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

Christine Wolf, Alexander Rapp, Nicole Berndt, Wolfgang Staroske, Max Schuster, Manuela Dobrick-Mattheuer, Stefanie Kretschmer, Nadja König, Thomas Kurth, Dagmar Wieczorek, Karin Kast, M. Cristina Cardoso, Claudia Günther and Min Ae Lee-Kirsch ()
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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
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

Nature Communications, 2016, vol. 7, issue 1, 1-11

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms11752

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