Regulation of Transcription by Synthetic DNA‐Bending Agents

Abstract

Gene expression is regulated by a complex interplay between binding and the three-dimensional arrangement of transcription factors with RNA polymerase and DNA. Previous studies have supported a direct role for DNA bending and conformation in gene expression, which suggests that agents that induce bends in DNA might be able to control gene expression. To test this hypothesis, we examined the effect of triple-helix-forming oligonucleotide (TFO) bending agents on the transcription of luciferase in an in vitro transcriptional/translational system. We find that transcription is regulated only by a TFO that induces a bend in the DNA. Related TFOs that do not induce bends in DNA have no effect on transcription. Reporter expression can be increased by as much as 80 % or decreased by as much as 50 % depending on the phasing of the upstream bend relative to the promoter. We interpret the results as follows: when the bend is positioned such that the upstream DNA is curved toward the RNA polymerase on the same DNA face, transcription is enhanced. When the upstream DNA is curved away, transcription is attenuated. These results support the hypothesis that DNA-bending agents might have the capability to regulate gene expression, thereby opening up a previously undervalued avenue in research on the artificial control of gene expression.

Design, Synthesis, and Structure−Activity Relationships of Benzophenone-Based Tetraamides as Novel Antibacterial Agents

“…Previous work in our laboratory focused on the role that the three-dimensional structure of DNA played on gene expression . One portion of these studies focused on the development of minor groove DNA binding agents with the potential to bend DNA.…”

DNA Compaction Induced by a Cationic Polymer or Surfactant Impact Gene Expression and DNA Degradation

“…in biotechnological applications. Sequence specific DNA-binding synthetic agents such as triplex-forming oligonucleotides [12]–[16], zinc-finger proteins [17]–[19], peptide nucleic acids [20]–[24], and synthetic polyamides [25], [26] have been used as gene silencers. However, these approaches rely on the base specificity of the promoter region for the binding of the agents that inhibit transcription, interfering with either the initiation of transcription or elongation.…”

Selective Preference of Parallel DNA Triplexes Is Due to the Disruption of Hoogsteen Hydrogen Bonds Caused by the Severe Nonisostericity between the G*GC and T*AT Triplets

“…Also, it has been shown earlier [ 83 ] that the GA step triplex junction interface also exhibits bending of ~ 17°. Besides, it is known that a tethered GT rich TFO induces a bend in the triplex formed [ 84 , 85 ] which regulates the transcription of Luciferase gene [ 86 ]. Therefore it might be speculated that bent triplexes could serve as recognition sites for triplex binding proteins.…”