Transcript-wide m6A methylation defines the efficiency of the cap-independent translation initiation

N6-methyladenosine (m6A) role in translation control and, particularly, in cap-independent initiation has attracted major attention. A common approach is to study the impact of m6A depending on its particular location in the transcripts, but the global impact of m6A along mRNAs remains unclear. Here, we combined ribosome profiling under conditions of mTOR inhibition and m6A mapping to identify distinct subsets of mRNAs that differ in their sensitivity to the suppression of cap-dependent initiation. The sensitivity was strongly correlated with the total m6A methylation of the transcripts. Further, we demonstrated that upon decreased mTOR activity, m6A methylation facilitated the enhanced association of mRNAs with components of the eIF4F complex. Thus, the efficiency of cap-independent translation initiation is primarily defined not by precise localization but by the total level of m6A methylation, and m6A has a compensatory role in maintaining translation when the canonical cap-dependent pathway is impaired. All in all, our findings underscore the significance of contemplating global m6A methylation status as a pivotal element in translational control, particularly under stress or signaling perturbations. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=79 SRC="FIGDIR/small/690160v2_ufig1.gif" ALT="Figure 1"> View larger version (17K): org.highwire.dtl.DTLVardef@e18178org.highwire.dtl.DTLVardef@fb0346org.highwire.dtl.DTLVardef@19406eaorg.highwire.dtl.DTLVardef@1520821_HPS_FORMAT_FIGEXP M_FIG C_FIG