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

doi:10.1038/s41467-021-21197-1

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 journal › Article › peer-review

14 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 language	English (US)
Article number	880
Journal	Nature communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-21197-1
State	Published - Dec 1 2021
Externally published	Yes

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).

Publisher link

10.1038/s41467-021-21197-1

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Hwang, S. Y., Jung, H., Mun, S., Lee, S., Park, K., Baek, S. C., Moon, H. C., Kim, H., Kim, B., Choi, Y., Go, Y. H., Tang, W., Choi, J., Choi, J. K., Cha, H. J., Park, H. Y., Liang, P., Kim, V. N., Han, K., & Ahn, K. (2021). L1 retrotransposons exploit RNA m⁶A modification as an evolutionary driving force. Nature communications, 12(1), [880]. https://doi.org/10.1038/s41467-021-21197-1

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title = "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 {\textquoteleft}writer{\textquoteright} METTL3 facilitates L1 retrotransposition, whereas m6A {\textquoteleft}eraser{\textquoteright} 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.",

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

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: {\textcopyright} 2021, The Author(s).",

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AU - Hwang, Sung Yeon

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AU - Lee, Sungwon

AU - Park, Kiwon

AU - Baek, S. Chan

AU - Moon, Hyungseok C.

AU - Kim, Hyewon

AU - Kim, Baekgyu

AU - Choi, Yongkuk

AU - Go, Young Hyun

AU - Tang, Wanxiangfu

AU - Choi, Jongsu

AU - Choi, Jung Kyoon

AU - Cha, Hyuk Jin

AU - Park, Hye Yoon

AU - Liang, Ping

AU - Kim, V. Narry

AU - Han, Kyudong

AU - Ahn, Kwangseog

N1 - 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).

PY - 2021/12/1

Y1 - 2021/12/1

N2 - 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.

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