Kretschmer, Stefanie ; Wolf, Christine ; König, Nadja ; Staroske, Wolfgang ; Guck, Jochen ; Häusler, Martin ; Luksch, Hella ; Nguyen, Laura A. ; Kim, Baek ; Alexopoulou, Dimitra ; Dahl, Andreas ; Rapp, Alexander ; Cardoso, M. Cristina ; Shevchenko, Anna ; Lee-Kirsch, Min Ae (2015)
SAMHD1 prevents autoimmunity by maintaining genome stability.
In: Annals of the rheumatic diseases, 74 (3)
Artikel, Bibliographie
Kurzbeschreibung (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.
| Typ des Eintrags: | Artikel |
|---|---|
| Erschienen: | 2015 |
| Autor(en): | Kretschmer, Stefanie ; Wolf, Christine ; König, Nadja ; Staroske, Wolfgang ; Guck, Jochen ; Häusler, Martin ; Luksch, Hella ; Nguyen, Laura A. ; Kim, Baek ; Alexopoulou, Dimitra ; Dahl, Andreas ; Rapp, Alexander ; Cardoso, M. Cristina ; Shevchenko, Anna ; Lee-Kirsch, Min Ae |
| Art des Eintrags: | Bibliographie |
| Titel: | SAMHD1 prevents autoimmunity by maintaining genome stability. |
| Sprache: | Englisch |
| Publikationsjahr: | 2015 |
| Titel der Zeitschrift, Zeitung oder Schriftenreihe: | Annals of the rheumatic diseases |
| Jahrgang/Volume einer Zeitschrift: | 74 |
| (Heft-)Nummer: | 3 |
| Kurzbeschreibung (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. |
| Fachbereich(e)/-gebiet(e): | 10 Fachbereich Biologie 10 Fachbereich Biologie > Cell Biology and Epigenetics |
| Hinterlegungsdatum: | 07 Apr 2015 06:56 |
| Letzte Änderung: | 07 Apr 2015 06:56 |
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