201. RNase H2, mutated in Aicardi-Goutières syndrome, promotes LINE-1 retrotransposition.
- Author
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Benitez-Guijarro M, Lopez-Ruiz C, Tarnauskaitė Ž, Murina O, Mian Mohammad M, Williams TC, Fluteau A, Sanchez L, Vilar-Astasio R, Garcia-Canadas M, Cano D, Kempen MH, Sanchez-Pozo A, Heras SR, Jackson AP, Reijns MA, and Garcia-Perez JL
- Subjects
- Cell Line, Tumor, Gene Knockout Techniques, HCT116 Cells, HeLa Cells, Humans, Reverse Transcription genetics, Ribonuclease H biosynthesis, Autoimmune Diseases of the Nervous System genetics, Long Interspersed Nucleotide Elements genetics, Nervous System Malformations genetics, Ribonuclease H genetics
- Abstract
Long INterspersed Element class 1 (LINE-1) elements are a type of abundant retrotransposons active in mammalian genomes. An average human genome contains ~100 retrotransposition-competent LINE-1s, whose activity is influenced by the combined action of cellular repressors and activators. TREX1, SAMHD1 and ADAR1 are known LINE-1 repressors and when mutated cause the autoinflammatory disorder Aicardi-Goutières syndrome (AGS). Mutations in RNase H2 are the most common cause of AGS, and its activity was proposed to similarly control LINE-1 retrotransposition. It has therefore been suggested that increased LINE-1 activity may be the cause of aberrant innate immune activation in AGS Here, we establish that, contrary to expectations, RNase H2 is required for efficient LINE-1 retrotransposition. As RNase H1 overexpression partially rescues the defect in RNase H2 null cells, we propose a model in which RNase H2 degrades the LINE-1 RNA after reverse transcription, allowing retrotransposition to be completed. This also explains how LINE-1 elements can retrotranspose efficiently without their own RNase H activity. Our findings appear to be at odds with LINE-1-derived nucleic acids driving autoinflammation in AGS., (© 2018 The Authors. Published under the terms of the CC BY 4.0 license.)
- Published
- 2018
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