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

• Published in: Nature (London) 2023-01, Vol.613 (7942), p.187-194
• Main Authors: Crossley, Magdalena P., Song, Chenlin, Bocek, Michael J., Choi, Jun-Hyuk, Kousouros, Joseph N., Sathirachinda, Ataya, Lin, Cindy, Brickner, Joshua R., Bai, Gongshi, Lans, Hannes, Vermeulen, Wim, Abu-Remaileh, Monther, Cimprich, Karlene A.
• Format: Article
• Language: English
• Subjects: 13/1; 13/106; 13/109; 13/2; 13/31; 13/51; 13/89; 14/19; 14/63; 38/22; 45/90; 631/250/262; 631/337/1427; 631/337/572; 82/80; Acids; Apoptosis; Ataxia; BRCA1 protein; Breast cancer; Cancer; Cell death; Cognitive ability; Cytoplasm; Cytoplasm - immunology; Cytoplasm - metabolism; Deoxyribonucleic acid; Deregulation; DNA; DNA - chemistry; DNA - immunology; DNA damage; DNA helicase; DNA Helicases - genetics; DNA Helicases - metabolism; Genes, BRCA1; Genomes; Genomic instability; Humanities and Social Sciences; Humans; Hybrids; Immune response; Immune system; Immunogenicity; Innate immunity; Innate Immunity Recognition; multidisciplinary; Multifunctional Enzymes - genetics; Multifunctional Enzymes - metabolism; Mutation; Neoplasms; Neurodegeneration; Nucleic Acid Heteroduplexes - chemistry; Nucleic Acid Heteroduplexes - immunology; Nucleic acids; Nucleotides; Pattern recognition; Pattern recognition receptors; R-Loop Structures - immunology; R-loops; Ribonucleic acid; RNA; RNA - chemistry; RNA - immunology; RNA helicase; RNA Helicases - genetics; RNA Helicases - metabolism; Science; Science (multidisciplinary); Spinocerebellar Ataxias - genetics; TLR3 protein; Toll-like receptors
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-022-05545-9

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 instability 1 , which has been linked to the action of endonucleases such as XPG 2 – 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 cells 10 . 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. RNA–DNA hybrids are immunogenic species that can aberrantly accumulate in the cytoplasm after R-loop processing, linking R-loop accumulation to cell death through the innate immune response.