Repression of translation of human estrogen receptor α by G-quadruplex formation

Graham D. Balkwill, Kamila Derecka, Thomas P. Garner, Charlie Hodgman, Anthony P.F. Flint, Mark S. Searle

Research output: Contribution to journalArticle

58 Scopus citations

Abstract

Tissue-specific expression of the human estrogen receptor α gene (ESR1) is achieved through multiple promoter sequences resulting in various mRNA transcripts encoding a common protein but differing in their 5′-untranslated region (5′-UTR). Many cancers are estrogen-sensitive with neoplastic growth stimulated through the estrogen receptor, a transcription factor that regulates developmental genes. We demonstrate that the human ESR1 gene is rich in potential quadruplex-forming sequences with 3 of 20 identified within exonic regions. In particular,we show using CD, UV, and NMR spectroscopy that a stable DNAG-quadruplex motif is formed within the exon C gene sequence. This motif, which PCR shows is transcribed in normal and neoplastic endometrium and in MCF-7 cells, forms a stable RNA quadruplex demonstrable by CD and UV analysis. Cloning the exon C G-quadruplex sequence upstream of a luciferase reporter gene caused a 6-fold reduction of enzymatic activity compared to a mutant sequence. We conclude that the exon C G-quadruplex motif is present in the 5′-UTR of the mRNA transcript, where it modulates the efficiency of translation.

Original languageEnglish (US)
Pages (from-to)11487-11495
Number of pages9
JournalBiochemistry
Volume48
Issue number48
DOIs
StatePublished - Dec 8 2009

ASJC Scopus subject areas

  • Biochemistry

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    Balkwill, G. D., Derecka, K., Garner, T. P., Hodgman, C., Flint, A. P. F., & Searle, M. S. (2009). Repression of translation of human estrogen receptor α by G-quadruplex formation. Biochemistry, 48(48), 11487-11495. https://doi.org/10.1021/bi901420k