G-quadruplex structure within the 5'-UTR of TRF2 mRNA represses translation in human cells

• Published in: Nucleic acids research 2010-11, Vol.38 (20), p.7187-7198
• Main Authors: Gomez, Dennis, Guédin, Aurore, Mergny, Jean-Louis, Salles, Bernard, Riou, Jean-François, Teulade-Fichou, Marie-Paule, Calsou, Patrick
• Format: Article
• Language: English
• Subjects: 5' Untranslated Regions; Base Sequence; Cell Line; G-Quadruplexes; Gene Expression Regulation; Genes, Reporter; Green Fluorescent Proteins - analysis; Green Fluorescent Proteins - genetics; Humans; Ligands; Molecular Sequence Data; Protein Biosynthesis; Regulatory Sequences, Ribonucleic Acid; RNA; RNA Stability; Telomeric Repeat Binding Protein 2 - genetics
• ISSN: 0305-1048; 1362-4962; 1362-4962
• DOI: 10.1093/nar/gkq563

Telomeres protect chromosome ends from being recognized as double-stranded breaks. Telomeric function is ensured by the shelterin complex in which TRF2 protein is an essential player. The G-rich strand of telomere DNA can fold into G-quadruplex (G4) structure. Small molecules stabilizing G4 structures, named G4 ligands, have been shown to alter telomeric functions in human cells. In this study, we show that a guanine-rich RNA sequence located in the 5'-UTR region of the TRF2 mRNA (hereafter 91TRF2G) is capable of forming a stable quadruplex that causes a 2.8-fold decrease in the translation of a reporter gene in human cells, as compared to a mutant 5'-UTR unable to fold into G4. We also demonstrate that several highly selective G4 ligands, the pyridine dicarboxamide derivative 360A and bisquinolinium compounds Phen-DC(3) and Phen-DC(6), are able to bind the 91TRF2G:RNA sequence and to modulate TRF2 protein translation in vitro. Since the naturally occurring 5'-UTR TRF2:RNA G4 element was used here, which is conserved in several vertebrate orthologs, the present data substantiate a potential translational mechanism mediated by a G4 RNA motif for the downregulation of TRF2 expression.