1. RNase H2, mutated in Aicardi‐Goutières syndrome, resolves co-transcriptional R-loops to prevent DNA breaks and inflammation
- Author
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Cristini, A, Tellier, M, Constantinescu, F, Accalai, C, Albulescu, LO, Heiringhoff, R, Bery, N, Sordet, O, Murphy, S, and Gromak, N
- Subjects
Inflammation ,Multidisciplinary ,DNA Breaks ,Ribonuclease H ,General Physics and Astronomy ,DNA ,Ribonuclease, Pancreatic ,General Chemistry ,Nervous System Malformations ,General Biochemistry, Genetics and Molecular Biology ,Autoimmune Diseases of the Nervous System ,Ribonucleases ,Endoribonucleases ,Humans ,RNA ,R-Loop Structures - 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.
- Published
- 2022