Triplex Forming Oligonucleotides (TFO)
editH-DNA Gene Expression
editAccording to several published articles, H-DNA has the ability to regulate gene expression depending on factors such as location and sequence proximity. Genetic sequences involved in gene expression and regulation are typically found in the promoter regions of the eukaryotic genome[1]. Intergenic regions of the prokaryotic genome have shown low traces of naturally occurring HDNA or triplex motifs. H-DNA structures have shown to be more prevalent in the eukaryotic genome, especially abundant in mammalian cells including humans (1 in every 50,000 bp)[1]. Consequently, the promoter region of genes have displayed the ability to form H-DNA with a higher frequency[1]. A bioinformatic analysis of the S. cerevisiae genome observed the occurrence of HDNA and other triplex DNA motifs in four organizational regions: introns, exons, promoter regions and miscellaneous regions.[2] The bioinformatic displayed a total of 148 HDNA or triplet DNA possible structures. The promoter region accounted for the higher frequency with 71 triplex structures, while the exons accounted for 57 triplex structure and the introns and miscellaneous accounted for 2 and 18 structure respectively[2].
In vitro and in vivo studies of eukaryotic genome expression resulted in either an up or down regulation or no change in the presence of H-DNA or triplex DNA motifs[1]. Kato et. al. reported an increase in upregulation expression of lacZ, when H-DNA was introduced to the B-lactamase promoter[3][1]. A similar study (Brachmachari et al.) reported no statistically significant inhibition of the lacZ reporter gene when H-DNA was inserted into the genome of mammalian COS cells[1]. In H-DNA formations adjacent to a TATA box in the promoter region, the H-DNA structure may destabilize the T-A bonds essential for transcription. The interference with the TATA box may inhibit the transcriptional machinery and transcription initiation which interferes with gene expression[1]. Other mechanisms associated with with the genomic expression of a genetic sequence in the presence of H-DNA involves TFOs. In vitro studies have highlighted a decrease in gene expression in the presence of TFOs in mammalian cells[4] A 13-mer AG motif oligonucleotide triplex complex (TFO complex) downregulated the transcription of ber/abl mRNA through competitive inhibition[5]. Direct inhibition of gene expression from H-DNA is key to mutagenesis, replication inhibition, and even DNA recombination in the genome
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- ^ a b c d e f g Jain, Aklank; Wang, Guliang; Vasquez, Karen M. (2008-8). "DNA Triple Helices: biological consequences and therapeutic potential". Biochimie. 90 (8): 1117–1130. doi:10.1016/j.biochi.2008.02.011. ISSN 0300-9084. PMC 2586808. PMID 18331847.
{{cite journal}}: Check date values in:|date=(help) - ^ a b Zain, R.; Sun, J-S (2003-05-01). "Do natural DNA triple-helical structures occur and function in vivo?". Cellular and Molecular Life Sciences CMLS. 60 (5): 862–870. doi:10.1007/s00018-003-3046-3. ISSN 1420-9071.
- ^ Kato, M.; Shimizu, N. (1992-10). "Effect of the potential triplex DNA region on the in vitro expression of bacterial beta-lactamase gene in superhelical recombinant plasmids". Journal of Biochemistry. 112 (4): 492–494. doi:10.1093/oxfordjournals.jbchem.a123927. ISSN 0021-924X. PMID 1491004.
{{cite journal}}: Check date values in:|date=(help) - ^ Seidman, Michael M.; Glazer, Peter M. (2003-08-15). "The potential for gene repair via triple helix formation". The Journal of Clinical Investigation. 112 (4): 487–494. doi:10.1172/JCI19552. ISSN 0021-9738. PMC 171401. PMID 12925687.
{{cite journal}}: CS1 maint: PMC format (link) - ^ Rapozzi, Valentina; Cogoi, Susanna; Spessotto, Paola; Risso, Angela; Bonora, Gian Maria; Quadrifoglio, Franco; Xodo, Luigi Emilio (2002-01). "Antigene Effect in K562 Cells of a PEG-Conjugated Triplex-Forming Oligonucleotide Targeted to thebcr/ablOncogene†". Biochemistry. 41 (2): 502–510. doi:10.1021/bi011314h. ISSN 0006-2960.
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