Effect of Aminofluorene and (Acetylamino)fluorene Adducts on the DNA Replication Mediated by Escherichia coli Polymerases I (Klenow Fragment) and III

Doisy, Richard; Tang, Moon‐shong

doi:10.1021/bi00013a027

Cited by 30 publications

(26 citation statements)

References 20 publications

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“…Although structurally similar, AF and AAF elicit significantly different biological responses. For example, the C8-dGuo-adduct of AF is bypassed by the E. coli pol III holoenzyme, although the efficiency of the bypass is dependent on the sequence (20,41). Pol III bypassed the C8-AF-adduct at the G 3 -position of the NarI recognition sequence with noticeably lower efficiency than modification of the G 1 -or G 2 -positions (20).…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…High-fidelity polymerases including replicative eukaryotic Pol δ 8 and E. coli Pol III 9 preferentially insert correct C and misinsert some A opposite [AF]G in vitro , but are impeded by the adduct 10-14 . However, the bypass of DNA lesions in vivo predominantly involves specialized translesion synthesis (TLS) Y-family polymerases that replace stalled high-fidelity polymerases 15-17 .…”

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confidence: 99%

Mechanism of error-free and semitargeted mutagenic bypass of an aromatic amine lesion by Y-family polymerase Dpo4

Rechkoblit

Kolbanovskiy

Malinina

et al. 2010

Nat Struct Mol Biol

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The aromatic amine carcinogen 2-aminofluorene (AF) forms covalent adducts with DNA, predominantly with guanine at the C8 position. Such lesions are bypassed by Y-family polymerases such as Dpo4 via error-free and error-prone mechanisms. We show that Dpo4 catalyzes elongation from a correct 3′-terminal C opposite [AF]G in a nonrepetitive template sequence with low efficiency. This extension leads to cognate full-length product, as well as mis-elongated products containing base mutations and deletions. Crystal structures of the Dpo4 ternary complex with the 3′-terminal primer C base opposite [AF]G in the anti conformation and with the AF-moiety positioned in the major groove, revealed both accurate and misalignment-mediated mutagenic extension pathways. The mutagenic template/primer-dNTP arrangement is promoted by interactions between the polymerase and the bulky lesion, rather than by a base pairstabilized misaligment. Further extension leads to semi-targeted mutations via this proposed polymerase-guided mechanism.

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“…The mutagenic consequences of each adduct are also quite distinct. The dG-C8-AAF adduct results in mostly frameshift mutations in bacteria, whereas the dG-C8-AF adduct produces predominantly base substitution mutations (2)(3)(4). These different properties are likely to be the result of differences in the structures that these adducts assume in DNA in the active site of the DNA polymerase.…”

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confidence: 99%

Interaction of Escherichia coli DNA Polymerase I (Klenow Fragment) with Primer-Templates ContainingN-Acetyl-2-aminofluorene or N-2-Aminofluorene Adducts in the Active Site

Dzantiev

Romano

1999

Journal of Biological Chemistry

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DNA adducts formed by aromatic amines such as N-acetyl-2-aminofluorene (AAF) and N-2-aminofluorene (AF) are known to cause mutations by interfering with the process of DNA replication. To understand this phenomenon better, a gel retardation assay was used to measure the equilibrium dissociation constants for the binding of an exonuclease-deficient Escherichia coli DNA polymerase I (Klenow fragment) to DNA primertemplates modified with an AAF or AF adduct. The results indicate that the nature of the adduct as well as the presence and nature of an added dNTP have a significant influence on the strength of the binding of the polymerase to the DNA. More specifically, it was found that the binding is 5-10-fold stronger when an AAF adduct, but not an AF adduct, is positioned in the enzyme active site. In addition, the polymerase was found to bind the unmodified primer-template less strongly in the presence of a noncomplementary dNTP than in the presence of the correct nucleotide. The same trend holds true for the primer-template having an AF adduct, although the magnitude of this difference was lower. In the case of the AAF adduct, the interaction of the polymerase with the primer-template was stronger and almost independent of the nucleotide present.It is well established that the presence of DNA adducts in the template strand can impede or block DNA synthesis at a replication fork. Although most bulky adducts inhibit DNA synthesis strongly, some can be bypassed readily in vitro. The well studied carcinogen N-acetyl-2-aminofluorene (AAF) 1 can form both types of adducts in DNA; N-(deoxyguanosin-8-yl)-2-acetylaminofluorene adducts (dG-C8-AAF) are known to be strong blocks to DNA synthesis, whereas N-(deoxyguanosin-8-yl)-2-aminofluorene adducts (dG-C8-AF) can be bypassed by all polymerases tested (1). The mutagenic consequences of each adduct are also quite distinct. The dG-C8-AAF adduct results in mostly frameshift mutations in bacteria, whereas the dG-C8-AF adduct produces predominantly base substitution mutations (2-4). These different properties are likely to be the result of differences in the structures that these adducts assume in DNA in the active site of the DNA polymerase. Structural and enzymatic studies on duplex DNA molecules have demonstrated that the AF adduct produces less distortion in the DNA helix than the AAF adduct (2, 5). Multidimensional NMR experiments show that the guanine bearing the C8-AAF adduct rotates from anti to syn conformation in the doublestranded DNA helix with the fluorene ring inserted into the helix (base displacement model (6)). This contrasts with the AF adduct, which can adopt interchangeable conformations: in one the fluorene remains outside the helix (outside binding model), whereas the other has the fluorene ring stacked within the helix (5). The ratio of these conformations seems to be dependent on the sequence within which the adduct lies (7). Although it has been assumed that the structural differences between the AAF and AF adducts are responsible for the observed in the...

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Effect of Aminofluorene and (Acetylamino)fluorene Adducts on the DNA Replication Mediated by Escherichia coli Polymerases I (Klenow Fragment) and III

Cited by 30 publications

References 20 publications

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

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

Mechanism of error-free and semitargeted mutagenic bypass of an aromatic amine lesion by Y-family polymerase Dpo4

Interaction of Escherichia coli DNA Polymerase I (Klenow Fragment) with Primer-Templates ContainingN-Acetyl-2-aminofluorene or N-2-Aminofluorene Adducts in the Active Site

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Effect of Aminofluorene and (Acetylamino)fluorene Adducts on the DNA Replication Mediated by Escherichia coli Polymerases I (Klenow Fragment) and III

Cited by 30 publications

References 20 publications

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

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

Mechanism of error-free and semitargeted mutagenic bypass of an aromatic amine lesion by Y-family polymerase Dpo4

Interaction of Escherichia coli DNA Polymerase I (Klenow Fragment) with Primer-Templates ContainingN-Acetyl-2-aminofluorene or N-2-Aminofluorene Adducts in the Active Site

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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

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