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

被引:162
作者
Gomez, Dennis [1 ,2 ]
Guedin, Aurore [3 ]
Mergny, Jean-Louis [3 ,4 ]
Salles, Bernard [1 ,2 ]
Riou, Jean-Francois [3 ]
Teulade-Fichou, Marie-Paule [5 ]
Calsou, Patrick [1 ,2 ]
机构
[1] CNRS, IPBS, F-31077 Toulouse, France
[2] Univ Toulouse, UPS, IPBS, F-31077 Toulouse, France
[3] Museum Natl Hist Nat, INSERM, Biophys Lab, CNRS,U565,UMR 7196, F-75231 Paris 05, France
[4] Univ Bordeaux 2, INSERM, Lab ARNA, Inst Europeen Chim Biol,U869, F-33607 Pessac, France
[5] Ctr Univ Paris XI, Inst Curie, CNRS, UMR 176, F-91405 Orsay, France
关键词
PROMOTER REGION; GENE-EXPRESSION; SMALL-MOLECULE; IN-VITRO; TELOMERE; DNA; INHIBITION; SEQUENCE; LIGANDS; BINDING;
D O I
10.1093/nar/gkq563
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:7187 / 7198
页数:12
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