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RPA and Rad51 constitute a cell intrinsic mechanism to protect the cytosol from self DNA

Author

Listed:
  • Christine Wolf

    (Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden)

  • Alexander Rapp

    (Technische Universität Darmstadt)

  • Nicole Berndt

    (Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden)

  • Wolfgang Staroske

    (Biotechnology Center, Technische Universität Dresden)

  • Max Schuster

    (Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden)

  • Manuela Dobrick-Mattheuer

    (Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden)

  • Stefanie Kretschmer

    (Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden)

  • Nadja König

    (Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden)

  • Thomas Kurth

    (Biotechnology Center, Technische Universität Dresden
    Center for Regenerative Therapies, Technische Universität Dresden)

  • Dagmar Wieczorek

    (Institute of Human Genetics, Heinrich-Heine-University, Medical Faculty)

  • Karin Kast

    (Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden)

  • M. Cristina Cardoso

    (Technische Universität Darmstadt)

  • Claudia Günther

    (Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden)

  • Min Ae Lee-Kirsch

    (Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden)

Abstract

Immune recognition of cytosolic DNA represents a central antiviral defence mechanism. Within the host, short single-stranded DNA (ssDNA) continuously arises during the repair of DNA damage induced by endogenous and environmental genotoxic stress. Here we show that short ssDNA traverses the nuclear membrane, but is drawn into the nucleus by binding to the DNA replication and repair factors RPA and Rad51. Knockdown of RPA and Rad51 enhances cytosolic leakage of ssDNA resulting in cGAS-dependent type I IFN activation. Mutations in the exonuclease TREX1 cause type I IFN-dependent autoinflammation and autoimmunity. We demonstrate that TREX1 is anchored within the outer nuclear membrane to ensure immediate degradation of ssDNA leaking into the cytosol. In TREX1-deficient fibroblasts, accumulating ssDNA causes exhaustion of RPA and Rad51 resulting in replication stress and activation of p53 and type I IFN. Thus, the ssDNA-binding capacity of RPA and Rad51 constitutes a cell intrinsic mechanism to protect the cytosol from self DNA.

Suggested Citation

  • Christine Wolf & Alexander Rapp & Nicole Berndt & Wolfgang Staroske & Max Schuster & Manuela Dobrick-Mattheuer & Stefanie Kretschmer & Nadja König & Thomas Kurth & Dagmar Wieczorek & Karin Kast & M. C, 2016. "RPA and Rad51 constitute a cell intrinsic mechanism to protect the cytosol from self DNA," Nature Communications, Nature, vol. 7(1), pages 1-11, September.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms11752
    DOI: 10.1038/ncomms11752
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    Cited by:

    1. Manuela Völkner & Felix Wagner & Lisa Maria Steinheuer & Madalena Carido & Thomas Kurth & Ali Yazbeck & Jana Schor & Stephanie Wieneke & Lynn J. A. Ebner & Claudia Toro Runzer & David Taborsky & Katja, 2022. "HBEGF-TNF induce a complex outer retinal pathology with photoreceptor cell extrusion in human organoids," Nature Communications, Nature, vol. 13(1), pages 1-22, December.
    2. Samuel D. Chauvin & Shoichiro Ando & Joe A. Holley & Atsushi Sugie & Fang R. Zhao & Subhajit Poddar & Rei Kato & Cathrine A. Miner & Yohei Nitta & Siddharth R. Krishnamurthy & Rie Saito & Yue Ning & Y, 2024. "Inherited C-terminal TREX1 variants disrupt homology-directed repair to cause senescence and DNA damage phenotypes in Drosophila, mice, and humans," Nature Communications, Nature, vol. 15(1), pages 1-23, December.

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