Chromosome Targeting at Short Polypurine Sites by Cationic Triplex-forming Oligonucleotides

Vásquez, Karen M.; Dagle, John M.; Weeks, Daniel L.; Glazer, Peter M.

doi:10.1074/jbc.m101797200

Cited by 82 publications

(80 citation statements)

References 53 publications

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“…Examples of such modifications include thioate linkages [56,57], N 3' − P 5' phosphoramidates [58,59], and morpholino phosphoramidate linkages [60]. The cationic phosphoramidate linkages, N,Ndiethylethylenediamine and N,N-dimethylaminopropylamine, confer increases in TFO binding affinity and intracellular activity [61]. Other promising oligonucleotide backbone modifications that allow for improvements in triplex formation include peptide nucleic acids (PNAs) and locked nucleic acids (LNAs).…”

Section: Chemical Modifications Of Tfosmentioning

confidence: 99%

DNA triple helices: Biological consequences and therapeutic potential

Jain

Wang²,

Vásquez³

2008

Biochimie

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269

199

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DNA structure is a critical element in determining its function. The DNA molecule is capable of adopting a variety of non-canonical structures, including three-stranded (i.e. triplex) structures, which will be the focus of this review. The ability to selectively modulate the activity of genes is a longstanding goal in molecular medicine. DNA triplex structures, either intermolecular triplexes formed by binding of an exogenously applied oligonucleotide to a target duplex sequence, or naturally occurring intramolecular triplexes (H-DNA) formed at endogenous mirror repeat sequences, present exploitable features that permit site-specific alteration of the genome. These structures can induce transcriptional repression and site-specific mutagenesis or recombination. Triplex-forming oligonucleotides (TFOs) can bind to duplex DNA in a sequence specific fashion with high affinity, and can be used to direct DNA-modifying agents to selected sequences. H-DNA plays important roles in vivo and is inherently mutagenic and recombinogenic, such that elements of the H-DNA structure may be pharmacologically exploitable. In this review we discuss the biological consequences and therapeutic potential of triple helical DNA structures. We anticipate that the information provided will stimulate further investigations aimed toward improving DNA triplexrelated gene targeting strategies for biotechnological and potential clinical applications.

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Section: Chemical Modifications Of Tfosmentioning

confidence: 99%

DNA triple helices: Biological consequences and therapeutic potential

Jain

Wang²,

Vásquez³

2008

Biochimie

Self Cite

269

199

View full text Add to dashboard Cite

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“…43 Briefly, two complementary 57-mer oligonucleotides containing the sequence corresponding to bp 157-213 of the SupFG1 reporter gene were synthesized, mixed 1:1 in 25 mM NaCl, heated to 90 °C for 20 min and allowed to slowly cool to room temperature to form duplex DNA. Following end labeling of the duplex using T4 polynucleotide kinase and γ 32 P-ATP, the duplex was purified by gel electrophoresis.…”

Section: Triplex Binding Assaysmentioning

confidence: 99%

Improved bioactivity of G-rich triplex-forming oligonucleotides containing modified guanine bases

Rogers

Lloyd

Tiwari

2014

Artificial DNA: PNA & XNA

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“…The main disadvantage is that the ODN needs to cross the nuclear membrane and access its DNA target within the densely packed chromatin structure [34]. Common disadvantages of the use of ODNs for targeting purposes are that the oligonucleotide needs to cross lipid membranes; for instance, hydrophilic ODN duplexes do not cross lipid membranes [35], and the fast degradative action of nucleases. These disadvantages can be circumvented by using single strands and by chemically modification of its phosphate or sugar groups.…”

Section: Introductionmentioning

confidence: 99%

Contributions of the loops on the stability and targeting of DNA pseudoknots

Reiling¹,

Marky²

2014

Bio Chem Comp

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Background: Pseudoknots have been found to play important roles in RNA function, examples include ribosomal frameshifting and in the 5' UTR of mRNA as riboswitches. In RNA frameshifting, there is a local formation of base-triplet stacks within the pseudoknot, increasing the stability of the terminal stem. The interaction of this triplex structure with the ribosome might help with the high-efficiency of frameshifting. The main objective of this work is to mimic RNA pseudoknots using DNA oligonucleotides for the control of gene expression. Specifically, we have designed a pair of DNA pseudoknots with different length in one of the loops to mimic the formation of a local triple helix, shown within RNA pseudoknots of the human telomerase. Methods: We have used a combination of temperature-dependent UV spectroscopy and calorimetric techniques to determine the thermodynamics for the unfolding of the pseudoknots and their targeting with complementary strands. The unfolding data is then used to create thermodynamic (Hess) cycles that correspond to each of the targeting reactions. The resulting data is then compared with the thermodynamic enthalpy data obtained directly from isothermal titration calorimetry. Results: UV melting curves of each pseudoknot show transitions with T M s independent of strand concentration, which confirms their intramolecular formation. Analysis of the differential scanning calorimetry (DSC) curves shows the pseudoknot with the longer thymine loop (PsK-9) to be more stable, by -5.7 kcal/mol, and to unfold with a higher enthalpy of 27.4 kcal/mol. The targeting of each pseudoknot yielded favorable reaction free energy contributions that were enthalpy driven. However, the disruption reaction of PsK-9 took place with a less favorable free energy term, by 0.7 kcal/mol, and less favorable enthalpy term, by 4.5 kcal/mol. Conclusion: The thermodynamic unfolding data showed that PsK-9 is more stable or more compact, due to the involvement of three loop thymines of PsK-9 in forming three T*AT base-triplets, or two T*AT/ T*AT base-triplet stacks, in the stem of this pseudoknot. The targeting thermodynamic data indicated that each complementary strand is able to disrupt the pseudoknots. However, the disruption of PsK-9 takes place with a less favorable free energy contribution, confirming the formation of a short and local triplex.

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Chromosome Targeting at Short Polypurine Sites by Cationic Triplex-forming Oligonucleotides

Cited by 82 publications

References 53 publications

DNA triple helices: Biological consequences and therapeutic potential

DNA triple helices: Biological consequences and therapeutic potential

Improved bioactivity of G-rich triplex-forming oligonucleotides containing modified guanine bases

Contributions of the loops on the stability and targeting of DNA pseudoknots

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