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Nat Commun. 2016 May 27;7:11752. doi: 10.1038/ncomms11752.

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

Author information

1
Department of Pediatrics, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany.
2
Department of Biology, Technische Universität Darmstadt, 64287 Darmstadt, Germany.
3
Department of Dermatology, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany.
4
Biotechnology Center, Technische Universität Dresden, 01307 Dresden, Germany.
5
Center for Regenerative Therapies, Technische Universität Dresden, 01307 Dresden, Germany.
6
Institute of Human Genetics, Heinrich-Heine-University, Medical Faculty, 40225 Düsseldorf, Germany.
7
Department of Gynecology, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany.

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.

PMID:
27230542
PMCID:
PMC4895045
DOI:
10.1038/ncomms11752
[Indexed for MEDLINE]
Free PMC Article

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