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

Author

Listed:
  • Magdalena P. Crossley

    (Stanford University)

  • Chenlin Song

    (Stanford University)

  • Michael J. Bocek

    (Stanford University)

  • Jun-Hyuk Choi

    (Stanford University
    Korea Research Institute of Standards and Science
    University of Science & Technology)

  • Joseph N. Kousouros

    (Stanford University)

  • Ataya Sathirachinda

    (Stanford University)

  • Cindy Lin

    (Stanford University
    Stanford University
    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
    Stanford University
    Stanford University)

  • Karlene A. Cimprich

    (Stanford University)

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.

Suggested Citation

  • 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 & Month, 2023. "R-loop-derived cytoplasmic RNA–DNA hybrids activate an immune response," Nature, Nature, vol. 613(7942), pages 187-194, January.
  • Handle: RePEc:nat:nature:v:613:y:2023:i:7942:d:10.1038_s41586-022-05545-9
    DOI: 10.1038/s41586-022-05545-9
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    Citations

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    Cited by:

    1. Miho M. Suzuki & Kenta Iijima & Koichi Ogami & Keiko Shinjo & Yoshiteru Murofushi & Jingqi Xie & Xuebing Wang & Yotaro Kitano & Akira Mamiya & Yuji Kibe & Tatsunori Nishimura & Fumiharu Ohka & Ryuta S, 2023. "TUG1-mediated R-loop resolution at microsatellite loci as a prerequisite for cancer cell proliferation," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    2. Athanasios Siametis & Kalliopi Stratigi & Despoina Giamaki & Georgia Chatzinikolaou & Alexia Akalestou-Clocher & Evi Goulielmaki & Brian Luke & Björn Schumacher & George A. Garinis, 2024. "Transcription stress at telomeres leads to cytosolic DNA release and paracrine senescence," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    3. Abdallah Gaballa & Anneli Gebhardt-Wolf & Bastian Krenz & Greta Mattavelli & Mara John & Giacomo Cossa & Silvia Andreani & Christina Schülein-Völk & Francisco Montesinos & Raphael Vidal & Carolin Kast, 2024. "PAF1c links S-phase progression to immune evasion and MYC function in pancreatic carcinoma," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    4. Xingxing Ren & Qiuyuan Liu & Peirong Zhou & Tingyue Zhou & Decai Wang & Qiao Mei & Richard A. Flavell & Zhanju Liu & Mingsong Li & Wen Pan & Shu Zhu, 2024. "DHX9 maintains epithelial homeostasis by restraining R-loop-mediated genomic instability in intestinal stem cells," Nature Communications, Nature, vol. 15(1), pages 1-17, December.

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