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

Wolf, Christine and Rapp, Alexander and Berndt, Nicole and Staroske, Wolfgang and Schuster, Max and Dobrick-Mattheuer, Manuela and Kretschmer, Stefanie and König, Nadja and Kurth, Thomas and Wieczorek, Dagmar and Kast, Karin and Cardoso, M. Cristina and Günther, Claudia and Lee-Kirsch, Min Ae (2016):
RPA and Rad51 constitute a cell intrinsic mechanism to protect the cytosol from self DNA.
In: Nature communications, 7, p. 11752. ISSN 2041-1723,
[Article]

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.

Item Type: Article
Erschienen: 2016
Creators: Wolf, Christine and Rapp, Alexander and Berndt, Nicole and Staroske, Wolfgang and Schuster, Max and Dobrick-Mattheuer, Manuela and Kretschmer, Stefanie and König, Nadja and Kurth, Thomas and Wieczorek, Dagmar and Kast, Karin and Cardoso, M. Cristina and Günther, Claudia and Lee-Kirsch, Min Ae
Title: RPA and Rad51 constitute a cell intrinsic mechanism to protect the cytosol from self DNA.
Language: English
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.

Journal or Publication Title: Nature communications
Journal volume: 7
Divisions: 10 Department of Biology
10 Department of Biology > Cell Biology and Epigenetics
Date Deposited: 31 May 2016 06:48
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