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

Magdalena P. Crossley, Chenlin Song, Michael J. Bocek, Jun Hyuk Choi, Joseph Kousorous, Ataya Sathirachinda, Cindy Lin, Joshua R. Brickner, Gongshi Bai, Hannes Lans, Wim Vermeulen, Monther Abu-Remaileh, Karlene A. Cimprich*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)187-194
Number of pages8
JournalNature
Volume613
Issue number7942
Early online date21 Dec 2022
DOIs
Publication statusPublished - 5 Jan 2023

Bibliographical note

Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature Limited.

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