The replication fate of R- and S-styrene oxide adducts on adenine N6 is dependent on both the chirality of the lesion and the local sequence context.

Latham, Gary J.; Zhou, Liang; Harris, Constance M.; Harris, Thomas M.; Lloyd, R. Stephen

doi:10.1016/s0021-9258(19)49480-5

Cited by 78 publications

(94 citation statements)

References 31 publications

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“…These results indicate that specific properties of a replicating polymerase are further influenced by the conformation of the damaged template. Similar observations have been made on interactions between DNA polymerases and adducts such as styrene oxide and aminofluorene (24,25,47,48).…”

Section: Discussionsupporting

confidence: 77%

“…This was analyzed by separation of the annealed mixture on a 10% native polyacrylamide gel followed by quantitation using the Phosphorlmager (Molecular Dynamics, Sunnyville, CA). Chain elongation conditions have been previously described (24,25). Nucleotide incorporation opposite the adducted site was determined by utilizing a 27mer primer in the polymerase extension reaction and incubated with the individual nucleotide triphosphates (750 ,uM final concentration of each nucleotide) along with one polymerase per reaction at concentrations used for the multiple-hit conditions.…”

Section: Polymerase Arrest Assaysmentioning

confidence: 99%

See 1 more Smart Citation

In vitroreplication by prokaryotic and eukaryotic polymerases on DNA templates containing site-specific and stereospecific benzo [a]pyrene-7, 8-dihydrodiol-9, 10-epoxide adducts

Chary

Lioyd

1995

Nucl Acids Res

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DNA adducts of the environmental carcinogen benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide (BPDE) interact stereospecifically with prokaryotic and eukaryotic polymerases in vitro. Toward understanding the capacity to replicate past different diastereomers of BPDE at specific sites in DNA, six deoxyoligonucleotides, each 33 bases long, were constructed with stereochemically defined BPDE adducts on adenine N6 at position two of the human N-ras codon 61. Four polymerases that were studied under single encounters with the template-primer complex terminated synthesis one base 3' to the lesion with all the adducted templates. When multiple encounters between polymerase and substrate were permitted, each of the polymerases analyzed revealed a unique pattern for a given adducted template. The general replication pattern was encompassed under two categories, reflecting the significance of the R and S configurations of C10 of the pyrenyl ring attached to the single-stranded DNA template. Furthermore, within each of these categories, every polymerase demonstrated distinct quantitative differences in product accumulation at a given site, for the various adducted templates. Among the polymerases utilized in this study, exonuclease-deficient Klenow fragment of polymerase I (exo- KF) exhibited the most efficient translesion synthesis resulting in approximately 16% full-length products with the modified templates bearing adducts with C10-S configuration. In contrast, chain elongation with bacteriophage T4 DNA polymerase bearing an active 3'-->5' exonucleolytic activity was most strongly inhibited by all six BPDE-adducted templates. Misincorporation of A opposite the adduct occurred in all the templates when polymerized with Sequenase, whereas exo- KF preferentially incorporated C opposite the C10-R BPDE adducts and A opposite the C10-S BPDE adducts.

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Section: Discussionsupporting

confidence: 77%

Section: Polymerase Arrest Assaysmentioning

confidence: 99%

In vitroreplication by prokaryotic and eukaryotic polymerases on DNA templates containing site-specific and stereospecific benzo [a]pyrene-7, 8-dihydrodiol-9, 10-epoxide adducts

Chary

Lioyd

1995

Nucl Acids Res

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“…In experiment I, where both SOSinduced and uninduced E. coli cells were used, progeny were analyzed by a combination of oligonucleotide hybridization and sequencing, following the approaches of the laboratories of Lawrence (30) and DiGiovanni (17). In experiment II, where only SOS-induced cells were used, a differential hybridization method of progeny analysis, based on that previously used by the laboratories of Lloyd and Moriya (15,16,41), was employed so that a larger number of progeny could be screened (Figure 3). Estimates of ligation efficiency varied from experiment to experiment (see the Supporting Information) but were substantially lower for context I(A) in experiment I and experiment IIa, in which the scaffold and cut M13 were annealed first and the adducted (or unadducted) 16-mer was added subsequently, than for the a All sequences are listed in the 5′-3′ direction.…”

Section: Resultsmentioning

confidence: 99%

Sequence Context Profoundly Influences the Mutagenic Potency of Trans-Opened Benzo[a]pyrene 7,8-Diol 9,10-Epoxide−Purine Nucleoside Adducts in Site-Specific Mutation Studies

et al. 1998

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The postoligomerization method was used to prepare oligonucleotide 16-mers that contained dAdo or dGuo adducts, derived from trans opening of each enantiomer of the two diastereomeric benzo[a]pyrene 7,8-diol 9,10-epoxides, in two sequence contexts. These 16 oligonucleotides, along with the four corresponding oligonucleotides containing unsubstituted purines, were ligated into single-stranded DNA from bacteriophage M13mp7L2 and transfected into Escherichia coli SMH77. The mutagenic effects of replication past these adducts were then evaluated. The various adduct isomers induced point mutations at different frequencies and with different distributions of mutation types, as was anticipated. However, sequence context had the most substantial effects on mutation frequency. A high frequency of deletions of a single guanine was found in a context where the dGuo adduct was at the 3'-end of a run of five guanines, whereas no single base deletion was found in the other context studied, 5'-CGA-3'. Mutation frequencies in constructs containing dAdo adducts were much higher in a 5'-TAG-3' context (37-58%, depending on the individual isomer) than in a 5'-GAT-3' context (5-20%), and for a given adduct, mutation frequency was up to 10-fold higher in the former sequence than in the latter. These findings indicate that sequence context effects need more thorough evaluation if the goal of understanding the mechanism through which DNA adducts lead to mutation is to be achieved.

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“…Site-specific mutagenesis studies of these regioisomeric N 6 -dA styrene oxide adducts also indicate low levels of mutations. 96 The observed structural similarities between the (2S)-N 6 -HB-dA adduct investigated here and other known N 6 -dA adducts predict that the (2S)-N 6 -HB-dA adduct will be weakly mutagenic. Detailed site-specific mutagenesis studies have not been reported for (2S)-N 6 -HB-dA.…”

mentioning

confidence: 57%

“…In contrast, Hennard et al showed that the R- and S- β- N 6 -adenyl-styrene adducts 3 (Chart ) exhibit similar major groove orientations of the styrene ring, which was attributed to the longer tether of the β adducts. Site-specific mutagenesis studies of these regioisomeric N 6 -dA styrene oxide adducts also indicate low levels of mutations …”

Section: Discussionmentioning

confidence: 99%

Major Groove Orientation of the (2S)-N⁶-(2-Hydroxy-3-buten-1-yl)-2′-deoxyadenosine DNA Adduct Induced by 1,2-Epoxy-3-butene

Kowal

Wickramaratne

Kotapati

et al. 2014

Chem. Res. Toxicol.

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1,3-Butadiene (BD) is an environmental and occupational toxicant classified as a human carcinogen. It is oxidized by cytochrome P450 monooxygenases to 1,2-epoxy-3-butene (EB), which alkylates DNA. BD exposures lead to large numbers of mutations at A:T base pairs even though alkylation of guanines is more prevalent, suggesting that one or more adenine adducts of BD play a role in BD-mediated genotoxicity. However, the etiology of BD-mediated genotoxicity at adenine remains poorly understood. EB alkylates the N6 exocyclic nitrogen of adenine to form N6-(hydroxy-3-buten-1-yl)-2′-dA ((2S)-N6-HB-dA) adducts (TretyakovaN.LinY.SangaiahR.UptonP. B.SwenbergJ. A.TretyakovaN.LinY.SangaiahR.UptonP. B.SwenbergJ. A.9054600Carcinogenesis199718137147). The structure of the (2S)-N6-HB-dA adduct has been determined in the 5′-d(C1G2G3A4C5Y6A7G8A9A10G11)-3′:5′-d(C12T13T14C15T16T17G18T19 C20C21G22)-3′ duplex [Y = (2S)-N6-HB-dA] containing codon 61 (underlined) of the human N-ras protooncogene, from NMR spectroscopy. The (2S)-N6-HB-dA adduct was positioned in the major groove, such that the butadiene moiety was oriented in the 3′ direction. At the Cα carbon, the methylene protons of the modified nucleobase Y6 faced the 5′ direction, which placed the Cβ carbon in the 3′ direction. The Cβ hydroxyl group faced toward the solvent, as did carbons Cγ and Cδ. The Cβ hydroxyl group did not form hydrogen bonds with either T16O4 or T17O4. The (2S)-N6-HB-dA nucleoside maintained the anti conformation about the glycosyl bond, and the modified base retained Watson–Crick base pairing with the complementary base (T17). The adduct perturbed stacking interactions at base pairs C5:G18, Y6:T17, and A7:T16 such that the Y6 base did not stack with its 5′ neighbor C5, but it did with its 3′ neighbor A7. The complementary thymine T17 stacked well with both 5′ and 3′ neighbors T16 and G18. The presence of the (2S)-N6-HB-dA resulted in a 5 °C reduction in the Tm of the duplex, which is attributed to less favorable stacking interactions and adduct accommodation in the major groove.

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The replication fate of R- and S-styrene oxide adducts on adenine N6 is dependent on both the chirality of the lesion and the local sequence context.

Cited by 78 publications

References 31 publications

In vitroreplication by prokaryotic and eukaryotic polymerases on DNA templates containing site-specific and stereospecific benzo [a]pyrene-7, 8-dihydrodiol-9, 10-epoxide adducts

In vitroreplication by prokaryotic and eukaryotic polymerases on DNA templates containing site-specific and stereospecific benzo [a]pyrene-7, 8-dihydrodiol-9, 10-epoxide adducts

Sequence Context Profoundly Influences the Mutagenic Potency of Trans-Opened Benzo[a]pyrene 7,8-Diol 9,10-Epoxide−Purine Nucleoside Adducts in Site-Specific Mutation Studies

Major Groove Orientation of the (2S)-N⁶-(2-Hydroxy-3-buten-1-yl)-2′-deoxyadenosine DNA Adduct Induced by 1,2-Epoxy-3-butene

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The replication fate of R- and S-styrene oxide adducts on adenine N6 is dependent on both the chirality of the lesion and the local sequence context.

Cited by 78 publications

References 31 publications

In vitroreplication by prokaryotic and eukaryotic polymerases on DNA templates containing site-specific and stereospecific benzo [a]pyrene-7, 8-dihydrodiol-9, 10-epoxide adducts

In vitroreplication by prokaryotic and eukaryotic polymerases on DNA templates containing site-specific and stereospecific benzo [a]pyrene-7, 8-dihydrodiol-9, 10-epoxide adducts

Sequence Context Profoundly Influences the Mutagenic Potency of Trans-Opened Benzo[a]pyrene 7,8-Diol 9,10-Epoxide−Purine Nucleoside Adducts in Site-Specific Mutation Studies

Major Groove Orientation of the (2S)-N6-(2-Hydroxy-3-buten-1-yl)-2′-deoxyadenosine DNA Adduct Induced by 1,2-Epoxy-3-butene

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Major Groove Orientation of the (2S)-N⁶-(2-Hydroxy-3-buten-1-yl)-2′-deoxyadenosine DNA Adduct Induced by 1,2-Epoxy-3-butene