Kretschmer S, Wolf C, Koenig N, Staroske W, Guck J, Haeusler M, Luksch H, Nguyen LA, Kim B, Alexopoulou D, Dahl A, Rapp A, Cardoso MC, Shevchenko A, Lee-Kirsch MA (2015)
Publication Type: Journal article
Publication year: 2015
Book Volume: 74
Article Number: e17
Journal Issue: 3
DOI: 10.1136/annrheumdis-2013-204845
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/cyclindependent kinase 1 in a cell cycle-dependent manner, and its level fluctuates during the cell cycle, with the lowest levels observed in G
APA:
Kretschmer, S., Wolf, C., Koenig, N., Staroske, W., Guck, J., Haeusler, M.,... Lee-Kirsch, M.A. (2015). SAMHD1 prevents autoimmunity by maintaining genome stability. Annals of the Rheumatic Diseases, 74(3). https://doi.org/10.1136/annrheumdis-2013-204845
MLA:
Kretschmer, Stefanie, et al. "SAMHD1 prevents autoimmunity by maintaining genome stability." Annals of the Rheumatic Diseases 74.3 (2015).
BibTeX: Download