Benitez-Guijarro, MariaLopez-Ruiz, CesarTarnauskaitė, ŽygimantėMurina, OlgaMian Mohammad, MahwishWilliams, Thomas CFluteau, AdelineSanchez, LauraVilar-Astasio, RaquelGarcia-Canadas, MartaCano, DavidKempen, Marie-Jeanne HcSanchez-Pozo, AntonioHeras, Sara RJackson, Andrew PReijns, Martin AmGarcia-Perez, Jose L2023-01-252023-01-252018-06-29http://hdl.handle.net/10668/12660Long 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.enAttribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/Aicardi‐Goutières SyndromeLINE‐1 retrotranspositionRNA:DNA hybridsRNase H2Autoimmune Diseases of the Nervous SystemCell Line, TumorGene Knockout TechniquesHCT116 CellsHeLa CellsHumansLong Interspersed Nucleotide ElementsNervous System MalformationsReverse TranscriptionRibonuclease Hresearch article29959219open access10.15252/embj.2017985061460-2075PMC6068448https://doi.org/10.15252/embj.201798506https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6068448/pdf