The dynamic character of the BCL2 promoter i-motif provides a mechanism for modulation of gene expression by compounds that bind selectively to the alternative DNA hairpin structure

Samantha Kendrick, Hyun Jin Kang, Mohammad P. Alam, Manikandadas M. Madathil, Prashansa Agrawal, Vijay Gokhale, Danzhou Yang, Sidney Hecht, Laurence H. Hurley

Research output: Contribution to journalArticle

116 Citations (Scopus)

Abstract

It is generally accepted that DNA predominantly exists in duplex form in cells. However, under torsional stress imposed by active transcription, DNA can assume nonduplex structures. The BCL2 promoter region forms two different secondary DNA structures on opposite strands called the G-quadruplex and the i-motif. The i-motif is a highly dynamic structure that exists in equilibrium with a flexible hairpin species. Here we identify a pregnanol derivative and a class of piperidine derivatives that differentially modulate gene expression by stabilizing either the i-motif or the flexible hairpin species. Stabilization of the i-motif structure results in significant upregulation of the BCL2 gene and associated protein expression; in contrast, stabilization of the flexible hairpin species lowers BCL2 levels. The BCL2 levels reduced by the hairpin-binding compound led to chemosensitization to etoposide in both in vitro and in vivo models. Furthermore, we show antagonism between the two classes of compounds in solution and in cells. For the first time, our results demonstrate the principle of small molecule targeting of i-motif structures in vitro and in vivo to modulate gene expression.

Original languageEnglish (US)
Pages (from-to)4161-4171
Number of pages11
JournalJournal of the American Chemical Society
Volume136
Issue number11
DOIs
StatePublished - Mar 19 2014

Fingerprint

Gene expression
DNA
Modulation
Gene Expression
Stabilization
G-Quadruplexes
Lead compounds
Derivatives
Etoposide
Transcription
Genetic Promoter Regions
Torsional stress
Up-Regulation
Genes
Proteins
Molecules
In Vitro Techniques

ASJC Scopus subject areas

  • Chemistry(all)
  • Catalysis
  • Biochemistry
  • Colloid and Surface Chemistry

Cite this

The dynamic character of the BCL2 promoter i-motif provides a mechanism for modulation of gene expression by compounds that bind selectively to the alternative DNA hairpin structure. / Kendrick, Samantha; Kang, Hyun Jin; Alam, Mohammad P.; Madathil, Manikandadas M.; Agrawal, Prashansa; Gokhale, Vijay; Yang, Danzhou; Hecht, Sidney; Hurley, Laurence H.

In: Journal of the American Chemical Society, Vol. 136, No. 11, 19.03.2014, p. 4161-4171.

Research output: Contribution to journalArticle

Kendrick, Samantha ; Kang, Hyun Jin ; Alam, Mohammad P. ; Madathil, Manikandadas M. ; Agrawal, Prashansa ; Gokhale, Vijay ; Yang, Danzhou ; Hecht, Sidney ; Hurley, Laurence H. / The dynamic character of the BCL2 promoter i-motif provides a mechanism for modulation of gene expression by compounds that bind selectively to the alternative DNA hairpin structure. In: Journal of the American Chemical Society. 2014 ; Vol. 136, No. 11. pp. 4161-4171.
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