遗传 ›› 2020, Vol. 42 ›› Issue (7): 669-679.doi: 10.16288/j.yczz.20-081

• 研究报告 • 上一篇    下一篇

SLFN14抗LINE-1分子机制研究

毛洋, 丁寄葳, 陈淑敏, 岑山(), 李晓宇()   

  1. 中国医学科学院&北京协和医学院医药生物技术研究所免疫生物学室,北京 100050
  • 收稿日期:2020-04-26 修回日期:2020-05-22 出版日期:2020-07-20 发布日期:2020-05-25
  • 通讯作者: 岑山,李晓宇 E-mail:shancen@imb.pumc.edu.cn;xiaoyulik@hotmail.com
  • 作者简介:毛洋,在读硕士研究生,专业方向:宿主因子对转座子调控机制研究。E-mail: yangmao-MY@outlook.com
  • 基金资助:
    国家科技重大专项编号(2018ZX10301408-004);中国医学科学院医学与健康创新工程项目资助编号(CIFMS 2016-I2M-2-002)

SLFN14 inhibits LINE-1 transposition activity

Mao Yang, Ding Jiwei, Chen Minshu, Cen Shan(), Li Xiaoyu()   

  1. Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
  • Received:2020-04-26 Revised:2020-05-22 Online:2020-07-20 Published:2020-05-25
  • Contact: Cen Shan,Li Xiaoyu E-mail:shancen@imb.pumc.edu.cn;xiaoyulik@hotmail.com
  • Supported by:
    Supported by the National Science and Technology Major Project of the Ministry of Science and Technology of China No(2018ZX10301408-004);Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences No(CIFMS 2016-I2M-2-002)

摘要:

长散在核重复序列1 (long interspersed nuclear element-1, LINE-1)是迄今为止发现的人体基因组中唯一具有自主转座活性的逆转录转座子,其转座常引起宿主基因组不稳定,从而导致包括癌症在内的各种严重基因疾病的发生。宿主因子在宿主抗LINE-1转座中发挥着重要作用。宿主因子SLFN14作为免疫系统重要组成员,具有抗病毒活性。本实验室研究发现SLFN14对于LINE-1的转座具有抑制作用。为进一步探究其具体的作用机制,通过对LINE-1复制周期中的转录、翻译、逆转录、整合环节进行实验分析,证实SLFN14能够通过影响LINE-1 mRNA转录过程及其半衰期,降低LINE-1 mRNA的水平,从而影响LINE-1蛋白及cDNA表达水平,最终导致LINE-1复制受阻。同时,通过对SLFN14活性中心的定位,本研究还发现SLFN14的抗LINE-1活性与其核糖核酸内切酶结构域和核糖体结合结构域密切相关。上述研究结果展示了SLFN14调控LINE-1复制的机制,进一步完善了宿主因子调控网络,为控制因LINE-1复制引起的基因组不稳定提供了新思路。

关键词: 转座, 逆转录转座子, LINE-1, SLFN14, 5?-UTR内部启动子区;

Abstract:

Long interspersed nuclear element-1 (LINE-1) is the only active autonomous transposon in the human genome. Its transposition frequently induces host genome instability, leading to a variety of genetic diseases, including cancers. The host factors play important roles in inhibiting LINE-1 retrotransposition. As an important component of the immune system, the host factor SLFN14 has antiviral activity. Our laboratory shows that SLFN14 possesses potent inhibitory activity against LINE-1 retrotransposition. To explore the potential mechanism of SLFN14 inhibition, we analyzed its effects on transcription, translation, reverse transcription and insertion in the LINE-1 replication cycle. We confirmed that SLFN14 could suppress the LINE-1 mRNA level by affecting its transcription and degradation, thereby diminishing the protein and cDNA levels of LINE-1, which eventually block the LINE-1 retrotransposition. Further, by mapping the active domains of SLFN14, we found its inhibitory activity on LINE-1 being closely related to its endoribonuclease and ribosome binding domains. These results demonstrate the mechanism of SLFN14 in regulating LINE-1 replication, which further provide new insights for improving the regulation network of host factors for controlling genomic instability caused by LINE-1 replication.

Key words: transposition, retrotransposon, LINE-1, SLFN14, 5 ?-UTR internal promotor region;