L1 retrotransposons exploit RNA m6A modification as an evolutionary driving force

Sung Yeon Hwang, Hyunchul Jung, Seyoung Mun, Sungwon Lee, Kiwon Park, S. Chan Baek, Hyungseok C. Moon, Hyewon Kim, Baekgyu Kim, Yongkuk Choi, Young Hyun Go, Wanxiangfu Tang, Jongsu Choi, Jung Kyoon Choi, Hyuk Jin Cha, Hye Yoon Park, Ping Liang, V. Narry Kim, Kyudong Han, Kwangseog Ahn

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

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.

Original languageEnglish (US)
Article number880
JournalNature communications
Volume12
Issue number1
DOIs
StatePublished - Dec 1 2021
Externally publishedYes

Bibliographical note

Funding Information:
This work was supported by the grants IBS-R008-D1, NRF-2020R1A5A1018081, and NRF-2020R1A2C3011298 (to K.A.), funding from the Fellowship for Fundamental Academic Fields of SNU (to S.-Y.H.), and the BK21 plus fellowship. We are grateful to J. L. Garica-Perez, W. An, A. Roy-Engel, and A.J. Doucet for providing the L1 plasmids. Computational comparative genomic work was facilitated by the Compute Canada high-performance computing facilities. We gratefully acknowledge Center for Bio-Medical Engineering Core Facility at Dankook University for data analysis including computer server.

Publisher Copyright:
© 2021, The Author(s).

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