Mechanism of Acetylaminofluorene‐dG Induced Frameshifting by Polymerase η

Schorr, Stephanie; Carell, Thomas

doi:10.1002/cbic.201000579

Cited by 13 publications

(21 citation statements)

References 26 publications

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“…The model 16-mer template (5′-CTCTCG 1 ATG 2 CCATCAC-3′) is patterned after the sequence used by Schorr and Carell in their primer kinetic studies 25 using polymerase η, except that G 2 was adducted with the fluorinated N -acetylaminofluorene (FAAF) (Fig. 1b).…”

Section: Resultsmentioning

confidence: 99%

“…Schorr and Carell 25 conducted primer extension studies with the human bypass pol η on several dG-AAF–modified Nar I sequences. The addition of the correct dC opposite the lesion during replication triggered the dC primer end to slip and resulted in the formation of various SMIs, depending on the base sequence context around the lesion.…”

Section: Discussionmentioning

confidence: 99%

“…6, 7, 24 Schorr and Carell recently conducted primer extension studies with the human bypass polymerase η on variations of the Nar I hot spot sequences. 25 Structural instability ensued after addition of the correct dC opposite dG-AAF triggered a slippage of the dC primer end to form various bulges, depending on the base sequence around the lesion. For example, dG 3 -AAF in the Nar I sequence (5′-G 1 G 2 C G 3 CC-3′) induced the −2 frameshift exclusively.…”

Section: Introductionmentioning

confidence: 99%

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Structure and Thermodynamic Insights on Acetylaminofluorene-Modified Deletion DNA Duplexes as Models for Frameshift Mutagenesis

Sandineni

Lin

MacKerell

et al. 2013

Chem. Res. Toxicol.

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2-Acetylaminofluorene (AAF) is a prototype arylamine carcinogen that forms C8-substituted dG-AAF and dG-AF as the major DNA lesions. The bulky N-acetylated dG-AAF lesion can induce various frameshift mutations depending on the base sequence around the lesion. We hypothesized that the thermodynamic stability of bulged-out slipped mutagenic intermediates (SMIs) is directly related to deletion mutations. The objective of the present study was to probe the structural/conformational basis of various dG-AAF–induced SMIs formed during a translesion synthesis. We performed spectroscopic, thermodynamic, and molecular dynamics studies of several AAF-modified 16-mer model DNA duplexes, including fully paired and −1, −2, and −3 deletion duplexes of the 5′-CTCTCGATG[FAAF]CCATCAC-3′ sequence and an additional −1 deletion duplex of the 5′-CTCTCGGCG[FAAF]CCATCAC-3′ NarI sequence. Modified deletion duplexes existed in a mixture of external B and stacked S conformers, with the population of the S conformer being ‘GC’ −1 (73%) > ‘AT’ −1 (72%) > full (60%) > −2 (55%) > −3 (37%). Thermodynamic stability was in the order of −1 deletion > −2 deletion > fully paired > −3 deletion duplexes. These results indicate that the stacked S-type conformer of SMIs are thermodynamically more stable than the conformationally flexible external B conformer. Results from the molecular dynamics simulations indicate perturbation of base stacking dominate the relative stability along with contributions from bending, duplex dynamics, solvation effects that are important in specific cases. Taken together, these results support a hypothesis that the conformational and thermodynamic stabilities of the SMIs are critical determinants for the induction of frameshift mutations.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Structure and Thermodynamic Insights on Acetylaminofluorene-Modified Deletion DNA Duplexes as Models for Frameshift Mutagenesis

Sandineni

Lin

MacKerell

et al. 2013

Chem. Res. Toxicol.

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“…128 In duplex DNA, dG-C8-AAF is known to rotate the guanine base to syn conformation, in contrast to an overwhelming anti conformation of an unmodified dG. 129,130 Biophysical and computational studies indicate that syn conformation in a base-displaced intercalated structure of the dG adduct allows formation of stable slipped intermediates.…”

Section: Tls Of Bulky Dg Lesionsmentioning

confidence: 99%

“…125,133 The role of pol η in bypassing misaligned adducts has been explored, which showed that depending on the base sequence, a cytosine inserted opposite the dG-C8 lesion slips to generate a −1, −2, or −3 frameshift intermediate that pol η can continue to replicate, in spite of a bulge. 128 In a crystal structure study, however, pol η was able to incorporate dCTP opposite the dG-C8-AAF adduct, in which TLS occured without rotation of the adduct into the anti conformation, and only one hydrogen bond was formed between the lesion and dCTP. 134 This structural investigation recognized pol η’s ability to perform error-free replication of dG-C8-AAF, in addition to its propensity to carry out frameshifts.…”

Section: Tls Of Bulky Dg Lesionsmentioning

confidence: 99%

Translesion Synthesis of 2′-Deoxyguanosine Lesions by Eukaryotic DNA Polymerases

Basu

Pande

Bose

2016

Chem. Res. Toxicol.

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With the discovery of translesion synthesis DNA polymerases, great strides have been made in the last two decades in understanding the mode of replication of various DNA lesions in prokaryotes and eukaryotes. A database search indicated that approximately 2000 articles on this topic have been published in this period. This includes research involving genetic and structural studies as well as in vitro experiments using purified DNA polymerases and accessory proteins. It is a daunting task to comprehend this exciting and rapidly emerging area of research. Even so, as the majority of DNA damage occurs at 2′-deoxyguanosine residues, this perspective attempts to summarize a subset of this field, focusing on the most relevant eukaryotic DNA polymerases responsible for their bypass.

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Synthesis of C8‐N‐Arylamine‐Modified 2′‐Deoxyguanosine‐5′‐Triphosphates and Their Effects on Primer Extension by DNA Polymerases

2015

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C8-N-arylamine adducts of 2'-deoxyguanosine (2'-dG) play an important role in the induction of the chemical carcinogenesis caused by aromatic amines. C8-N-acetyl-N-arylamine dG adducts that differ in their substitution pattern in the aniline moiety were converted by cycloSal technology into the corresponding C8-N-acetyl-N-arylamine-2'-deoxyguanosine-5'-triphosphates and C8-NH-arylamine-2'-deoxyguanosine-5'-triphosphates. Their conformation preference has been investigated by NOE spectroscopy and DFT calculations. The substrate properties of the C8-dG adducts were studied in primer-extension assays by using Klenow fragment exo(-) of Escherichia coli DNA polymerase I and human DNA polymerase β. It was shown that the incorporation was independent of the substitution pattern in the aryl moiety and the N-acetyl group. Although the triphosphates were poor substrates for the human polymerases, they were incorporated twice before the termination of the elongation process occurred; this might demonstrate the importance of C8-N-arylamine-2'-deoxyguanosine-5'-triphosphates in chemical carcinogenesis.

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Mechanism of Acetylaminofluorene‐dG Induced Frameshifting by Polymerase η

Abstract: Side‐stepping thermodynamics. In contrast to the traditional benzoin reaction, which can yield a mixture of homo and mixed adducts, only one regioisomer was obtained from the new cyanide‐catalyzed silyl benzoin reaction between acylsilanes and aldehydes (see scheme).

Cited by 13 publications

References 26 publications

Structure and Thermodynamic Insights on Acetylaminofluorene-Modified Deletion DNA Duplexes as Models for Frameshift Mutagenesis

Structure and Thermodynamic Insights on Acetylaminofluorene-Modified Deletion DNA Duplexes as Models for Frameshift Mutagenesis

Translesion Synthesis of 2′-Deoxyguanosine Lesions by Eukaryotic DNA Polymerases

Synthesis of C8‐N‐Arylamine‐Modified 2′‐Deoxyguanosine‐5′‐Triphosphates and Their Effects on Primer Extension by DNA Polymerases

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