eIF4A alleviates the translational repression mediated by classical secondary structures more than by G-quadruplexes

Nucleic Acids Research
Joseph A WaldronJohn Le Quesne

Abstract

Increased activity of the mRNA helicase eIF4A drives cellular malignancy by reprogramming cellular translation, and eIF4A activity is the direct or indirect target of many emerging cancer therapeutics. The enriched presence of (GGC)4 motifs, which have the potential to fold into two-layered G-quadruplexes, within the 5'UTRs of eIF4A-dependent mRNAs suggests that eIF4A is required for the unwinding of these structures within these eIF4A-controlled mRNAs. However, the existence of folded G-quadruplexes within cells remains controversial, and G-quadruplex folding is in direct competition with classical Watson-Crick based secondary structures. Using a combination of reverse transcription stalling assays and 7-deazaguanine incorporation experiments we find that (GGC)4 motifs preferentially form classical secondary structures rather than G-quadruplexes in full-length mRNAs. Furthermore, using translation assays with the eIF4A inhibitor hippuristanol, both in vitro and in cells, we find that eIF4A activity alleviates translational repression of mRNAs with 5'UTR classical secondary structures significantly more than those with folded G-quadruplexes. This was particularly evident in experiments using a G-quadruplex stabilizing ligand, w...Continue Reading

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Citations

Jan 27, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Zhi-Yin SunTian-Miao Ou
Mar 27, 2020·Frontiers in Oncology·Dayanidhi RamanJulie A Rhoades Sterling
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May 16, 2019·Journal of Experimental & Clinical Cancer Research : CR·Zhan-Hong ChenFeng Wang
Jun 25, 2020·International Journal of Molecular Sciences·Leo Shen, Jerry Pelletier
Dec 3, 2020·Nucleic Acids Research·Prakash KharelPavel Ivanov

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Methods Mentioned

BETA
footprinting
circular dichroism
FCS
in vitro transcription
Reverse
Assay
transfection
Reverse transcription stalling

Software Mentioned

GQRS mapper
GenScript
RNAfold

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