mRNA structural elements immediately upstream of the start codon dictate dependence upon eIF4A helicase activity.

Autor: Waldron JA; Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow, G61 1BD, UK. J.Waldron@beatson.gla.ac.uk., Tack DC; Department of Biology, Pennsylvania State University, University Park, PA, 16802, USA.; Department of Chemistry, Pennsylvania State University, University Park, PA, 16802, USA.; Present Address: Spectrum Health Office of Research, 100 Michigan Street NE, Mail Code 038, Grand Rapids, MI, 49503, USA., Ritchey LE; Department of Chemistry, Pennsylvania State University, University Park, PA, 16802, USA.; Center for RNA Molecular Biology, Pennsylvania State University, University Park, PA, 16802, USA.; Present Address: Department of Chemistry, University of Pittsburgh at Johnstown, Johnstown, PA, 15904, USA., Gillen SL; Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow, G61 1BD, UK., Wilczynska A; Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow, G61 1BD, UK., Turro E; Department of Haematology, University of Cambridge, Cambridge, UK.; Medical Research Council Biostatistics Unit, Cambridge Institute of Public Health, Cambridge, UK.; National Health Service Blood and Transplant, Cambridge, UK.; National Institute for Health Research BioResource, Cambridge University Hospitals, Cambridge, UK., Bevilacqua PC; Department of Chemistry, Pennsylvania State University, University Park, PA, 16802, USA.; Center for RNA Molecular Biology, Pennsylvania State University, University Park, PA, 16802, USA.; Department of Biochemistry & Molecular Biology, Pennsylvania State University, University Park, PA, 16802, USA., Assmann SM; Department of Biology, Pennsylvania State University, University Park, PA, 16802, USA.; Center for RNA Molecular Biology, Pennsylvania State University, University Park, PA, 16802, USA., Bushell M; Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow, G61 1BD, UK. m.bushell@beatson.gla.ac.uk.; Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Glasgow, G61 1QH, UK. m.bushell@beatson.gla.ac.uk., Le Quesne J; Medical Research Council Toxicology Unit, University of Cambridge, Hodgkin Building, Lancaster Road, Leicester, LE1 7HB, UK. jlq2@leicester.ac.uk.; Leicester Cancer Research Centre, University of Leicester, Leicester, UK. jlq2@leicester.ac.uk.
Jazyk: angličtina
Zdroj: Genome biology [Genome Biol] 2019 Dec 30; Vol. 20 (1), pp. 300. Date of Electronic Publication: 2019 Dec 30.
DOI: 10.1186/s13059-019-1901-2
Abstrakt: Background: The RNA helicase eIF4A1 is a key component of the translation initiation machinery and is required for the translation of many pro-oncogenic mRNAs. There is increasing interest in targeting eIF4A1 therapeutically in cancer, thus understanding how this protein leads to the selective re-programming of the translational landscape is critical. While it is known that eIF4A1-dependent mRNAs frequently have long GC-rich 5'UTRs, the details of how 5'UTR structure is resculptured by eIF4A1 to enhance the translation of specific mRNAs are unknown.
Results: Using Structure-seq2 and polysome profiling, we assess global mRNA structure and translational efficiency in MCF7 cells, with and without eIF4A inhibition with hippuristanol. We find that eIF4A inhibition does not lead to global increases in 5'UTR structure, but rather it leads to 5'UTR remodeling, with localized gains and losses of structure. The degree of these localized structural changes is associated with 5'UTR length, meaning that eIF4A-dependent mRNAs have greater localized gains of structure due to their increased 5'UTR length. However, it is not solely increased localized structure that causes eIF4A-dependency but the position of the structured regions, as these structured elements are located predominantly at the 3' end of the 5'UTR.
Conclusions: By measuring changes in RNA structure following eIF4A inhibition, we show that eIF4A remodels local 5'UTR structures. The location of these structural elements ultimately determines the dependency on eIF4A, with increased structure just upstream of the CDS being the major limiting factor in translation, which is overcome by eIF4A activity.
Databáze: MEDLINE
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