The transcriptional complex between the BCL2 i-motif and hnRNP LL is a molecular switch for control of gene expression that can be modulated by small molecules

Hyun Jin Kang, Samantha Kendrick, Sidney M. Hecht, Laurence Hurley

Research output: Contribution to journalArticle

103 Citations (Scopus)

Abstract

In a companion paper (DOI: 10.021/ja410934b) we demonstrate that the C-rich strand of the cis-regulatory element in the BCL2 promoter element is highly dynamic in nature and can form either an i-motif or a flexible hairpin. Under physiological conditions these two secondary DNA structures are found in an equilibrium mixture, which can be shifted by the addition of small molecules that trap out either the i-motif (IMC-48) or the flexible hairpin (IMC-76). In cellular experiments we demonstrate that the addition of these molecules has opposite effects on BCL2 gene expression and furthermore that these effects are antagonistic. In this contribution we have identified a transcriptional factor that recognizes and binds to the BCL2 i-motif to activate transcription. The molecular basis for the recognition of the i-motif by hnRNP LL is determined, and we demonstrate that the protein unfolds the i-motif structure to form a stable single-stranded complex. In subsequent experiments we show that IMC-48 and IMC-76 have opposite, antagonistic effects on the formation of the hnRNP LL-i-motif complex as well as on the transcription factor occupancy at the BCL2 promoter. For the first time we propose that the i-motif acts as a molecular switch that controls gene expression and that small molecules that target the dynamic equilibrium of the i-motif and the flexible hairpin can differentially modulate gene expression.

Original languageEnglish (US)
Pages (from-to)4172-4185
Number of pages14
JournalJournal of the American Chemical Society
Volume136
Issue number11
DOIs
StatePublished - Mar 19 2014

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Switch Genes
Heterogeneous-Nuclear Ribonucleoproteins
Gene expression
Switches
Gene Expression
Molecules
Protein Unfolding
Transcription factors
Transcription
DNA
Transcription Factors
Experiments
Proteins
IMC-76
IMC-48

ASJC Scopus subject areas

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

Cite this

The transcriptional complex between the BCL2 i-motif and hnRNP LL is a molecular switch for control of gene expression that can be modulated by small molecules. / Kang, Hyun Jin; Kendrick, Samantha; Hecht, Sidney M.; Hurley, Laurence.

In: Journal of the American Chemical Society, Vol. 136, No. 11, 19.03.2014, p. 4172-4185.

Research output: Contribution to journalArticle

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