L1 retrotransposons exploit RNA m⁶A modification as an evolutionary driving force.

Abstract

L1 retrotransposons can pose a threat to genome integrity. The host has evolved to restrict L1 replication. However, mechanisms underlying L1 propagation out of the host surveillance remains unclear. Here, we propose an evolutionary survival strategy of L1, which exploits RNA m⁶A modification. We discover that m⁶A 'writer' METTL3 facilitates L1 retrotransposition, whereas m⁶A 'eraser' ALKBH5 suppresses it. The essential m⁶A cluster that is located on L1 5' UTR serves as a docking site for eukaryotic initiation factor 3 (eIF3), enhances translational efficiency and promotes the formation of L1 ribonucleoprotein. Furthermore, through the comparative analysis of human- and primate-specific L1 lineages, we find that the most functional m⁶A motif-containing L1s have been positively selected and became a distinctive feature of evolutionarily young L1s. Thus, our findings demonstrate that L1 retrotransposons hijack the RNA m⁶A modification system for their successful replication.