitutions but exclusively a single nucleotide deletion at the site of the lesion, indicating different processing of the lesion by polymerases I and III in vivo [405]. With G as the 3 nearest neighbour base, ␣dA resulted in relatively efficient translesion bypass and a low mutation frequency (1%) whereas with T ␣dA caused a stronger inhibition of translesion and a high level of deletion (26%). Two decades ago, ␣dATP was shown to function as a substrate for DNA polymerase ␣, although with low efficiency [406]. The ␣dA is a substrate for E. coli Nfo in dsDNA [404] (Table 5). Adenine N1 -oxide (Fig. 9) is formed as a major product in DNA by H2 O2 under non-radical conditions, and it has been detected in cellular DNA after exposure to non-lethal concentrations of H2 O2 [407,408].

65

7. Dimeric base lesions Ionising radiation, especially in the absence of oxygen, induces several tandem base products in DNA in which adjacent bases are linked to each other with one covalent bond. These intrastrand cross-links include the thymine-guanine([5-methyl]-8) (T∧ G) and the guanine-thymine(8-[5-methyl]) (G∧ T) dimers in which methyl carbon of thymine is covalently linked to the C8 of an adjacent guanine (Fig. 10). Both have been identified in calf thymus DNA following X- and/or ␥-irradiation under anoxic conditions [100,409]. This contrasts with the 6-hydroxythymineguanine (5-8) (Th6∧ G) and the guanine-6-hydroxythymine (8-5) (G∧ Th6 ) dimers (Fig. 10), which have been isolated and identified only using short oligomers such as d(CpGpTpA) and d(CpApTpG) [97,410]. Similar to T∧ G and G∧ T the thymine-adenine([5-methyl]-8) (T∧ A) and the adenine-thymine (8-[5-methyl]) (A∧ T) dimers (Fig. 10) have been identified in calf thymus DNA following ␥-irradiation under anoxic conditions. T∧ G and G∧ T were produced in higher yields than T∧ A and A∧ T, and the yields were higher when the purine base was positioned 5 to the thymine base [409]. The cytosine-guanine (5-8) (C∧ G) dimer as well as two stereoisomers of the dihydrouracilguanine(5-8) (dHU∧ G) dimer have not yet been observed in DNA but have been identified in short oligomers following X-irradiation as mentioned above (Fig. 10) [410]. Very few data exists on the biological implications and possible repair of dimeric base lesions in DNA.

Acknowledgements SB and ES acknowledge support from the Research Council of Norway and the Norwegian Cancer Society. We are grateful to Drs. Serge Boiteux and Jean Cadet for providing data prior to publication. References [1] C. von Sonntag, The Chemical Basis of Radiation Biology, Taylor and Francis, London, 1987. [2] G.W. Teebor, R.J. Boorstein, J. Cadet, The repairability of oxidative free radical mediated damage to DNA: a review, Int. J. Radiat. Biol. 54 (1988) 131–150.

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