Mechanism of Frameshift (Deletion) Generated by Acetylaminofluorene-Derived DNA Adducts in Vitro

Shibutani, Shinya; Suzuki, N.; Grollman, Arthur P.

doi:10.1021/bi048087e

Cited by 21 publications

(16 citation statements)

References 29 publications

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“…When a shorter primer 10-mer was used to initiate the primer extension reaction from two bases prior to the lesion, only one-base deletions were generated during DNA synthesis Table 2 Shibutani and Grollman, 1993 , indicating that the first pathway was thought to be operative. This result was consistent with data obtained using the 13-mer with dA Shibutani et al, 2004 . Similar results were observed when GG or AA was 5' to the dG-AAF.…”

Section: Frequency Of Deletions Generated On Templates Containing Itesupporting

confidence: 92%

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Requirements for frameshift (deletion) during translesion synthesis

Shibutani

2004

Environ. Mutagen Res.

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Base substitutions and frameshift deletion mutations generating in cells are associated with aging, genetic diseases and initiation of cancer. A base substitution induces a point mutation, resulting in a single incorrect amino acid in the protein sequence whereas a frameshift alters the entire amino acid sequence upstream of the mutation. Frameshift deletions are formed during translesion synthesis past endogenous or exogenous DNA damage Ripley, 1990 . Fresco and Alberts 1960 suggest-ed that loops in duplex DNA might lead to the formation of deletions. The concept of slipped mispairing was proposed by Streisinger et al. 1966 and1985 to account for the increased frequency of frameshift detected in iterated nucleotide sequences. Fowler et al. 1974 introduced a mechanism for substitution errors involving transient misalignment of the template-primer complex. Kunkel and co-workers Kunkel and Soni, 1988;Bebenek and Kunkel, 1990;Kunkel, 1990 showed that frameshift deletions were induced by base mismatches, and proposed two alternative pathways; namely, misinsertion preceding misalignment Fig. 1A Summar yFrameshift deletion is induced by many types of DNA damage in cells. However, the mechanism by which deletions are generated has not been extensively explored. The number of deletions during DNA synthesis catalyzed by the 3' 5' exonuclease-free exo Klenow fragment of Escherichia coli DNA polymerase I pol I was determined systematically on dG-acetylaminofluorene dG-AAF -modified oligodeoxynucleotides templates with different bases 3' and/or 5' to the lesion. Under conditions where the dNMP deoxynucleoside 3'-monophosphate positions opposite dG-AAF can pair with its complementary base at the 5' flanking position, one-base deletions are produced. Since the relative frequency of base insertion opposite the lesion followed the order: dCMP dAMP dGMP dTMP, frequency of generating deletions paralleled to the insertion frequency of dNTP opposite the lesion. Inhibition of chain extension from the dC:dG-AAF pair also be involved in the formation of deletions. These results were supported by steady-state kinetic studies. Two and more base deletions were formed in a similar manner to that observed for one-base deletions. When the dG-AAF-modified templates containing iterated bases 5' to the lesion were used, shorter deletions predominated. The formation of deletions was reduced when exo + Klenow fragment was used, suggesting that the proofreading function of the enzyme minimizes the deletion formation. Thus, the ability of generating deletions depends on the a the nature of base inserted opposite the lesion, b sequence context to the lesion, and c the overall rate of translesion DNA synthesis past the lesion. The mechanism for deletions by E. coli DNA pol I may be applied to predict the nature of deletions generated by a variety of DNA adducts and by other prokaryotic and eukaryotic DNA polymerases.

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Section: Frequency Of Deletions Generated On Templates Containing Itesupporting

confidence: 92%

“…I describe here describe the mechanism of frameshift deletion which occurs at DNA adducts during DNA synthesis catalyzed by DNA polymerases. Our results with damaged DNA adduct strongly support the former mechanism Shibutani and Grollman, 1993;Shibutani et al, 2004 .…”

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confidence: 87%

Requirements for frameshift (deletion) during translesion synthesis

Shibutani

2004

Environ. Mutagen Res.

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“…Alternatively, the deletion may involve a misinsertion of dGTP opposite the modified base followed by slippage and extension (83). This misinsertion may utilize a Hoogsteen interaction with the incoming dGTP with the syn-conformation of the C8-modified dGuo.…”

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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“…The fact that retardation of DNA synthesis persists even after incorporation of the base immediately opposite of the lesion has an important implication for the mechanisms of mutagenesis (56)(57)(58)(59)(60)(61)(62). Such a delay during TLS increases the propensity to produce a family of misaligned slipped mutagenic intermediates (SMI), a model that is known to lead to frameshift mutations by a variety of bulky DNA adducts including AF and AAF.…”

Section: Mutational Implication Of the Long-range Af-conformational Hmentioning

confidence: 99%

“…The sequence context is a critical factor, which can be used to predict the nature of various targeted or semitargeted deletions. For example, it has been shown in Escherichia coli that insertion of a correct dCMP (most frequent) opposite of the AAF-lesion can produce one-, two-or longer-base deletions with high frequency when the appropriate complementary base match is available 5' to the lesion (59)(60)(61)(62). Analogous insertion-misalignment mechanisms could also be applied to mammalian cells (57).…”

Section: Mutational Implication Of the Long-range Af-conformational Hmentioning

confidence: 99%

Examination of the Long-range Effects of Aminofluorene-induced Conformational Heterogeneity and Its Relevance to the Mechanism of Translesional DNA Synthesis

Meneni¹,

Liang²,

Cho³

2007

Journal of Molecular Biology

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SUMMARYAdduct-induced conformational heterogeneity complicates the understanding of how DNA adducts exert mutation. A case in point is the N-deacetylated AF lesion [N-(2′-deoxyguanosin-8-yl)-2-aminofluorene], the major adduct derived from the strong liver carcinogen N-acetyl-2-aminofluorene. Three conformational families have been previously characterized and are dependent on the positioning of the aminofluorene rings: B is in the 'B-DNA' major groove, S is 'stacked' into the helix with base-displacement, and W is 'wedged' into the minor groove. In the present study, we conducted 19 F NMR, CD, Tm, and modeling experiments at various primer positions with respect to a template modified by a fluorine tagged AF-adduct (FAF). In the first set, the FAF-G was paired with C and in the second set it was paired with A. The FAF-G:C oligonucleotides were found to preferentially adopt the B-or S-conformers while the FAF-G:A mismatch ones preferred the B-and W-conformers. The conformational preferences of both series were dependent on temperature and complementary strand length; the largest differences in conformation were displayed at lower temperatures. The CD and Tm results are in general agreement with the NMR data. Molecular modeling indicated that the aminofluorene moiety in the minor groove of the W-conformer would impose a steric clash with the tight-packing amino acid residues on the DNA binding area of the Bacillus fragment (BF), a replicative DNA polymerase. In the case of the B-type conformer, the carcinogenic moiety resides in the solvent-exposed major groove throughout the replication/ translocation process. The present dynamic NMR results, combined with previous primer extension kinetic data by Miller and Grollman, support a model in which adduct-induced conformational heterogeneities at positions remote from the replication fork affect polymerase function through a long-range DNA-protein interaction.

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Mechanism of Frameshift (Deletion) Generated by Acetylaminofluorene-Derived DNA Adducts in Vitro

Cited by 21 publications

References 29 publications

Requirements for frameshift (deletion) during translesion synthesis

Requirements for frameshift (deletion) during translesion synthesis

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

Examination of the Long-range Effects of Aminofluorene-induced Conformational Heterogeneity and Its Relevance to the Mechanism of Translesional DNA Synthesis

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Mechanism of Frameshift (Deletion) Generated by Acetylaminofluorene-Derived DNA Adducts in Vitro

Cited by 21 publications

References 29 publications

Requirements for frameshift (deletion) during translesion synthesis

Requirements for frameshift (deletion) during translesion synthesis

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

Examination of the Long-range Effects of Aminofluorene-induced Conformational Heterogeneity and Its Relevance to the Mechanism of Translesional DNA Synthesis

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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