DNA Adduct Formation of the Food Carcinogen 2-Amino-3-methylimidazo[4,5-f]quinoline at the C-8 and N2 Atoms of Guanine

Turesky, Robert J.; Markovic, Jovanka

doi:10.1021/tx00042a007

Cited by 53 publications

(76 citation statements)

References 39 publications

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“…The adduct was incorporated at all three positions of the NarI recognition sequence (5′-G 1 G 2 CG 3 CC-3′) (12)(13)(14). This sequence contains a frameshift-prone CG-dinucleotide repeat sequence and is a hotspot for arylamine modification (58).…”

Section: Discussionmentioning

confidence: 99%

“…The dGuo-N 2 -IQ adduct was incorporated into all three dGuo positions of the NarI recognition sequence (12)(13)(14) and the G 1 -position of codon-12 of the Ras gene (15). The modified duplexes were significantly destabilized vs the unmodified duplex as measured by T m analysis; the destabilization was also larger than the corresponding dGuo-C8-IQ adduct in identical sequences.…”

Section: Discussionmentioning

confidence: 99%

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Synthesis of Oligonucleotides Containing the N²-Deoxyguanosine Adduct of the Dietary Carcinogen 2-Amino-3-methylimidazo[4,5-f]quinoline

Stover

Rizzo

2007

Chem. Res. Toxicol.

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Abstract2-Amino-3-methylimidazo [4,5-f]quinoline (IQ) is a highly mutagenic heterocyclic amine formed in all cooked meats. IQ has been found to be a potent inducer of frameshift mutations in bacteria and carcinogenic in laboratory animals. Upon metabolic activation, IQ forms covalent adducts at the C8-and N 2 -positions of deoxyguanosine with a relative ratio of up to ~4:1. We have previously incorporated the major dGuo-C8-IQ adduct into oligonucleotides through the corresponding phosphoramidite reagent. We report here the sequence-specific synthesis of oligonucleotides containing the minor dGuo-N 2 -IQ adduct. Thermal melting analysis revealed that the dGuo-N 2 -IQ adduct significantly destabilizes duplex DNA.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Synthesis of Oligonucleotides Containing the N²-Deoxyguanosine Adduct of the Dietary Carcinogen 2-Amino-3-methylimidazo[4,5-f]quinoline

Stover

Rizzo

2007

Chem. Res. Toxicol.

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“…In general, aryl nitrenium ions react predominantly at the C8-position of dGuo. In some cases, a minor N 2 -adduct has also been characterized (11,12). Feeding studies with laboratory animals suggest that the minor N 2 -adducts are more persistent due to less efficient repair and therefore may be more important to the carcinogenic properties of arylamines (1,13,14).…”

Section: Introductionmentioning

confidence: 99%

Translesion Synthesis Past the C8- and N²-Deoxyguanosine Adducts of the Dietary Mutagen 2-Amino-3-methylimidazo[4,5-f]quinoline in the NarI Recognition Sequence by Prokaryotic DNA Polymerases

Stover

Chowdhury

Hong

et al. 2006

Chem. Res. Toxicol.

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Abstract2-Amino-3-methylimidazo [4,5-f]quinoline (IQ) is found in cooked meats and forms DNA adducts at the C8-and N 2 -positions of dGuo after appropriate activation. IQ is a potent inducer of frameshift mutations in bacteria and is carcinogenic in laboratory animals. We have incorporated both IQ-adducts into the G 1 -and G 3 -positions of the NarI recognition sequence (5′-G 1 G 2 CG 3 CC-3′), which is a hotspot for arylamine modification. The in vitro replication of the oligonucleotides was examined with Escherichia coli pol I Klenow fragment exo − , E. coli pol II exo − , and Sulfolobus solfataricus P2 DNA polymerase IV (Dpo4), and the extension products were sequenced by tandem mass spectrometry. Replication of the C8-adduct at the G 3 -position resulted in two-base deletions with all three polymerases, whereas error-free bypass and extension was observed at the G 1 -position. The N 2 -adduct was bypassed and extended by all three polymerases when positioned at the G 1 -position, and the error-free product was observed. The N 2 -adduct at the G 3 -position was more blocking and was bypassed and extended only by Dpo4 to produce an error-free product. These results indicate that the replication of the IQ-adducts of dGuo is strongly influenced by the local sequence and the regioisomer of the adduct. These results also suggest a possible role for pol II and IV in the error-prone bypass of the C8-IQ-adduct leading to frameshift mutations in reiterated sequences, whereas noniterated sequences result in error-free bypass.

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“…The N2 atom of G is easily modified by formaldehyde (6), acetaldehyde (7), and the oxidation products of heterocyclic amines (e.g. 2-amino-3-methylimidazo [4,5-f]quinoline (8)) and polycyclic aromatic hydrocarbons (e.g. benzo[a]pyrene (9)), forming various N 2 -G derivatives, such as Me, Et, 2-amino-3-methylimidazo [4,5-f]quinoline, and benzo[a]pyrene diol epoxide adducts.…”

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confidence: 99%

Kinetic Analysis of Translesion Synthesis Opposite Bulky N2- and O6-Alkylguanine DNA Adducts by Human DNA Polymerase REV1

Choi

Guengerich

2008

Journal of Biological Chemistry

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REV1, a Y family DNA polymerase (pol), is involved in replicative bypass past DNA lesions, so-called translesion DNA synthesis. In addition to a structural role as a scaffold protein, REV1 has been proposed to play a catalytic role as a dCTP transferase in translesion DNA synthesis past abasic and guanine lesions in eukaryotes. To better understand the catalytic function of REV1 in guanine lesion bypass, purified recombinant human REV1 was studied with two series of guanine lesions, N 2 -alkylG adducts (in oligonucleotides) ranging in size from methyl (Me) to CH 2 (6-benzo[a]pyrenyl) (BP) and O 6 -alkylG adducts ranging from Me to 4-oxo-4-(3-pyridyl)butyl (Pob). REV1 readily produced 1-base incorporation opposite G and all G adducts except for O 6 -PobG, which caused almost complete blockage. Steadystate kinetic parameters (k cat /K m ) were similar for insertion of dCTP opposite G and N 2 -G adducts but were severely reduced opposite the O 6 -G adducts. REV1 showed apparent pre-steadystate burst kinetics for dCTP incorporation only opposite N 2 -BPG and little, if any, opposite G, N 2 -benzyl (Bz)G, or O 6 -BzG. The maximal polymerization rate (k pol 0.9 s ؊1 ) opposite N 2 -BPG was almost the same as opposite G, with only slightly decreased binding affinity to dCTP (2.5-fold). REV1 bound N 2 -BPG-adducted DNA 3-fold more tightly than unmodified G-containing DNA. These results and the lack of an elemental effect ((S p )-2-deoxycytidine 5-O-(1-thiotriphosphate)) suggest that the late steps after product formation (possibly product release) become rate-limiting in catalysis opposite N 2 -BPG. We conclude that human REV1, apparently the slowest Y family polymerase, is kinetically highly tolerant to N 2 -adduct at G but not to O 6 -adducts.Cellular DNA is continuously attacked by various endogenous and exogenous agents. Although the resulting lesions can be removed by versatile cellular repair systems, many DNA lesions escape repair and are usually present in replicating DNA. Facing DNA lesions during DNA replication, DNA polymerases often show unusual behavior, such as misinsertion, slippage, and blockage, which can give rise to mutations or cell death (1). Therefore, the characterization of interaction of DNA polymerases with DNA lesions is crucial for understanding the mechanism of mutagenesis in cells in detail (2). Human cells possess at least 15 different DNA polymerases, the physiological functions of most of which are still unclear. Replicative DNA polymerases, such as pol 2 ␣, ␦, and ⑀, are intolerant of DNA distortions caused by many DNA lesions and thus are blocked (3). As a tolerance mechanism to this replication blockade, cells utilize the specialized translesion synthesis (TLS) DNA polymerases, which have a spacious active site to replicate past replication fork-blocking lesions (4). Many of human TLS DNA polymerases belong to the recently discovered Y family, including pol , pol , pol , and REV1 (5). Y family members often have different properties of bypass ability and fidelity opposite various DNA ...

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DNA Adduct Formation of the Food Carcinogen 2-Amino-3-methylimidazo[4,5-f]quinoline at the C-8 and N2 Atoms of Guanine

Cited by 53 publications

References 39 publications

Synthesis of Oligonucleotides Containing the N²-Deoxyguanosine Adduct of the Dietary Carcinogen 2-Amino-3-methylimidazo[4,5-f]quinoline

Synthesis of Oligonucleotides Containing the N²-Deoxyguanosine Adduct of the Dietary Carcinogen 2-Amino-3-methylimidazo[4,5-f]quinoline

Translesion Synthesis Past the C8- and N²-Deoxyguanosine Adducts of the Dietary Mutagen 2-Amino-3-methylimidazo[4,5-f]quinoline in the NarI Recognition Sequence by Prokaryotic DNA Polymerases

Kinetic Analysis of Translesion Synthesis Opposite Bulky N2- and O6-Alkylguanine DNA Adducts by Human DNA Polymerase REV1

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DNA Adduct Formation of the Food Carcinogen 2-Amino-3-methylimidazo[4,5-f]quinoline at the C-8 and N2 Atoms of Guanine

Cited by 53 publications

References 39 publications

Synthesis of Oligonucleotides Containing the N2-Deoxyguanosine Adduct of the Dietary Carcinogen 2-Amino-3-methylimidazo[4,5-f]quinoline

Synthesis of Oligonucleotides Containing the N2-Deoxyguanosine Adduct of the Dietary Carcinogen 2-Amino-3-methylimidazo[4,5-f]quinoline

Translesion Synthesis Past the C8- and N2-Deoxyguanosine Adducts of the Dietary Mutagen 2-Amino-3-methylimidazo[4,5-f]quinoline in the NarI Recognition Sequence by Prokaryotic DNA Polymerases

Kinetic Analysis of Translesion Synthesis Opposite Bulky N2- and O6-Alkylguanine DNA Adducts by Human DNA Polymerase REV1

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Synthesis of Oligonucleotides Containing the N²-Deoxyguanosine Adduct of the Dietary Carcinogen 2-Amino-3-methylimidazo[4,5-f]quinoline

Synthesis of Oligonucleotides Containing the N²-Deoxyguanosine Adduct of the Dietary Carcinogen 2-Amino-3-methylimidazo[4,5-f]quinoline

Translesion Synthesis Past the C8- and N²-Deoxyguanosine Adducts of the Dietary Mutagen 2-Amino-3-methylimidazo[4,5-f]quinoline in the NarI Recognition Sequence by Prokaryotic DNA Polymerases