C-Linked 8-aryl guanine nucleobase adducts: biological outcomes and utility as fluorescent probes

Manderville, Richard A.; Wetmore, Stacey D.

doi:10.1039/c6sc00053c

Cited by 35 publications

(44 citation statements)

References 104 publications

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“…8-Thienyl-dG was found to increase the thermostability in each of the four syn positions by 7–10°C and its double incorporation by 18.5°C, and substituting all four syn dGs, Δ T m was higher than 36°C [ 114 ]. Stability changes resulting from the syn versus anti glycosidic conformations of dG derivatives were similar to 8-(p-cyanophenyl)-dG in TBA and 8-furyl-dG in A(htel-21) GQ systems [ 115 ]. 8-Furylguanine was also incorporated into each of the three tetrads of A(htel-21) and the effects of salts and cosolvents (acetonitrile, PEG-600, and N-methyl-mesoporphyrin) were examined on the structure.…”

Section: Stabilization or Destabilization Of A Gq By The Same Syntmentioning

confidence: 99%

In What Ways Do Synthetic Nucleotides and Natural Base Lesions Alter the Structural Stability of G-Quadruplex Nucleic Acids?

Sági¹

2017

Journal of Nucleic Acids

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Synthetic analogs of natural nucleotides have long been utilized for structural studies of canonical and noncanonical nucleic acids, including the extensively investigated polymorphic G-quadruplexes (GQs). Dependence on the sequence and nucleotide modifications of the folding landscape of GQs has been reviewed by several recent studies. Here, an overview is compiled on the thermodynamic stability of the modified GQ folds and on how the stereochemical preferences of more than 70 synthetic and natural derivatives of nucleotides substituting for natural ones determine the stability as well as the conformation. Groups of nucleotide analogs only stabilize or only destabilize the GQ, while the majority of analogs alter the GQ stability in both ways. This depends on the preferred syn or anti N-glycosidic linkage of the modified building blocks, the position of substitution, and the folding architecture of the native GQ. Natural base lesions and epigenetic modifications of GQs explored so far also stabilize or destabilize the GQ assemblies. Learning the effect of synthetic nucleotide analogs on the stability of GQs can assist in engineering a required stable GQ topology, and exploring the in vitro action of the single and clustered natural base damage on GQ architectures may provide indications for the cellular events.

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Section: Stabilization or Destabilization Of A Gq By The Same Syntmentioning

confidence: 99%

In What Ways Do Synthetic Nucleotides and Natural Base Lesions Alter the Structural Stability of G-Quadruplex Nucleic Acids?

Sági¹

2017

Journal of Nucleic Acids

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“…These aromatic mutagens are knownt ob ee nzymatically converted into aryl radicals, reactingw ith the guanine base to yield 8-aryl-guanine derivatives that closely resemble bromo analogues in their propensity to adopt a syn conformation. [35,36] Likewise, DNA lesionsl ike 8-oxo-guanine or 8-methyl-guanine form in vivo by oxidative damage or alkylation and are suggested to contribute to carcinogenic effects. [37,38] We herein report on the impact of systematic nonmatching 8-BrG substitutions in the MYC quadruplex.…”

Section: Introductionmentioning

confidence: 99%

Loop Length Affects Syn–Anti Conformational Rearrangements in Parallel G‐Quadruplexes

Karg

Weisz

2018

Chemistry A European J

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A G-quadruplex forming sequence from the MYC promoter region was modified with syn-favoring 8-bromo-2'-deoxyguanosine residues. Depending on the number and position of modifications in the intramolecular parallel G-quadruplex, substitutions with the bromoguanosine analogue at the 5'-tetrad induce conformational rearrangements with concerted all-anti to all-syn transitions for all residues of the modified G-quartet. No unfavorable steric interactions of the C8-substituents in the medium grooves are apparent in the high-resolution structure as determined for a tetrasubstituted MYC quadruplex that exclusively forms the all-syn isomer. In contrast, considerable steric clashes with 5'-phosphate oxygen atoms for those analogues that follow a less flexible 1-nucleotide loop in the native all-anti conformation seem to constitute the major driving force for the tetrad inversion and allow for the rational design of appropriately substituted sequences. Correlations found between the population of species subjected to a tetrad flip and melting temperatures indicate that more effective conformational transitions are compromised by lower thermal stabilities of the modified parallel quadruplexes.

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“…Compared to the double helix, G-quadruplexes (GQs) are compact, highly polymorphic, may be involved in telomerase inhibition 6 , and are produced by a number of guanine (G)-rich aptamers that bind small molecules 7 , proteins 8 and metal ion targets 9 with high affinity and specificity. The fluorescent-based strategies to visualize duplex-GQ exchange include extrinsic “label-free” dyes 10 , covalently attached end-labels 11 , 12 and internal-labels that include fluorescent base analogues (FBAs) 13 – 15 , which are structural mimics of the canonical nucleic acid bases 16 . Our research has focused on the utility of FBAs, particularly 8-aryl-2′-deoxyguanosine (8-aryl-dG) bases, for the development of aptasensors for proteins 14 , 15 , food toxins 7 and metal ions 17 .…”

Section: Introductionmentioning

confidence: 99%

“…The fluorescent-based strategies to visualize duplex-GQ exchange include extrinsic “label-free” dyes 10 , covalently attached end-labels 11 , 12 and internal-labels that include fluorescent base analogues (FBAs) 13 – 15 , which are structural mimics of the canonical nucleic acid bases 16 . Our research has focused on the utility of FBAs, particularly 8-aryl-2′-deoxyguanosine (8-aryl-dG) bases, for the development of aptasensors for proteins 14 , 15 , food toxins 7 and metal ions 17 . As proof-of-concept for the utility of 8-aryl-dG bases, we commonly employ the 15-mer thrombin binding aptamer (TBA, 5′-GGTTGGTGTGGTTGG) 18 that folds into a unimolecular antiparallel GQ upon binding thrombin and certain metal ions 19 .…”

Section: Introductionmentioning

confidence: 99%

A 5′-BODIPY End-label for Monitoring DNA Duplex-Quadruplex Exchange

Deore

Soldatov

Manderville

2018

Sci Rep

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Fluorescent probes that can distinguish different DNA topologies through changes in optical readout are sought after for DNA-based diagnostics. In this work, the 4,4-difluoro-4-bora-3a, 4a-diaza-s-indacene (BODIPY) chromophore attached to cyanophenyl substituents (BODIPY-CN) has been tethered to the 5′-end of the 15-mer thrombin binding aptamer (TBA) that contains the guanine (G) nucleobase. TBA folds into a unimolecular antiparallel G-quadruplex (GQ) upon binding thrombin and certain metal ions. The 5′-BODIPY-CN-TBA sample possesses a Stokes shift of ~40 nm with wavelengths of excitation/emission at 550/590 nm and exhibits a 2-fold increase in emission intensity compared to the free BODIPY-CN in aqueous buffer that possesses a brightness (εΦfl) of ~16,956 M−1. cm−1. However, when 5′-BODIPY-CN-TBA is base-paired to a complementary strand in the B-form duplex, the emission of the BODIPY-CN end-label increases 7-fold, 14-fold compared to the free-dye. This signal-on response enables the BODIPY-CN end-label to serve as a quencher-free fluorescent probe for monitoring duplex-GQ exchange. The visible end-label minimally perturbs GQ stability and thrombin binding affinity, and the modified TBA can act as a combinatorial logic circuit having INHIBIT logic functions. These attributes make BODIPY-CN a highly useful end-label for creating nanomolecular devices derived from G-rich oligonucleotides.

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C-Linked 8-aryl guanine nucleobase adducts: biological outcomes and utility as fluorescent probes

Abstract: We summarize the utility and biological outcomes resulting from direct attachment of aryl residues to the 8-site of the guanine nucleobase to afford mutagenic lesions and fluorescent probes in G-quadruplex structures.

Cited by 35 publications

References 104 publications

In What Ways Do Synthetic Nucleotides and Natural Base Lesions Alter the Structural Stability of G-Quadruplex Nucleic Acids?

In What Ways Do Synthetic Nucleotides and Natural Base Lesions Alter the Structural Stability of G-Quadruplex Nucleic Acids?

Loop Length Affects Syn–Anti Conformational Rearrangements in Parallel G‐Quadruplexes

A 5′-BODIPY End-label for Monitoring DNA Duplex-Quadruplex Exchange

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