Targeting G-quadruplex structure in the human c-Kit promoter with short PNA sequences

Bioconjug Chem. 2011 Apr 20;22(4):654-63. doi: 10.1021/bc100444v. Epub 2011 Mar 16.

Abstract

The cKit87up sequence d((5')AGGGAGGGCGCTGGGAGGAGGG(3')) can form a unique G-quadruplex structure in the promoter region of the human c-kit protooncogene. It provides a peculiar platform for the design of selective quadruplex-binding agents, which could potentially repress the protooncogene transcription. In this study, we examined the binding of a small library of PNA probes (P1-P5) targeting cKit87up quadruplex in either K(+)- or NH(4)(+)-containing solutions by using a combination of UV, CD, PAGE, ITC, and ESI-MS methodologies. Our results showed that (1) P1-P4 interact with the cKit87up quadruplex, and (2) the binding mode depends on the quadruplex stability. In K(+) buffer, P1-P4 bind the ckit87up quadruplex structure as "quadruplex-binding agents". The same holds for P1 in NH(4)(+) solution. On the contrary, in NH(4)(+) solution, P2-P4 overcome the quadruplex structure by forming PNA/DNA hybrid complexes, thus acting as "quadruplex openers".

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • G-Quadruplexes*
  • Humans
  • Models, Molecular
  • Oligonucleotide Probes / chemical synthesis
  • Oligonucleotide Probes / chemistry*
  • Peptide Nucleic Acids / chemical synthesis
  • Peptide Nucleic Acids / chemistry*
  • Proto-Oncogene Proteins c-kit / chemistry*

Substances

  • Oligonucleotide Probes
  • Peptide Nucleic Acids
  • Proto-Oncogene Proteins c-kit