An RNA G-Quadruplex Is Essential for Cap-Independent Translation Initiation in Human VEGF IRES

RNA G-quadruplexes located within the 5'-UTR of mRNA are almost always known to be associated with repression of cap-dependent translation. However, in this report we present functional as well as structural evidence that sequence redundancy in a G-rich segment within the 5'-UTR of human VEGF mRNA supports a 'switchable' RNA G-quadruplex structure that is essential for IRES-mediated translation initiation. Additionally, utilization of a specific combination of G-tracts within this segment allows for the conformational switch that implies a tunable regulatory role of the quadruplex structure in translation initiation. A sequence engineered from a functionally handicapped mutant moderately rescued the activity, further indicating the importance of G-quadruplex structure for VEGF IRES-A function. This to our knowledge is the first report of a conformationally flexible RNA G-quadruplex which is essential for IRES-mediated translation initiation.