Ping Liang, Hye Won Kim, Baekgyu Kim, Sung-Yeon Hwang, Jongsu Choi, Jung Kyoon Choi, Hyungseok C. Moon, Kiwon Park, Seyoung Mun, Yongkuk Choi, V. Narry Kim, Young-Hyun Go, S. Chan Baek, Hye Yoon Park, Kwangseog Ahn, Kyudong Han, Hyuk-Jin Cha, Hyunchul Jung, Wanxiangfu Tang, and Sungwon Lee
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. L1 is a group of active retrotransposons in humans. Here the authors show that m6A modifications on L1 RNA increase translation efficiency and retrotransposition in human cells. M6A motifs are more enriched in evolutionary young L1s.