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Extended report
SAMHD1 prevents autoimmunity by maintaining genome stability
  1. Stefanie Kretschmer1,
  2. Christine Wolf1,
  3. Nadja König1,
  4. Wolfgang Staroske2,
  5. Jochen Guck2,3,
  6. Martin Häusler4,
  7. Hella Luksch1,
  8. Laura A Nguyen5,
  9. Baek Kim5,6,
  10. Dimitra Alexopoulou2,7,
  11. Andreas Dahl2,7,
  12. Alexander Rapp8,
  13. M Cristina Cardoso8,
  14. Anna Shevchenko9,
  15. Min Ae Lee-Kirsch1
  1. 1Department of Pediatrics, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
  2. 2Biotechnology Center, Technische Universität Dresden, Dresden, Germany
  3. 3Cavendish Laboratory, Department of Physics, University of Cambridge, Cambridge, UK
  4. 4Department of Pediatrics, University Hospital, University of Aachen, Aachen, Germany
  5. 5Department of Pediatrics, Center for Drug Discovery, Emory University, Atlanta, Georgia, USA
  6. 6College of Pharmacy, Kyung-Hee University, Seoul, South Korea
  7. 7Center for Regenerative Therapies, Technische Universität Dresden, Dresden, Germany
  8. 8Department of Biology, Technische Universität Darmstadt, Germany
  9. 9Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany
  1. Correspondence to Professor Min Ae Lee-Kirsch, Department of Pediatrics, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany, Fetscherstr 74, Dresden 01307, Germany; minae.lee-kirsch{at}uniklinikum-dresden.de

Abstract

Objectives The HIV restriction factor, SAMHD1 (SAM domain and HD domain-containing protein 1), is a triphosphohydrolase that degrades deoxyribonucleoside triphosphates (dNTPs). Mutations in SAMHD1 cause Aicardi–Goutières syndrome (AGS), an inflammatory disorder that shares phenotypic similarity with systemic lupus erythematosus, including activation of antiviral type 1 interferon (IFN). To further define the pathomechanisms underlying autoimmunity in AGS due to SAMHD1 mutations, we investigated the physiological properties of SAMHD1.

Methods Primary patient fibroblasts were examined for dNTP levels, proliferation, senescence, cell cycle progression and DNA damage. Genome-wide transcriptional profiles were generated by RNA sequencing. Interaction of SAMHD1 with cyclin A was assessed by coimmunoprecipitation and fluorescence cross-correlation spectroscopy. Cell cycle-dependent phosphorylation of SAMHD1 was examined in synchronised HeLa cells and using recombinant SAMHD1. SAMHD1 was knocked down by RNA interference.

Results We show that increased dNTP pools due to SAMHD1 deficiency cause genome instability in fibroblasts of patients with AGS. Constitutive DNA damage signalling is associated with cell cycle delay, cellular senescence, and upregulation of IFN-stimulated genes. SAMHD1 is phosphorylated by cyclin A/cyclin-dependent kinase 1 in a cell cycle-dependent manner, and its level fluctuates during the cell cycle, with the lowest levels observed in G1/S phase. Knockdown of SAMHD1 by RNA interference recapitulates activation of DNA damage signalling and type 1 IFN activation.

Conclusions SAMHD1 is required for genome integrity by maintaining balanced dNTP pools. dNTP imbalances due to SAMHD1 deficiency cause DNA damage, leading to intrinsic activation of IFN signalling. These findings establish a novel link between DNA damage signalling and innate immune activation in the pathogenesis of autoimmunity.

  • Autoimmune Diseases
  • Autoimmunity
  • Fibroblasts
  • Systemic Lupus Erythematosus

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