Targeting Abasic Sites and Single Base Bulges in DNA with Metalloinsertors

Zeglis, Brian M.; Boland, Jennifer A.; Barton, Jacqueline K.

doi:10.1021/ja801479y

Cited by 75 publications

(63 citation statements)

References 33 publications

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“…Failure to repair AP sites poses a severe challenge to polymerases and also leads to strand breaks, DNA cross-links, and transcriptional mutations, resulting in cellular dysfunction (1,2,4). Common detection methods for AP sites include using aldehyde-reactive probes (5,6) followed by an ELISA-like assay (7), fluorescence microscopy (8), or atomic force microscopy (9); various metalloinsertors (10), mass spectrometry (11), and isotope labels (12) can also help visualize this lesion. There is urgent need for methods that provide surrounding sequence information and have the ability to detect multiple damage sites per strand, a phenomenon of significant biological importance (13).…”

Section: Alpha-hemolysin | Crown Ethers | Single-molecule Detection |mentioning

confidence: 99%

Crown ether–electrolyte interactions permit nanopore detection of individual DNA abasic sites in single molecules

Fleming

White

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

129

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DNA abasic (AP) sites are one of the most frequent lesions in the genome and have a high mutagenic potential if unrepaired. After selective attachment of 2-aminomethyl-18-crown-6 (18c6), individual AP lesions are detected during electrophoretic translocation through the bacterial protein ion channel α-hemolysin (α-HL) embedded in a lipid bilayer. Interactions between 18c6 and Na þ produce characteristic pulse-like current amplitude signatures that allow the identification of individual AP sites in single molecules of homopolymeric or heteropolymeric DNA sequences. The bulky 18c6-cation complexes also dramatically slow the DNA motion to more easily recordable levels. Further, the behaviors of the AP-18c6 adduct are different with respect to the directionalities of DNA entering the protein channel, and they can be precisely manipulated by altering the cation (Li þ , Na þ or K þ ) of the electrolyte. This method permits detection of multiple AP lesions per strand, which is unprecedented in other work. Additionally, insights into the thermodynamics and kinetics of 18c6-cation interactions at a singlemolecule level are provided by the nanopore measurement.alpha-hemolysin | crown ethers | single-molecule detection | DNA damage

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Section: Alpha-hemolysin | Crown Ethers | Single-molecule Detection |mentioning

confidence: 99%

Crown ether–electrolyte interactions permit nanopore detection of individual DNA abasic sites in single molecules

Fleming

White

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

129

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“…Many attempts have been made to prepare such compounds. Examples of promising bulge-binding agents discovered to date are: those based on NCSchrom, a wedge-shaped enediyne antitumor antibiotic neocarzinostatin chromophore, 2-acylamino-1,8-naphthyridine, rhodium intercalators, the zinc(II) complex of 1-(4-quinoylyl)methyl-1,4,7,10-tetraazacyclododecane, and dinuclear ruthenium complexes [8][9][10][11][12][13].…”

Section: Introductionmentioning

confidence: 99%

Recognition of DNA bulges by dinuclear iron(II) metallosupramolecular helicates

2014

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Bulged DNA structures are of general biological significance because of their important roles in a number of biochemical processes. Compounds capable of targeting bulged DNA sequences can be used as probes for studying their role in nucleic acid function, or could even have significant therapeutic potential. The interaction of [Fe 2 L 3 ] 4+ metallosupramolecular helicates (L = C 25 H 20 N 4 ) with DNA duplexes containing bulges has been studied by measurement of the DNA melting temperature and gel electrophoresis. This study was aimed at exploring binding affinities of the helicates for DNA bulges of various sizes and nucleotide sequences. The studies reported herein reveal that both enantiomers of [Fe 2 L 3 ] 4+ bind to DNA bulges containing at least two unpaired nucleotides. In addition, these helicates show considerably enhanced affinity for duplexes containing unpaired pyrimidines in the bulge and/or pyrimidines flanking the bulge on both sides. We suggest that the bulge creates the structural motif, such as the triangular prismatic pocket formed by the unpaired bulge bases, to accommodate the [Fe 2 L 3 ] 4+ helicate molecule, and is probably responsible for the affinity for duplexes with a varying number of bulge bases. Our results reveal that DNA bulges represent another example of unusual DNA structures recognized by dinuclear iron(II) ([Fe 2 L 3 ] 4+ ) supramolecular helicates.

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“…5 Until now, aryl-nucleobase conjugates efficiently recognized complementary nucleobases by affinity increase, 4 Zn-cyclene derivatives showed highly selective interactions 35 with uracil and thymine caused by specific coordination of Zn with two keto-groups. 6 Very recently, abasic sites and single base bulges in DNA were efficiently recognized by metalloinsertors, 7 or small-ligand-immobilized biosensor was applied for detecting thymine-related single-nucleotide 40 polymorphisms (SNPs). 8 However, longer oligo-dT sequences were not specifically recognised until now, especially in respect to closely related uracil analogues.…”

Section: Introductionmentioning

confidence: 99%

Dibenzotetraaza[14]annulene–adenine conjugate recognizes complementary poly dT among ss-DNA/ss-RNA sequences

et al. 2013

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First published on the web Xth XXXXXXXXX 200X DOI:Among three novel DBTAA derivatives only DBTAA-propyl-adenine conjugate 1 showed recognition of the consecutive oligo dT sequence by increased affinity and specific induced chirooptical response in comparison to other single stranded RNA and DNA; whereby of particular 10 importance is up until now unique efficient differentiation between dT and rU. At variance, its close analogue DBTAA-hexyl-adenine 2 did not reveal any selectivity among ss-DNA/RNA pointing out to the important role of steric factors (linker length); moreover non-selectivity of the reference compound (3, lacking adenine) stressed the importance of adenine interactions in the 1 selectivity. 15 IntroductionBoth, DNA and RNA exhibit a wide range of structural topologies, among which different single stranded (ss-) sequences are quite numerous. While ss-sequences are ubiquitous part of the RNA folding landscape, there are fewer 20 observations of stable ss-DNA cases, such as hairpins 1 or abasic sites, 2 to name some of them. Since ds-DNA is protected from reaction with a number of chemical and biological nucleases, 3 many studies have been aimed at exploiting the vulnerable ss-DNA. A number of small 25 molecules were synthesized that bind specifically at abasic lesions with an idea to inhibit the DNA repair system and in that way pronounce the action of antitumor drugs. 4 Moreover, recently many research groups have explored the potential of the DNA as a template for arraying multichromophoric 30 systems, among which non-covalent ss-DNA-associated dyes attracted considerable attention. 5 Until now, aryl-nucleobase conjugates efficiently recognized complementary nucleobases by affinity increase, 4 Zn-cyclene derivatives showed highly selective interactions 35 with uracil and thymine caused by specific coordination of Zn with two keto-groups. 6 Very recently, abasic sites and single base bulges in DNA were efficiently recognized by metalloinsertors, 7 or small-ligand-immobilized biosensor was applied for detecting thymine-related single-nucleotide 40 polymorphisms (SNPs). 8 However, longer oligo-dT sequences were not specifically recognised until now, especially in respect to closely related uracil analogues. Within the last decade we showed that small modifications in structure of aryl-nucleobase conjugates can control their selectivity toward 45 various ss-and ds-polynucleotide sequences. 9 On the other hand, for the dibenzotetraaza [14]annulene (DBTAA) derivatives we recently showed that the interactions of side-chains can finely tune selectivity toward various DNA/RNA and consequently control their biological 50 activity. 10a Specific properties of the DBTAA moiety, such as larger aromatic surface than the most of until now used arylmoieties and pronounced out-of-plane flexibility, offered intriguing possibilities in design of novel aryl-nucleobase conjugates. The very last generation of DBTAA derivatives 55 showed high (sub-micromolar) DNA/RNA affinity and selectivity toward dA-d...

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Targeting Abasic Sites and Single Base Bulges in DNA with Metalloinsertors

Cited by 75 publications

References 33 publications

Crown ether–electrolyte interactions permit nanopore detection of individual DNA abasic sites in single molecules

Crown ether–electrolyte interactions permit nanopore detection of individual DNA abasic sites in single molecules

Recognition of DNA bulges by dinuclear iron(II) metallosupramolecular helicates

Dibenzotetraaza[14]annulene–adenine conjugate recognizes complementary poly dT among ss-DNA/ss-RNA sequences

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