The mutagenicity and DNA base sequence changes induced by 1-nitroso- and 1-nitropyrene in the cl gene of lambda prophage

Stanton, Caroline A.; Garner, Colin; Martin, Carl N.

doi:10.1093/carcin/9.7.1153

Cited by 23 publications

(28 citation statements)

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“…In both mammalian cells and bacteria, the major DNA adduct formed by 1-NP is N-(deoxyguanosin-8-yl)-1-aminopyrene [22][23][24]. 1-NP is also activated to a mutagenic DNA-binding species in bacterial cells via nitroreduction [25,26] to form N-(deoxyguanosin-8-yl)-1-aminopyrene as the major carcinogen-DNA adduct [23,27,28]. This adduct has also been detected in vivo but appears to account for only 20-57% of the total DNA binding [24].…”

Section: Discussionmentioning

confidence: 99%

Ki-ras mutation and cell proliferation of lung lesions induced by 1-nitropyrene in A/J mice

Bai¹,

Nakanishi²,

Takayama³

et al. 1998

Mol. Carcinog.

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In this study, lung lesions were found in male A/J mice 24 wk after intraperitoneal injection of 1-nitropyrene (1-NP). The lesions were classified into three categories: alveolar/bronchiolar hyperplasia, adenoma, and adenocarcinoma. The proliferation kinetics of cells in the lesions were evaluated by assessing proliferating cell nuclear antigen (PCNA) expression and silver-staining nucleolar organizer regions (AgNORs). Furthermore, the role of the Ki-ras gene in tumorigenesis was studied by detecting point mutations in Ki-ras codons 12, 13, and 61 by polymerase chain reaction and sequence analysis. The PCNA-positive rates (+/- standard deviations) in various samples were as follows: 0% for specimens from six untreated animals and six uninvolved areas, 4.26 +/- 3.94% for 19 hyperplasias (hyperplasias vs normal lung tissue, P < 0.01), 13.24 +/- 6.35% for 25 adenomas (adenomas vs hyperplasias, P < 0.01), and 38.0 +/- 9.63% for four adenocarcinomas (adenocarcinomas vs adenomas, P < 0.01). The corresponding mean AgNOR scores were as follows: 1.10 +/- 0.05 for the untreated animals, 1.32 +/- 0.09 for the uninvolved areas, 1.72 +/- 0.59 for the hyperplasias (hyperplasias vs normal lung tissue, P > 0.05), 2.74 +/- 0.70 for the adenomas (adenomas vs hyperplasias, P < 0.01), and 5.22 +/- 0.62 for the adenocarcinomas (adenocarcinomas vs adenomas, P < 0.01). Ki-ras gene mutations were identified in three of four (75%) adenocarcinomas, six of 23 (26%) adenomas, and two of 17 (12%) hyperplasias. No mutations were found in normal lung tissue. The most frequent Ki-ras mutation was an arginine (CGA)AT --> GC transition at codon 61 in exon 2. The PCNA-positive rates and AgNOR scores of cases with Ki-ras mutations were higher than those without an identified mutation (P < 0.05). Ki-ras mutations at codon 61 (Arg) may therefore influence the growth or development of 1-NP-induced lung lesions in A/J mice.

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Section: Discussionmentioning

confidence: 99%

Ki-ras mutation and cell proliferation of lung lesions induced by 1-nitropyrene in A/J mice

Bai¹,

Nakanishi²,

Takayama³

et al. 1998

Mol. Carcinog.

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“…For example, AF dG mainly causes base substitution mutations 33,34 and induces a mixture of B and S damaged DNA conformations, 35 whereas AAF dG mainly promotes frameshift mutations 36,37 and a small amount of substitution mutations 37 but induces a mixture of the B, W, and S DNA conformations. 20 Finally, 1AP dG predominantly induces frameshift mutagenesis in bacteria 38 and results in the S conformation of damaged DNA. 39 Despite previous efforts toward elucidating the relationship between adduct structure and mutagenicity for individual N-linked C 8 -dG lesions, 23,24,39−41 systematic attempts to understand the effects of the size and shape of the NCA moiety on the structural characteristics of damaged (adducted) DNA are scarce.…”

Section: ■ Introductionmentioning

confidence: 99%

“…For example, AF dG mainly causes base substitution mutations , and induces a mixture of B and S damaged DNA conformations, whereas AAF dG mainly promotes frameshift mutations , and a small amount of substitution mutations but induces a mixture of the B, W, and S DNA conformations . Finally, 1AP dG predominantly induces frameshift mutagenesis in bacteria and results in the S conformation of damaged DNA …”

Section: Introductionmentioning

confidence: 99%

Effect of Size and Shape of Nitrogen-Containing Aromatics on Conformational Preferences of DNA Containing Damaged Guanine

Kung

Sharma

Wetmore

2018

J. Chem. Inf. Model.

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The present work investigates the effects of the size and shape of the nitrogen-containing aromatic (NCA) skeleton on the structure of DNA damaged through adduct formation at C of 2'-deoxyguanosine (dG), a common DNA lesion associated with chemical carcinogenesis. Specifically, density functional theory (DFT) calculations (B3LYP-D3) and molecular dynamics (MD) simulations (AMBER) are performed on seven model adducts with systematic expansion of the NCA moiety. DFT calculations reveal that the NCA moiety shape affects the structure at the nucleobase-carcinogen linkage. Approximately 4.5 μs of MD simulations on damaged oligonucleotides adopting three established conformational themes (namely, B, W, and S) illustrate that the structure and lesion-site stabilization strongly depend on the NCA moiety shape and size, which provides insight into the repair propensity of C-dG adducted DNA. Our results add bulky moiety shape to the growing list of previously established effects on the conformational and repair outcomes of damaged DNA (i.e., size, ionization state, substitution, linker type, and DNA sequence). Furthermore, this work illustrates the utility of a systematic set of model DNA lesions for understanding the structure-activity relationship for DNA damaged by carcinogens of different sizes and shapes, which should be used in future studies of the cellular processing of damaged DNA.

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“…one-base deletions or additions (13). In a subsequent study in pBR322, -1 deletions and all the targeted base substitutions were observed, but +1 additions were not detected (14).…”

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confidence: 79%

Solution Structure of theN-(Deoxyguanosin-8-yl)-1-aminopyrene ([AP]dG) Adduct Opposite dA in a DNA Duplex

Krishnasamy

Hingerty

et al. 1999

Biochemistry

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Solution structural studies have been undertaken on the aminopyrene-C(8)-dG ([AP]dG) adduct in the d(C5-[AP]G6-C7). d(G16-A17-G18) sequence context in an 11-mer duplex with dA opposite [AP]dG, using proton-proton distance and intensity restraints derived from NMR data in combination with distance-restrained molecular mechanics and intensity-restrained relaxation matrix refinement calculations. The exchangeable and nonexchangeable protons of the aminopyrene and the nucleic acid were assigned following analysis of two-dimensional NMR data sets on the [AP]dG.dA 11-mer duplex in H2O and D2O solution. The broadening of several resonances within the d(G16-A17-G18) segment positioned opposite the [AP]dG6 lesion site resulted in weaker NOEs, involving these protons in the adduct duplex. Both proton and carbon NMR data are consistent with a syn glycosidic torsion angle for the [AP]dG6 residue in the adduct duplex. The aminopyrene ring of [AP]dG6 is intercalated into the DNA helix between intact Watson-Crick dC5.dG18 and dC7.dG16 base pairs and is in contact with dC5, dC7, dG16, dA17, and dG18 residues that form a hydrophobic pocket around it. The intercalated AP ring of [AP]dG6 stacks over the purine ring of dG16 and, to a lesser extent dG18, while the looped out deoxyguanosine ring of [AP]dG6 stacks over dC5 in the solution structure of the adduct duplex. The dA17 base opposite the adduct site is not looped out of the helix but rather participates in an in-plane platform with adjacent dG18 in some of the refined structures of the adduct duplex. The solution structures are quite different for the [AP]dG.dA 11-mer duplex containing the larger aminopyrene ring (reported in this study) relative to the previously published [AF]dG.dA 11-mer duplex containing the smaller aminofluorene ring (Norman et al., Biochemistry 28, 7462-7476, 1989) in the same sequence context. Both the modified syn guanine and the dA positioned opposite it are stacked into the helix with the aminofluorene chromophore displaced into the minor groove in the latter adduct duplex. By contrast, the aminopyrenyl ring participates in an intercalated base-displaced structure in the present study of the [AP]dG.dA 11-mer duplex and in a previously published study of the [AP]dG.dC 11-mer duplex (Mao et al., Biochemistry 35, 12659-12670, 1996). Such intercalated base-displaced structures without hydrogen bonding between the [AP]dG adduct and dC or mismatched dA residues positioned opposite it, if present at a replication fork, may cause polymerase stalling and formation of a slipped intermediate that could produce frameshift mutations, the most dominant mutagenic consequence of the [AP]dG lesion.

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The mutagenicity and DNA base sequence changes induced by 1-nitroso- and 1-nitropyrene in the cl gene of lambda prophage

Cited by 23 publications

References 0 publications

Ki-ras mutation and cell proliferation of lung lesions induced by 1-nitropyrene in A/J mice

Ki-ras mutation and cell proliferation of lung lesions induced by 1-nitropyrene in A/J mice

Effect of Size and Shape of Nitrogen-Containing Aromatics on Conformational Preferences of DNA Containing Damaged Guanine

Solution Structure of theN-(Deoxyguanosin-8-yl)-1-aminopyrene ([AP]dG) Adduct Opposite dA in a DNA Duplex

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