Schlafen-5 inhibits LINE-1 retrotransposition

Jiwei Ding; Shujie Wang; Qipeng Liu; Yuqing Duan; Tingting Cheng; Zhongjie Ye; Zhanding Cui; Ao Zhang; Qiuyu Liu; Zixiong Zhang; Ning Zhang; Qian Liu; Ni An; Jianyuan Zhao; Dongrong Yi; Quanjie Li; Jing Wang; Yongxin Zhang; Ling Ma; Saisai Guo; Jinhui Wang; Chen Liang; Jinming Zhou; Shan Cen; Xiaoyu Li

doi:10.1016/j.isci.2023.107968

Schlafen-5 inhibits LINE-1 retrotransposition

iScience. 2023 Sep 19;26(10):107968. doi: 10.1016/j.isci.2023.107968. eCollection 2023 Oct 20.

Authors

Jiwei Ding¹, Shujie Wang¹, Qipeng Liu¹, Yuqing Duan¹, Tingting Cheng¹, Zhongjie Ye¹, Zhanding Cui¹, Ao Zhang¹, Qiuyu Liu¹, Zixiong Zhang¹, Ning Zhang¹, Qian Liu¹, Ni An¹, Jianyuan Zhao¹, Dongrong Yi¹, Quanjie Li¹, Jing Wang¹, Yongxin Zhang¹, Ling Ma¹, Saisai Guo¹, Jinhui Wang², Chen Liang³, Jinming Zhou⁴, Shan Cen¹, Xiaoyu Li¹

Affiliations

¹ Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
² Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
³ The Lady Davis Institute-Jewish General Hospital, Montreal, QC H3T 1E2, Canada.
⁴ Key Laboratory of the Ministry of Education for Advanced Catalysis Materials, Department of Chemistry, Zhejiang Normal University, 688 Yingbin Road, Jinhua 321004, China.

Abstract

Long interspersed element 1 (LINE-1) is the only currently known active autonomous transposon in humans, and its retrotransposition may cause deleterious effects on the structure and function of host cell genomes and result in sporadic genetic diseases. Host cells therefore developed defense strategies to restrict LINE-1 mobilization. In this study, we demonstrated that IFN-inducible Schlafen5 (SLFN5) inhibits LINE-1 retrotransposition. Mechanistic studies revealed that SLFN5 interrupts LINE-1 ribonucleoprotein particle (RNP) formation, thus diminishing nuclear entry of the LINE-1 RNA template and subsequent LINE-1 cDNA production. The ability of SLFN5 to bind to LINE-1 RNA and the involvement of the helicase domain of SLFN5 in its inhibitory activity suggest a mechanism that SLFN5 binds to LINE-1 RNA followed by dissociation of ORF1p through its helicase activity, resulting in impaired RNP formation. These data highlight a new mechanism of host cells to restrict LINE-1 mobilization.

Keywords: Molecular biology; Molecular genetics.