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

Jixun Dai, Thomas S. Dexheimer, Ding Chen, Megan Carver, A. Ambrus, Roger A. Jones, Danzhou Yang

Research output: Contribution to journalArticle

294 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1096-1098
Number of pages3
JournalJournal of the American Chemical Society
Volume128
Issue number4
DOIs
Publication statusPublished - Feb 1 2006

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G-Quadruplexes
Guanine
Nucleotides
Genetic Promoter Regions
GC Rich Sequence
Oncogene Proteins
Cell death
Gene expression
Isomers
Tumors
Nuclear magnetic resonance
Apoptosis
Pharmaceutical Preparations
bcl-2 Genes
Oncogenes
Gene Expression
purine

ASJC Scopus subject areas

  • Chemistry(all)

Cite this

An intramolecular G-quadruplex structure with mixed parallel/antiparallel G-strands formed in the human BCL-2 promoter region in solution. / Dai, Jixun; Dexheimer, Thomas S.; Chen, Ding; Carver, Megan; Ambrus, A.; Jones, Roger A.; Yang, Danzhou.

In: Journal of the American Chemical Society, Vol. 128, No. 4, 01.02.2006, p. 1096-1098.

Research output: Contribution to journalArticle

Dai, Jixun ; Dexheimer, Thomas S. ; Chen, Ding ; Carver, Megan ; Ambrus, A. ; Jones, Roger A. ; Yang, Danzhou. / An intramolecular G-quadruplex structure with mixed parallel/antiparallel G-strands formed in the human BCL-2 promoter region in solution. In: Journal of the American Chemical Society. 2006 ; Vol. 128, No. 4. pp. 1096-1098.
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AB - 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.

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