Oligonucleotide probes containing pyrimidine analogs reveal diminished hydrogen bonding capacity of the DNA adduct O6-methyl-G in DNA duplexes

Angelov, T.; Dahlmann, Heidi A.; Sturla, Shana J.

doi:10.1016/j.bmc.2013.07.036

Cited by 8 publications

(7 citation statements)

References 23 publications

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“…We hypothesized that the larger synthetic bases were more effective for sensing alkylation sites because generally, larger nucleobases π ‐stack more strongly than smaller nucleobases due to having a larger area of overlap with neighbouring bases. This model is supported by data regarding nucleosides with benzene, naphthalene, and pyrene nucleobases, as well as expanded natural nucleobases (in so‐called expanded ‘ x ’‐and widened ‘ y ’‐DNA) . Given that larger nucleobases facilitate π ‐stacking within the DNA duplex, we designed new expanded nucleoside analogues ExBenzi and ExBIM ( Figure ,b ), which both stabilize O 6 ‐MeG in preference to G. These structures were critical for a first in‐gene colorimetric quantification of O 6 ‐alkylG; however several fundamental questions remained open concerning these structures such as the basis of their improved performance, selectivity, and intrinsic fluorescence behaviour …”

Section: Introductionmentioning

confidence: 72%

Fluorescent Nucleobase Analogues with Extended Pi Surfaces Stabilize DNA Duplexes Containing O⁶‐Alkylguanine Adducts

Dahlmann

Berger

Kung

et al. 2018

Helvetica Chimica Acta

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Chemical alkylation of DNA produces potentially toxic and mutagenic damage such as O6‐alkylguanine (O6‐alkylG) adducts. Non‐natural nucleoside analogues that pair with DNA adducts provide a potential basis for studying damaged DNA. Herein, we evaluated the base pairing properties of elongated nucleoside analogues containing napthalene‐derived tricyclic nucleobases as DNA adduct‐pairing nucleoside analogues in DNA hybridization probes. DNA duplex melting studies revealed that the elongated nucleoside analogs formed more stable base pairs opposite O6‐alkylG than G and were better able to distinguish between G, O6‐alkylG, and an abasic site than any previously described nucleoside analogue. DNA duplexes containing an elongated base analogue exhibited different fluorescence intensities when paired opposite O6‐alkylG vs. G or abasic sites. Their selectivity for stabilizing alkylated DNA make the elongated hydrophobic base analogues improved candidates for incorporating into DNA hybridization probes targeting O6‐alkylG.

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Section: Introductionmentioning

confidence: 72%

Fluorescent Nucleobase Analogues with Extended Pi Surfaces Stabilize DNA Duplexes Containing O⁶‐Alkylguanine Adducts

Dahlmann

Berger

Kung

et al. 2018

Helvetica Chimica Acta

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“…It is not known whether this approach is viable for sensing O 6 -MeG in mixtures of targets. With the goal of expanding alkylation adduct recognition, we have devised a class of synthetic nucleosides with mixed aromatic and H-bonding moieties. − The first example was a perimidinone-derived nucleoside (Per, Figure S1) that formed more stable DNA duplexes when paired with O 6 -benzylguanine ( O 6 -BnG) than with G . In a recent proof-of-principle study, we demonstrated that coupling hybridization probes containing Per with gold nanoparticles (AuNPs) allowed for the quantification of the model O 6 -alkylG adduct O 6 -BnG within a defined, albeit non-biologically relevant, DNA sequence in the presence of excess unmodified DNA strands …”

Section: Introductionmentioning

confidence: 99%

In-Gene Quantification of O⁶-Methylguanine with Elongated Nucleoside Analogues on Gold Nanoprobes

et al. 2016

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Exposure of DNA to chemicals can result in the formation of DNA adducts, a molecular initiating event in genotoxin-induced carcinogenesis. O(6)-Methylguanine (O(6)-MeG) is a highly mutagenic DNA adduct that forms in human genomic DNA upon reaction with methylating agents of dietary, environmental, or endogenous origin. In this work, we report the design and synthesis of novel non-natural nucleoside analogues 1'-β-[1-naphtho[2,3-d]imidazol-2(3H)-one)]-2'-deoxy-d-ribofuranose and 1'-β-[1-naphtho[2,3-d]imidazole]-2'-deoxy-d-ribofuranose and their use for quantifying O(6)-MeG within mutational hotspots of the human KRAS gene. The novel nucleoside analogues were incorporated into oligonucleotides conjugated to gold nanoparticles to comprise a DNA hybridization probe system for detecting O(6)-MeG in a sequence-specific manner on the basis of colorimetric readout of the nanoparticles. The concept described herein is unique in utilizing new nucleoside analogues with elongated hydrophobic surfaces to successfully measure in-gene abundance of O(6)-MeG in mixtures with competing unmodified DNA.

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“…Complementing structural insight, the strategy of using synthetic nucleotides to probe interactions with damaged sites in DNA has been informative. , Previously, we have developed adduct-directed nucleoside analogues that vary in size, π surface area, and hydrogen-bonding potential. These modified bases were found to stabilize duplexes containing O 6 -alkylguanine DNA adducts. − With the use of a specialized Pol it has been shown that a synthetic nucleotide can promote full extension past O 6 -benzylguanine adduct . However, several of these analogues can be inserted opposite a distortion and block further extension .…”

Section: Introductionmentioning

confidence: 99%

Nucleotides with Altered Hydrogen Bonding Capacities Impede Human DNA Polymerase η by Reducing Synthesis in the Presence of the Major Cisplatin DNA Adduct

et al. 2015

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Human DNA polymerase η (hPol η) contributes to anticancer drug resistance by catalyzing the replicative bypass of DNA adducts formed by the widely used chemotherapeutic agent cis-diamminedichloroplatinum (cisplatin). A chemical basis for overcoming bypass-associated resistance requires greater knowledge of how small molecules influence the hPol η-catalyzed bypass of DNA adducts. In this study, we demonstrated how synthetic nucleoside triphosphates act as hPol η substrates and characterized their influence on hPol η-mediated DNA synthesis over unmodified and platinated DNA. The single nucleotide incorporation efficiency of the altered nucleotides varied by more than 10-fold and the higher incorporation rates appeared to be attributable to the presence of an additional hydrogen bond between incoming dNTP and templating base. Finally, full-length DNA synthesis in the presence of increasing concentrations of synthetic nucleotides reduced the amount of DNA product independent of the template, representing the first example of hPol η inhibition in the presence of a platinated DNA template.

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Oligonucleotide probes containing pyrimidine analogs reveal diminished hydrogen bonding capacity of the DNA adduct O6-methyl-G in DNA duplexes

Cited by 8 publications

References 23 publications

Fluorescent Nucleobase Analogues with Extended Pi Surfaces Stabilize DNA Duplexes Containing O⁶‐Alkylguanine Adducts

Fluorescent Nucleobase Analogues with Extended Pi Surfaces Stabilize DNA Duplexes Containing O⁶‐Alkylguanine Adducts

In-Gene Quantification of O⁶-Methylguanine with Elongated Nucleoside Analogues on Gold Nanoprobes

Nucleotides with Altered Hydrogen Bonding Capacities Impede Human DNA Polymerase η by Reducing Synthesis in the Presence of the Major Cisplatin DNA Adduct

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Oligonucleotide probes containing pyrimidine analogs reveal diminished hydrogen bonding capacity of the DNA adduct O6-methyl-G in DNA duplexes

Cited by 8 publications

References 23 publications

Fluorescent Nucleobase Analogues with Extended Pi Surfaces Stabilize DNA Duplexes Containing O6‐Alkylguanine Adducts

Fluorescent Nucleobase Analogues with Extended Pi Surfaces Stabilize DNA Duplexes Containing O6‐Alkylguanine Adducts

In-Gene Quantification of O6-Methylguanine with Elongated Nucleoside Analogues on Gold Nanoprobes

Nucleotides with Altered Hydrogen Bonding Capacities Impede Human DNA Polymerase η by Reducing Synthesis in the Presence of the Major Cisplatin DNA Adduct

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Fluorescent Nucleobase Analogues with Extended Pi Surfaces Stabilize DNA Duplexes Containing O⁶‐Alkylguanine Adducts

Fluorescent Nucleobase Analogues with Extended Pi Surfaces Stabilize DNA Duplexes Containing O⁶‐Alkylguanine Adducts

In-Gene Quantification of O⁶-Methylguanine with Elongated Nucleoside Analogues on Gold Nanoprobes