RNase H2, mutated in Aicardi‐Goutières syndrome, resolves co-transcriptional R-loops to prevent DNA breaks and inflammation

Agnese Cristini, Michael Tellier, Flavia Constantinescu, Clelia Accalai, Laura Oana Albulescu, Robin Heiringhoff, Nicolas Bery, Olivier Sordet, Shona Murphy and Natalia Gromak ()
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Agnese Cristini: University of Oxford
Michael Tellier: University of Oxford
Flavia Constantinescu: University of Oxford
Clelia Accalai: University of Oxford
Laura Oana Albulescu: University of Oxford
Robin Heiringhoff: University of Oxford
Nicolas Bery: University of Oxford, John Radcliffe Hospital
Olivier Sordet: Cancer Research Center of Toulouse, INSERM, Université de Toulouse, Université Toulouse III Paul Sabatier, CNRS
Shona Murphy: University of Oxford
Natalia Gromak: University of Oxford

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: Abstract RNase H2 is a specialized enzyme that degrades RNA in RNA/DNA hybrids and deficiency of this enzyme causes a severe neuroinflammatory disease, Aicardi Goutières syndrome (AGS). However, the molecular mechanism underlying AGS is still unclear. Here, we show that RNase H2 is associated with a subset of genes, in a transcription-dependent manner where it interacts with RNA Polymerase II. RNase H2 depletion impairs transcription leading to accumulation of R-loops, structures that comprise RNA/DNA hybrids and a displaced DNA strand, mainly associated with short and intronless genes. Importantly, accumulated R-loops are processed by XPG and XPF endonucleases which leads to DNA damage and activation of the immune response, features associated with AGS. Consequently, we uncover a key role for RNase H2 in the transcription of human genes by maintaining R-loop homeostasis. Our results provide insight into the mechanistic contribution of R-loops to AGS pathogenesis.

Date: 2022
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DOI: 10.1038/s41467-022-30604-0

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