A G-quadruplex structure within the 5'-UTR of TRF2 mRNA represses translation in human cells.
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.
Gomez
Dennis
D
CNRS, IPBS (Institut de Pharmacologie et de Biologie Structurale), 205 route de Narbonne, 31077 Toulouse, Université de Toulouse, UPS, IPBS, F-31077 Toulouse, France.
Guédin
Aurore
A
Mergny
Jean-Louis
JL
Salles
Bernard
B
Riou
Jean-François
JF
Teulade-Fichou
Marie-Paule
MP
Calsou
Patrick
P
D020121:5' Untranslated Regions; D001483:Base Sequence; D002460:Cell Line; D054856:G-Quadruplexes; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins / Q000032:analysis / Q000235:genetics; D006801:Humans; D008024:Ligands; D008969:Molecular Sequence Data; D014176:Protein Biosynthesis; D020871:RNA Stability; D038621:Regulatory Sequences, Ribonucleic Acid; D035341:Telomeric Repeat Binding Protein 2 / Q000235:genetics*
D020121:5' Untranslated Regions; D008024:Ligands; D038621:Regulatory Sequences, Ribonucleic Acid; C504753:TERF2 protein, human; D035341:Telomeric Repeat Binding Protein 2; D049452:Green Fluorescent Proteins