ATP-Independent Initiation during Cap-Independent Translation of m6A-Modified mRNA

The methylation of adenosine in the N-6 position (m(6)A) is a widely used modification of eukaryotic mRNAs. Its importance for the regulation of mRNA translation was put forward recently, essentially due to the ability of methylated mRNA to be translated in conditions of inhibited cap-dependent translation initiation, e.g., under stress. However, the peculiarities of translation initiation on m(6)A-modified mRNAs are not fully known. In this study, we used toeprinting and translation in a cell-free system to confirm that m(6)A-modified mRNAs can be translated in conditions of suppressed cap-dependent translation. We show for the first time that m(6)A-modified mRNAs display not only decreased elongation, but also a lower efficiency of translation initiation. Additionally, we report relative resistance of m(6)A-mRNA translation initiation in the absence of ATP and inhibited eIF4A activity. Our novel findings indicate that the scanning of m(6)A-modified leader sequences is performed by a noncanonical mechanism.

Automated summary

The study confirms that m(6)A-modified mRNAs can be translated under conditions of cap-dependent translation inhibition, but with lower translation initiation efficiency. Additionally, the translation elongation of m(6)A-mRNAs is slower.