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R-loop-derived cytoplasmic RNA–DNA hybrids activate an immune response
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Journal Article
R-loop-derived cytoplasmic RNA–DNA hybrids activate an immune response
2023
Overview
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.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ 13/106
/ 13/109
/ 13/2
/ 13/31
/ 13/51
/ 13/89
/ 14/19
/ 14/63
/ 38/22
/ 45/90
/ 82/80
/ Acids
/ Ataxia
/ Cancer
/ DNA
/ Genomes
/ Humanities and Social Sciences
/ Humans
/ Hybrids
/ Multifunctional Enzymes - genetics
/ Multifunctional Enzymes - metabolism
/ Mutation
/ Nucleic Acid Heteroduplexes - chemistry
/ Nucleic Acid Heteroduplexes - immunology
/ Pattern recognition receptors
/ R-Loop Structures - immunology
/ R-loops
/ RNA
/ Science
