Original Article

Journal of Molecular Medicine

, Volume 91, Issue 6, pp 759-770

First online:

Single-stranded nucleic acids promote SAMHD1 complex formation

  • Victoria TünglerAffiliated withChildren’s Hospital, Technical University Dresden
  • , Wolfgang StaroskeAffiliated withBiotechnology Center, Technical University Dresden
  • , Barbara KindAffiliated withChildren’s Hospital, Technical University Dresden
  • , Manuela DobrickAffiliated withChildren’s Hospital, Technical University Dresden
  • , Stefanie KretschmerAffiliated withChildren’s Hospital, Technical University Dresden
  • , Franziska SchmidtAffiliated withChildren’s Hospital, Technical University Dresden
  • , Claudia KrugAffiliated withChildren’s Hospital, Technical University Dresden
  • , Mike LorenzAffiliated withMax Planck Institute of Molecular Cell Biology and Genetics
  • , Osvaldo CharaAffiliated withCenter for Information Services and High Performance Computing, Technical University DresdenInstitute of Physics of Liquids and Biological Systems (IFLYSIB), CONICET, National University of La Plata
    • , Petra SchwilleAffiliated withBiotechnology Center, Technical University DresdenMax Planck Institute of Biochemistry
    • , Min Ae Lee-KirschAffiliated withChildren’s Hospital, Technical University Dresden Email author 

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SAM domain and HD domain-containing protein 1 (SAMHD1) is a dGTP-dependent triphosphohydrolase that degrades deoxyribonucleoside triphosphates (dNTPs) thereby limiting the intracellular dNTP pool. Mutations in SAMHD1 cause Aicardi–Goutières syndrome (AGS), an inflammatory encephalopathy that mimics congenital viral infection and that phenotypically overlaps with the autoimmune disease systemic lupus erythematosus. Both disorders are characterized by activation of the antiviral cytokine interferon-α initiated by immune recognition of self nucleic acids. Here we provide first direct evidence that SAMHD1 associates with endogenous nucleic acids in situ. Using fluorescence cross-correlation spectroscopy, we demonstrate that SAMHD1 specifically interacts with ssRNA and ssDNA and establish that nucleic acid-binding and formation of SAMHD1 complexes are mutually dependent. Interaction with nucleic acids and complex formation do not require the SAM domain, but are dependent on the HD domain and the C-terminal region of SAMHD1. We finally demonstrate that mutations associated with AGS exhibit both impaired nucleic acid-binding and complex formation implicating that interaction with nucleic acids is an integral aspect of SAMHD1 function.


SAMHD1 Aicardi–Goutières syndrome Fluorescence cross-correlation spectroscopy Nucleic acids