R-loop-derived cytoplasmic RNA–DNA hybrids activate an immune response

Magdalena P. Crossley, Chenlin Song, Michael J. Bocek, Jun-Hyuk Choi, Joseph N. Kousouros, Ataya Sathirachinda, Cindy Lin, Joshua R. Brickner, Gongshi Bai, Hannes Lans, Wim Vermeulen, Monther Abu-Remaileh and Karlene A. Cimprich ()
Additional contact information
Magdalena P. Crossley: Stanford University
Chenlin Song: Stanford University
Michael J. Bocek: Stanford University
Jun-Hyuk Choi: Stanford University
Joseph N. Kousouros: Stanford University
Ataya Sathirachinda: Stanford University
Cindy Lin: Stanford University
Joshua R. Brickner: Stanford University
Gongshi Bai: Stanford University
Hannes Lans: Erasmus University Medical Center
Wim Vermeulen: Erasmus University Medical Center
Monther Abu-Remaileh: Stanford University
Karlene A. Cimprich: Stanford University

Nature, 2023, vol. 613, issue 7942, 187-194

Abstract: Abstract R-loops are RNA–DNA-hybrid-containing nucleic acids with important cellular roles. Deregulation of R-loop dynamics can lead to DNA damage and genome instability1, which has been linked to the action of endonucleases such as XPG2–4. However, the mechanisms and cellular consequences of such processing have remained unclear. Here we identify a new population of RNA–DNA hybrids in the cytoplasm that are R-loop-processing products. When nuclear R-loops were perturbed by depleting the RNA–DNA helicase senataxin (SETX) or the breast cancer gene BRCA1 (refs. 5–7), we observed XPG- and XPF-dependent cytoplasmic hybrid formation. We identify their source as a subset of stable, overlapping nuclear hybrids with a specific nucleotide signature. Cytoplasmic hybrids bind to the pattern recognition receptors cGAS and TLR3 (ref. 8), activating IRF3 and inducing apoptosis. Excised hybrids and an R-loop-induced innate immune response were also observed in SETX-mutated cells from patients with ataxia oculomotor apraxia type 2 (ref. 9) and in BRCA1-mutated cancer cells10. These findings establish RNA–DNA hybrids as immunogenic species that aberrantly accumulate in the cytoplasm after R-loop processing, linking R-loop accumulation to cell death through the innate immune response. Aberrant R-loop processing and subsequent innate immune activation may contribute to many diseases, such as neurodegeneration and cancer.

Date: 2023
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DOI: 10.1038/s41586-022-05545-9

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