Journal
CELL CYCLE
Volume 14, Issue 11, Pages 1657-1665Publisher
TAYLOR & FRANCIS INC
DOI: 10.1080/15384101.2015.1030558
Keywords
cyclin-dependent kinase; HIV-1; virus restriction; SAMHD1; cyclin
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Funding
- Spanish Ministerio de Economia y Competitividad (MINECO)
- Fondo de Investigacion Sanitaria (FIS) [BFU2012-31569, FIS PI13-01083, FIS CP14/00016]
- HIV BioBank RIS [RD06/0006/0035]
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Cyclins control the activation of cyclin-dependent kinases (CDK), which in turn, control the cell cycle and cell division. Intracellular availability of deoxynucleotides (dNTP) plays a fundamental role in cell cycle progression. SAM domain and HD domain-containing protein 1 (SAMHD1) degrades nucleotide triphosphates and controls the size of the dNTP pool. SAMHD1 activity appears to be controlled by CDK. Here, we show that knockdown of cyclin D3 a partner of CDK6 and E2 a partner of CDK2 had a major impact in SAMHD1 phosphorylation and inactivation and led to decreased dNTP levels and inhibition of HIV-1 at the reverse transcription step in primary human macrophages. The effect of cyclin D3 RNA interference was lost after degradation of SAMHD1 by HIV-2 Vpx, demonstrating the specificity of the mechanism. Cyclin D3 inhibition correlated with decreased activation of CDK2. Our results confirm the fundamental role of the CDK6-cyclin D3 pair in controlling CDK2-dependent SAMHD1 phosphorylation and dNTP pool in primary macrophages.
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