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

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. Synopsis Several mechanisms exist to restrict LINE‐1 retrotransposition, some of which involve TREX1, SAMHD1 or ADAR1, proteins mutated in Aicardi‐Goutières syndrome (AGS), a type I interferonopathy. Mutations in RNase H2 also cause AGS. However, RNase H2 activity promotes rather than restricts LINE‐1 mobilisation. Efficient LINE‐1 retrotransposition requires cellular RNase H2 activity. Mobilization of vertebrate retrotransposons without an RNase H domain is severely compromised in RNASEH2A knockout cells, whereas those with their own RNase H activity are not affected. Increased cellular RNase H activity against RNA:DNA hybrids by overexpression allows increased LINE‐1 retrotransposition. Knockout cells complemented with RNASEH2A carrying disease mutations have impaired LINE‐1 retrotransposition. RNase H2 likely acts on the LINE‐1 RNA:cDNA hybrid, allowing second strand synthesis and productive retrotransposition to occur. Graphical Abstract In contrast to other Aicardi‐Goutières associated proteins that act to restrict LINE‐1 retrotranspostion, RNase H2 activity facilitates LINE‐1 mobilisation.