RNase H2, mutated in Aicardi‐Goutières syndrome, promotes LINE‐1 retrotransposition

• Maria Benitez‐Guijarro ^[1] ; Cesar Lopez‐Ruiz ^[1] ; Žygimantė Tarnauskaitė ^[2] ; Olga Murina ^[2] ; Mahwish Mian Mohammad ^[3] ; Thomas C Williams ^[2] ; Adeline Fluteau ^[2] ; Laura Sanchez ^[1] ; Raquel Vilar‐Astasio ^[1] ; Marta Garcia‐Canadas ^[1] ; David Cano ^[1] ; Marie‐Jeanne HC Kempen ^[2] ; Antonio Sanchez‐Pozo ^[1] ; Sara R Heras ^[1] ; Andrew P Jackson ^[2] ; Martin AM Reijns ^[2] ; Jose L Garcia‐Perez ^[1]
  1. [1] Universidad de Granada

     Universidad de Granada

     Granada, España

     
  2. [2] 2 MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine Western General Hospital University of Edinburgh Edinburgh UK
  3. [3] 2 MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine Western General Hospital University of Edinburgh Edinburgh UK; 6Present address: CNRS ‐ UMR 8200 Institut Gustave Roussy Villejuif France

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• Localización: EMBO journal: European Molecular Biology Organization, ISSN 0261-4189, Vol. 37, Nº. 15, 2018
• Idioma: inglés
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  • 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.