An intramolecular G-quadruplex structure with mixed parallel/antiparallel G-strands formed in the human BCL-2 promoter region in solution

J Am Chem Soc. 2006 Feb 1;128(4):1096-8. doi: 10.1021/ja055636a.

Abstract

We report the first G-quadruplex structure formed in the promoter region of the human bcl-2. Bcl-2 is a potent oncoprotein that functions as an inhibitor of cell apoptosis and has been found to be aberrantly overexpressed in a wide range of human tumors. A highly GC-rich region upstream of the P1 promoter plays an important role in the regulation of the transcriptional activity of the bcl-2 oncogene. The purine-rich strand of this region contains multiple runs of guanines and can form three distinct intramolecular G-quadruplexes in K+-containing solution. Of these, the G-quadruplex formed within the middle four consecutive guanine runs has been shown to be the most stable G-quadruplex structure, while it is also a mixture of loop isomers. The predominant G-quadruplex structure formed in this region was studied by NMR. Our results demonstrate a novel folding of a unique intramolecular G-quadruplex structure with mixed parallel/antiparallel G-strands. This G-quadruplex structure contains three G-tetrads connected with a single-nucleotide double-chain-reversal side loop and two lateral loops. The first three-nucleotide CGC loop in the bcl-2 promoter sequence forms a lateral loop, as opposed to a double-chain-reversal side loop observed in a similar sequence in the c-MYC promoter, which appears to largely determine the overall folding of the bcl-2 G-quadruplex. Furthermore, both the bcl-2 and c-MYC promoter sequences contain the G3NG3 sequence motif, which forms a stable double-chain-reversal, parallel-stranded structural motif. This predominant bcl-2 G-quadruplex represents an attractive novel target for the design of new anticancer drugs that specifically modulate bcl-2 gene expression.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Base Sequence
  • Circular Dichroism
  • DNA / chemistry*
  • DNA / genetics*
  • G-Quadruplexes
  • Genes, bcl-2*
  • Guanine / chemistry
  • Humans
  • Nuclear Magnetic Resonance, Biomolecular
  • Nucleic Acid Conformation
  • Promoter Regions, Genetic*
  • Solutions

Substances

  • Solutions
  • Guanine
  • DNA