Translesion Synthesis across 1,N6-(2-Hydroxy-3-hydroxymethylpropan-1,3-diyl)-2′-deoxyadenosine (1,N6-γ-HMHP-dA) Adducts by Human and Archebacterial DNA Polymerases

Kotapati, Srikanth; Maddukuri, Leena; Wickramaratne, Susith; Seneviratne, Uthpala; Goggin, Melissa; Pence, Matthew G.; Villalta, Peter W.; Guengerich, F. Peter; Marnett, Lawrence J.; Tretyakova, Natalia

doi:10.1074/jbc.m112.396788

Cited by 18 publications

(68 citation statements)

References 45 publications

(18 reference statements)

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“…As observed previously for C5-thymine lesions (36), hPol was more efficient than hPol . Higher catalytic efficiency of hPol than hPol is consistent with previous reports for other bulky nucleobase lesions such as exocyclic adducts (35,(71)(72)(73) and DNA-glutathione conjugates (74). Unlike C5-thymine-peptide lesions, which induce high numbers of frameshift and base substitution mutations upon primer extension in the presence of hPol and hPol (36), C7-G conjugated DPCs were not miscoding.…”

Section: 64supporting

confidence: 78%

Bypass of DNA-Protein Cross-links Conjugated to the 7-Deazaguanine Position of DNA by Translesion Synthesis Polymerases

Wickramaratne

Mukherjee

et al. 2016

Journal of Biological Chemistry

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DNA-protein cross-links (DPCs) are bulky DNA lesions that form both endogenously and following exposure to bis-electrophiles such as common antitumor agents. The structural and biological consequences of DPCs have not been fully elucidated due to the complexity of these adducts. The most common site of DPC formation in DNA following treatment with bis-electrophiles such as nitrogen mustards and cisplatin is the N7 position of guanine, but the resulting conjugates are hydrolytically labile and thus are not suitable for structural and biological studies. In this report, hydrolytically stable structural mimics of N7-guanine-conjugated DPCs were generated by reductive amination reactions between the Lys and Arg side chains of proteins/peptides and aldehyde groups linked to 7-deazaguanine residues in DNA. These model DPCs were subjected to in vitro replication in the presence of human translesion synthesis DNA polymerases. DPCs containing full-length proteins (11-28 kDa) or a 23-mer peptide blocked human polymerases and . DPC conjugates to a 10-mer peptide were bypassed with nucleotide insertion efficiency 50 -100-fold lower than for native G. Both human polymerase (hPol) and hPol inserted the correct base (C) opposite the 10-mer peptide cross-link, although small amounts of T were added by hPol . Molecular dynamics simulation of an hPol ternary complex containing a template-primer DNA with dCTP opposite the 10-mer peptide DPC revealed that this bulky lesion can be accommodated in the polymerase active site by aligning with the major groove of the adducted DNA within the ternary complex of polymerase and dCTP.

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Section: 64supporting

confidence: 78%

Bypass of DNA-Protein Cross-links Conjugated to the 7-Deazaguanine Position of DNA by Translesion Synthesis Polymerases

Wickramaratne

Mukherjee

et al. 2016

Journal of Biological Chemistry

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“…These electrophilic epoxides are held responsible for the carcinogenicity and mutagenicity of BD because of their propensity to react with DNA to form covalent nucleobase adducts [15–19], which can cause DNA polymerase errors [20–23]. Sensitive and specific quantitative methods for BD-DNA adducts in vivo are needed because they can be used in human cancer risk assessment [24, 25].…”

Section: Introductionmentioning

confidence: 99%

NanoLC/ESI⁺ HRMS³ Quantitation of DNA Adducts Induced by 1,3-Butadiene

Sangaraju

Villalta

Wickramaratne

et al. 2014

J. Am. Soc. Mass Spectrom.

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Human exposure to 1,3-butadiene (BD) present in automobile exhaust, cigarette smoke, and forest fires is of great concern because of its potent carcinogenicity. The adverse health effects of BD are mediated by its epoxide metabolites such as 3,4-epoxy-1-butene (EB), which covalently modify genomic DNA to form promutagenic nucleobase adducts. Because of their direct role in cancer, BD-DNA adducts can be used as mechanism-based biomarkers of BD exposure. In the present work, a mass spectrometry-based methodology was developed for accurate, sensitive, and precise quantification of EB-induced N-7-(1-hydroxy-3-buten-2-yl) guanine (EB-GII) DNA adducts in vivo. In our approach, EB-GII adducts are selectively released from DNA backbone by neutral thermal hydrolysis, followed by ultrafiltration, offline HPLC purification, and isotope dilution nanoLC/ESI+-HRMS3 analysis on an Orbitrap Velos mass spectrometer. Following method validation, EB-GII lesions were quantified in human fibrosarcoma (HT1080) cells treated with micromolar concentrations of EB and in liver tissues of rats exposed to sub ppm concentrations of BD (0.5–1.5 ppm). EB-GII concentrations increased linearly from 1.15±0.23 to 10.11±0.45adducts per 108 nucleotides in HT1080 cells treated with 0.5–10 μM DEB. EB-GII concentrations in DNA of laboratory rats exposed to 0.5, 1.0 and 1.5 ppm BD were 0.17±0.05, 0.33±0.08, and 0.50±0.04 adducts per 108 nucleotides, respectively. We also used the new method to determine the in vivo half-life of EB-GII adducts in rat liver DNA (2.20±0.12 days) and to detect EB-GII in human blood DNA. To our knowledge, this is the first application of nanoLC/ESI+-HRMS3 Orbitrap methodology to quantitative analysis of DNA adducts in vivo.

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“…(Studies with REV1, which is highly selective for incorporation of C, 47 were not considered here.) High dCTP misincorporation was detected opposite the N 6 dA-(OH) 2 butyl-GSH adduct with Pol T7 (0.85) or Pol κ (0.45) (Figure 2, Table 1), which is of interest in that Pol κ is known to insert mainly T (and some A and G) opposite 1, N 6 -γ-HMHP-dA (formed from DEB) 45 and mainly A opposite 7,8-dihydro-8-oxo-2´-deoxyguanosine. 48 …”

Section: Discussionmentioning

confidence: 94%

“…The order of bypass efficiency, Pol T7 ~ Pol η > Dpo4 > Pol κ > Pol ι (Figure 1), is similar to the reported bypass efficiency past N 2 ,3-ethenoguanine by these polymerases. 32,42 Compared with Pol κ and Pol ι, Pol η exhibited higher bypass efficiency past the adducts 1, N 6 -ethenoadenine 43,44 and 1, N 6 -(2-hydroxy-3-hydroxymethylpropan-1,3-diyl)-2´-deoxyadenosine (1, N 6 -γ-HMHP-dA) adduct (formed from DEB), 45 which has been proposed to contribute to mutagenicity of BD. 16 However, Pol ι showed some single base incorporation opposite 1, N 6 -γ-HMHP-dA, 45 and did not extend primer well opposite N 2 ,3-ethenoguanine.…”

Section: Discussionmentioning

confidence: 99%

“…32,42 Compared with Pol κ and Pol ι, Pol η exhibited higher bypass efficiency past the adducts 1, N 6 -ethenoadenine 43,44 and 1, N 6 -(2-hydroxy-3-hydroxymethylpropan-1,3-diyl)-2´-deoxyadenosine (1, N 6 -γ-HMHP-dA) adduct (formed from DEB), 45 which has been proposed to contribute to mutagenicity of BD. 16 However, Pol ι showed some single base incorporation opposite 1, N 6 -γ-HMHP-dA, 45 and did not extend primer well opposite N 2 ,3-ethenoguanine. 42 The ability of Pol T7, a high-fidelity processive polymerase, to efficiently bypass these large adducts positioned at a Watson-Crick pairing site, is surprising, in light of previous work with N 2 dG adducts.…”

Section: Discussionmentioning

confidence: 99%

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Replication past the Butadiene Diepoxide-Derived DNA Adduct S-[4-(N⁶-Deoxyadenosinyl)-2,3-dihydroxybutyl]glutathione by DNA Polymerases

Cho

Guengerich

2013

Chem. Res. Toxicol.

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1,2,3,4-Diepoxybutane (DEB), a metabolite of the carcinogen butadiene, has been shown to cause glutathione (GSH)-dependent base-substitution mutations, especially A:T to G:C in Salmonella typhimurium TA1535 (Chem. Res. Toxicol. 23, 1544 (2010)) and Escherichia coli TRG8 cells (Chem. Res. Toxicol. 25, 1522 (2012)). We previously identified S-[4-(N6-deoxyadenosinyl)-2,3-dihydroxybutyl]GSH (N6dA-(OH)2butyl-GSH) as a major adduct in the reaction of S-(2-hydroxy-3,4-epoxybutyl)glutathione (DEB-GSH conjugate) with nucleosides and calf thymus DNA and in vivo in livers of mice and rats treated with DEB (Chem. Res. Toxicol. 25, 706 (2012)). For investigation of the miscoding potential of the major DEB-GSH conjugate-derived DNA adduct (N6dA-(OH)2butyl-GSH) and the effect of GSH conjugation on replication of DEB, extension studies were performed in duplex DNA substrates containing the site specifically-incorporated N6dA-(OH)2butyl-GSH adduct, N6-(2,3,4-trihydroxybutyl)deoxyadenosine adduct (N6dA-butanetriol), or unmodified deoxyadenosine (dA) by human DNA polymerases (Pol) η, ι, and κ, bacteriophage polymerase T7, and Sulfolobus solfataricus polymerase Dpo4. Although dTTP incorporation was the most preferred addition opposite the N6dA-(OH)2butyl-GSH adduct, N6dA-butanetriol adduct, or unmodified dA by all polymerases, dCTP misincorporation frequency opposite N6dA-(OH)2butyl-GSH was significantly higher than that opposite the N6dA-butanetriol adduct or unmodified dA by Pol κ or Pol T7. LC-MS/MS analysis of full-length primer extension products confirmed that Pol κ or Pol T7 incorporated the incorrect base C opposite N6dA-(OH)2butyl-GSH lesion. These results indicate the relevance of GSH-containing adducts for the A:T to G:C mutations produced by DEB.

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Translesion Synthesis across 1,N6-(2-Hydroxy-3-hydroxymethylpropan-1,3-diyl)-2′-deoxyadenosine (1,N6-γ-HMHP-dA) Adducts by Human and Archebacterial DNA Polymerases

Abstract: adducts are formed in DNA by 1,2,3,4-diepoxybutane (metabolite of human carcinogen 1,3-butadiene). Results: hpols and carry out translesion synthesis, incorporating T, G, or A opposite the 1,N

Cited by 18 publications

References 45 publications

Bypass of DNA-Protein Cross-links Conjugated to the 7-Deazaguanine Position of DNA by Translesion Synthesis Polymerases

Bypass of DNA-Protein Cross-links Conjugated to the 7-Deazaguanine Position of DNA by Translesion Synthesis Polymerases

NanoLC/ESI⁺ HRMS³ Quantitation of DNA Adducts Induced by 1,3-Butadiene

Replication past the Butadiene Diepoxide-Derived DNA Adduct S-[4-(N⁶-Deoxyadenosinyl)-2,3-dihydroxybutyl]glutathione by DNA Polymerases

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Translesion Synthesis across 1,N6-(2-Hydroxy-3-hydroxymethylpropan-1,3-diyl)-2′-deoxyadenosine (1,N6-γ-HMHP-dA) Adducts by Human and Archebacterial DNA Polymerases

Abstract: adducts are formed in DNA by 1,2,3,4-diepoxybutane (metabolite of human carcinogen 1,3-butadiene). Results: hpols and carry out translesion synthesis, incorporating T, G, or A opposite the 1,N

Cited by 18 publications

References 45 publications

Bypass of DNA-Protein Cross-links Conjugated to the 7-Deazaguanine Position of DNA by Translesion Synthesis Polymerases

Bypass of DNA-Protein Cross-links Conjugated to the 7-Deazaguanine Position of DNA by Translesion Synthesis Polymerases

NanoLC/ESI+ HRMS3 Quantitation of DNA Adducts Induced by 1,3-Butadiene

Replication past the Butadiene Diepoxide-Derived DNA Adduct S-[4-(N6-Deoxyadenosinyl)-2,3-dihydroxybutyl]glutathione by DNA Polymerases

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Product

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NanoLC/ESI⁺ HRMS³ Quantitation of DNA Adducts Induced by 1,3-Butadiene

Replication past the Butadiene Diepoxide-Derived DNA Adduct S-[4-(N⁶-Deoxyadenosinyl)-2,3-dihydroxybutyl]glutathione by DNA Polymerases