Structural and biochemical impact of C8-aryl-guanine adducts within the NarI recognition DNA sequence: influence of aryl ring size on targeted and semi-targeted mutagenicity

Sproviero, Michael; Verwey, Anne M. R.; Rankin, Katherine M.; Witham, Aaron A.; Soldatov, D. V.; Manderville, Richard A.; Fekry, Mostafa I.; Sturla, Shana J.; Sharma, Purshotam; Wetmore, Stacey D.

doi:10.1093/nar/gku1093

Cited by 37 publications

(218 citation statements)

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“…This may have implications for the downstream cellular events similar to the recent studies that indicated the presence of bulky arylamine substitutions in the major groove prevent translesion synthesis [29,30]; (iii) Watson-Crick base-pair hydrogenbonds are more or less maintained in all three platinated-DNAs with the exception of the hydrogen-bond between the O2 atom of g6 and N2(H21) atom of C19 which was characterized by a drop in occupancy in all three platinated-DNAs. The hydrogen-bond between O4 atom of T8 and N6(H61) atom of A17 also showed a drop in occupancy with cisplatin-DNA and oxaliplatin-DNA adducts.…”

Section: Discussionmentioning

confidence: 71%

Comprehensive Comparative Analysis of the Morphological Changes in a 12-mer DNA Oligonucleotide upon Platination by Cisplatin, Oxaliplatin and BNP3029 (a Substituted Cyano ligand-based Platinum analogue) using Molecular Dynamics Simulation Studies

PNV¹,

Py²,

Ar³

et al. 2014

J Phys Chem Biophys

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and (vi) increased replicative bypass (or trans-lesion synthesis).In order to develop platinum analogues that overcome the aforementioned limitations, key characteristics were evaluated in studies reported herein, and a series of platinum analogues with substituted cyano groups as the carrier ligand were synthesized [5]. In an earlier study, ab initio computational studies on cisplatin, oxaliplatin and BNP3029 (Figure 1), a representative substituted cyano ligand from our novel platinum complexes [6], were reported. Herein, we present a comprehensive comparative computational study on the geometrical and morphological changes induced by cisplatin, oxaliplatin and BNP3029 upon binding to a 12-mer DNA oligonucleotide using molecular dynamics simulations with key findings described using Kolmogorov-Smirnov based statistical analyses [7]. Materials and Methods Molecular dynamics (MD) simulation: B-DNA and platinated-DNA with cisplatin, oxaliplatin and BNP3029MD simulations were carried out using the AMBER6.0 suite of programs [8] employing the parm99 forcefield. For a better description of α/γ backbone angle conformers in DNA, the parm99 forcefield was modified with the inclusion of parmbsc0 forcefield [9] AbstractCisplatin is an important anti-cancer agent widely used in the clinic; however, it has several notable limitations. To develop novel platinum analogues, key characteristics were considered that may result in more effective platinum analogues. In this study, we present comprehensive molecular dynamics simulation studies using a 12-mer DNA (5'-CCTCTggTCTCC-3', gg= the site of platination) oligonucleotide which was platinated with cisplatin (1), oxaliplatin_1R_2R (2), and BNP3029 (3, a novel substituted cyano platinum analogue, PtCl 2 [N≡C(CH 2 ) 3 (C 6 H 5 )] 2 ), and analyzed the large data output using the Kolmogorov-Smirnov statistical analyses. In summary, data indicated that BNP3029-DNA had less A-like DNA morphology in comparison to cisplatin-DNA and oxaliplatin-DNA thus maintaining a more B-like DNA form. BNP3029 demonstrated more potent cytotoxic activity, relative to cisplatin and oxaliplatin, in a variety of human cancer cell lines, including several platinum-resistant cell lines. 5'-TCTCCGGTCTCC-3' DNA sequence for B-DNA was used for each MD run. In the case of platinated-DNA, N7 atoms of the two guanines (gg) attach to platinum atom forming the platinum-DNA adduct (5'-TCTCCggTCTCC-3'). Published parameters for terms involving platinum with DNA bases (such as bond, angle and dihedral) were employed [10]. The only deviation from the published parameters was the use of 1.8 Å vdW radius for platinum in the current study based on the recommendation of smaller radius for platinum [11] compared to the 2.2 Å radius used in reference 10. J Phys Chem Total number of MD runsFor B-DNA, five separate runs were performed starting from the same topology and coordinates for the randomly generated initial velocities by using five different seeds. For four of the seeds, MD runs were performed for a period of 10 n...

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Section: Discussionmentioning

confidence: 71%

Comprehensive Comparative Analysis of the Morphological Changes in a 12-mer DNA Oligonucleotide upon Platination by Cisplatin, Oxaliplatin and BNP3029 (a Substituted Cyano ligand-based Platinum analogue) using Molecular Dynamics Simulation Studies

PNV¹,

Py²,

Ar³

et al. 2014

J Phys Chem Biophys

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“…26 In contrast, the chlorinated O-linked adducts strongly stalled insertion one base across from the lesion (at position 1; see numbering of template in Figure 4a, FLE by the polymerase adds 7 bases (up to position 7 on the gel)). Replication past [PCP]G was more strongly blocked than replication past [TCP]G, as some +6 and …”

Section: Chemical Research In Toxicologymentioning

confidence: 99%

“…For example, approximately 12 and 16% of the extended primers were further extended to include four C bases opposite [TCP]G and [PCP]G, respectively, which is indicative of polymerase slippage. 26 In the presence of all four dNTPs (Figure 6c), [PhO]G was extended to create a full-length product. Extension past both chlorinated adducts increased, with faint bands detected corresponding to a full-length product.…”

Section: And a Benzo-[a]pyrene Diol Epoxide (Bpde) Adduct Of Da ([Bpdmentioning

confidence: 99%

“…21,22 C-Linked C8-dG adducts also have a strong tendency to induce polymerase slippage when inserted into the G3-position of NarI. 26 In this case, the Clinked adducts do not stabilize the SMI, but they have a strong syn-conformational preference (25−27 kJ mol −1 ). 26,27 Insertion of C opposite C-linked adducts requires the polymerase to flip the adduct from its stable syn-conformation into the energetically destabilized anti-conformation.…”

Section: Chemical Research In Toxicologymentioning

confidence: 99%

“…The single-ringed N-linked C8-aniline-dG adduct preferentially induces B-type conformation and lacks potent mutagenicity. 25 In contrast to N-linked C8-dG adducts, C-linked lesions tend to induce B-type conformation, although conformational heterogeneity is observed depending on the size of the C8-aryl ring, 26 the nature and placement of substituents on the C8-aryl ring, 27 and the adduct ionization state. 28 Thus, C-and Nlinked adducts have different mutagenic outcomes.…”

Section: ■ Introductionmentioning

confidence: 99%

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Chlorine Functionalization of a Model Phenolic C8-Guanine Adduct Increases Conformational Rigidity and Blocks Extension by a Y-Family DNA Polymerase

Witham

Verwey

Sproviero

et al. 2015

Chem. Res. Toxicol.

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Certain phenoxyl radicals can attach covalently to the C8-site of 2'-deoxyguanosine (dG) to afford oxygen-linked C8-dG adducts. Such O-linked adducts can be chemically synthesized through a nucleophilic displacement reaction between a phenolate and a suitably protected 8-Br-dG derivative. This permits the generation of model O-linked C8-dG adducts on scales suitable for insertion into oligonucleotide substrates using solid-phase DNA synthesis. Variation of the C8-aryl moiety provides an opportunity to derive structure-activity relationships on adduct conformation in duplex DNA and replication bypass by DNA polymerases. In the current study, the influence of chlorine C8-dG functionalization on in vitro DNA replication by Klenow fragment exo(-) (Kf(-)) and the Y-family polymerase (Sulfolobus solfataricus P2 DNA polymerase IV (Dpo4)) has been determined. Model O-linked C8-dG adducts derived from the pentachlorophenoxyl radical ([PCP]G) and 2,4,6-trichlorophenoxyl radical ([TCP]G) were inserted into the reiterated G3-position of the NarI sequence (12-mer, NarI(12); and 22-mer, NarI(22)), which is a known hotspot for frameshift mutations mediated by N-linked polycyclic C8-dG adducts in bacterial mutagenesis. Within the NarI(12) duplex, the unsubstituted C8-phenoxy-dG ([PhO]G) adduct adopts a minimally perturbed B-form helix. Chlorination of [PhO]G to afford [PCP]G does not significantly change the adduct conformation within the NarI(12) duplex, as predicted by molecular dynamics simulations. However, when using NarI(22) for DNA synthesis in vitro, the chlorinated [PCP]G and [TCP]G lesions significantly block DNA replication by Kf(-) and Dpo4, whereas [PhO]G is readily bypassed. These findings highlight the impact that chlorine substituents impart to bulky C8-dG lesions.

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Expanding APEX2 Substrates for Proximity‐Dependent Labeling of Nucleic Acids and Proteins in Living Cells

Zhou

Wang

et al. 2019

Angewandte Chemie

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The subcellular organization of biomolecules such as proteins and nucleic acids is intimately linked to their biological functions.A PEX2, an engineered ascorbate peroxidase that enables proximity-dependent labeling of proteins in living cells,has emerged as apowerful tool for deciphering the molecular architecture of various subcellular structures.However,only phenolic compounds have thus far been employed as APEX2 substrates,and the resulting phenoxyl radicals preferentially react with electron-rich amino acid residues.T his narrowscope of substrates could potentially limit the application of APEX2. In this study,wescreened apanel of aromatic compounds and identified biotin-conjugated arylamines as novel probes with significantly higher reactivity towards nucleic acids.A sademonstration of the spatial specificity and depth of coverageinmammalian cells,weapplied APEX2 labeling with biotin-aniline (Btn-An) in the mitochondrial matrix, capturing all 13 mitochondrial messenger RNAs and none of the cytoplasmic RNAs.A PEX2-mediated Btn-An labeling of RNAi st hus ap romising method for mapping the subcellular transcriptome,w hich could shed light on its functions in cell physiology.

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Structural and biochemical impact of C8-aryl-guanine adducts within the NarI recognition DNA sequence: influence of aryl ring size on targeted and semi-targeted mutagenicity

Cited by 37 publications

References 72 publications

Comprehensive Comparative Analysis of the Morphological Changes in a 12-mer DNA Oligonucleotide upon Platination by Cisplatin, Oxaliplatin and BNP3029 (a Substituted Cyano ligand-based Platinum analogue) using Molecular Dynamics Simulation Studies

Comprehensive Comparative Analysis of the Morphological Changes in a 12-mer DNA Oligonucleotide upon Platination by Cisplatin, Oxaliplatin and BNP3029 (a Substituted Cyano ligand-based Platinum analogue) using Molecular Dynamics Simulation Studies

Chlorine Functionalization of a Model Phenolic C8-Guanine Adduct Increases Conformational Rigidity and Blocks Extension by a Y-Family DNA Polymerase

Expanding APEX2 Substrates for Proximity‐Dependent Labeling of Nucleic Acids and Proteins in Living Cells

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