Nucleosome core particles inhibit DNA triple helix formation

Brown, Philip M.; Fox, Keith R.

doi:10.1042/bj3190607

Cited by 40 publications

(36 citation statements)

References 36 publications

(59 reference statements)

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“…The selection between different homopurine-homopyrimidine DNA tracts on hTERT promoter was based on their chromatin organization and is supported by a number of researches both in vitro and in vivo, suggesting a decreased target accessibility to TFOs in the nucleosomal environment [29][30][31].…”

Section: Discussionmentioning

confidence: 97%

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A model for triple helix formation on human telomerase reverse transcriptase (hTERT) promoter and stabilization by specific interactions with the water soluble perylene derivative, DAPER

Rossetti

D'Isa

Mauriello

et al. 2007

Biophysical Chemistry

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This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Montesano 49, I-80131 Napoli, Italy. A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT*corresponding author A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT 2 ABSTRACTThe promoter of human telomerase reverse transcriptase (hTERT) gene, in the region from -1000 to +1, contains two homopurine-homopyrimidine sequences (-835/-814 and -108/-90), that can be considered as potential targets to triple helix forming oligonucleotides (TFOs) for applying antigene strategy.We have chosen the sequence (-108/-90) on the basis of its unfavorable Since DAPER is a symmetric molecule, the induced Circular Dichroism (CD) spectra in the range 400-600 nm, allows us to obtain information on drug binding to triplex and duplex DNA. The drug induced ellipticity is significantly higher in the case of triplex with respect to duplex and, surprisingly, it increases at decreasing of DNA. A model is proposed where self-stacked DAPER binds to triplex or to duplex narrow grooves.

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Section: Discussionmentioning

confidence: 97%

“…In vivo chromosomal DNA is packaged by histone proteins into nucleosomes [28], so that the accessibility of TFO target sequences will be significantly decreased in chromatin with respect to naked DNA [29][30][31].…”

Section: Binding Affinity Of Tfos To the Selected Target Sequence On mentioning

confidence: 99%

A model for triple helix formation on human telomerase reverse transcriptase (hTERT) promoter and stabilization by specific interactions with the water soluble perylene derivative, DAPER

Rossetti

D'Isa

Mauriello

et al. 2007

Biophysical Chemistry

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“…187 Polyamines also promote triplex formation under physiological pH, 188 as do some charge-neutralizing basic polypeptides. 189 In addition to the effects of cations and pH, 190,191 triplex formation is also highly dependent on temperature, organic solvents 2,73,[192][193][194] and chromatin accessibility, 122,195 all of which complicate in silico assessments of the potential of a given TFO and target sequence to form triplexes in vivo. So far, little is known about how local microenvironments and the involvement of other factors such as proteins might favor the formation and/or increase the stability of particular types of triplexes in vivo.…”

Section: Future Prospectsmentioning

confidence: 99%

Potential in vivo roles of nucleic acid triple-helices

2011

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“…In addition, chromosomal DNA is tightly packed into a chromatin structure restricting the accessibility of chromosomal DNA to TFOs (Brown et al, 1996). Using a restriction protection assay to detect triplex-directed psoralen crosslink in genomic DNA, Macris and Glazer (2003) found the accessibility for a chromosomal site to a TFO was substantially increased when transcription was induced at the target site.…”

Section: Page 15 Of 35mentioning

confidence: 99%

The Lack of Mutagenic Potential of a Guanine-Rich Triplex Forming Oligonucleotide in Physiological Conditions

et al. 2016

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Triplex forming oligonucleotides (TFOs) bind in the major groove of DNA duplex in a sequence-specific manner imparted by Hoogsteen hydrogen bonds. There have been several reports demonstrating the ability of guanine-rich TFOs to induce targeted mutagenesis on an exogenous plasmid or an endogenous chromosomal locus. In particular, a 30mer guanine-rich triplex forming oligonucleotide, AG30, optimally designed to target the supFG1 reporter gene was reported to be mutagenic in the absence of DNA reactive agents in cultured cells and in vivo. Here, we investigated the mutagenic potential of AG30 using the supFG1 shuttle vector forward mutation assay under physiological conditions. We also assessed the triplex binding potential of AG30 alongside cytotoxic and mutagenic assessment. In a cell free condition, AG30 was able to bind its polypurine target site in the supFG1 gene in the absence of potassium chloride and also aligned with a 5-fold increase in the mutant frequency when AG30 was pre-incubated with the supFG1 plasmid in the absence of potassium prior to transfection into COS-7 cells. However, when we analysed triplex formation of AG30 and the supFG1 target duplex at physiological potassium levels, triplex formation was inhibited due to the formation of competing secondary structures.Subsequent assessment of mutant frequency under physiological conditions, by pretransfecting COS-7 cells with the supFG1 plasmid prior to AG30 treatment led to a very small increase (1.4-fold) in the mutant frequency. Transfection of cells with even higher concentrations of AG30 did result in an elevated mutagenic response but this was also seen with a scrambled sequence, and was therefore considered unlikely to be biologically relevant as an associated increase in cytotoxicity was also apparent. Our findings also provide further assurance on the low potential of triplex-mediated mutation as a consequence of unintentional genomic DNA binding by therapeutic antisense oligonucleotides.

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Nucleosome core particles inhibit DNA triple helix formation

Cited by 40 publications

References 36 publications

A model for triple helix formation on human telomerase reverse transcriptase (hTERT) promoter and stabilization by specific interactions with the water soluble perylene derivative, DAPER

A model for triple helix formation on human telomerase reverse transcriptase (hTERT) promoter and stabilization by specific interactions with the water soluble perylene derivative, DAPER

Potential in vivo roles of nucleic acid triple-helices

The Lack of Mutagenic Potential of a Guanine-Rich Triplex Forming Oligonucleotide in Physiological Conditions

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