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

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 , which has been linked to the action of endonucleases such as XPG . However, the mechanisms and cellular consequences of such processing h...

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Bibliographic Details
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:
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
Humans
Hybrids
Immune response
Immune system
Immunogenicity
Innate immunity
Innate Immunity Recognition
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
Spinocerebellar Ataxias - genetics
TLR3 protein
Toll-like receptors
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Summary: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 , which has been linked to the action of endonucleases such as XPG . 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. ), 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.  ), 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.  ) and in BRCA1-mutated cancer cells . 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.
ISSN:0028-0836
1476-4687
DOI:10.1038/s41586-022-05545-9