Azacytidine Induces Global DNA Hypomethylation and Increases Cellular and Nuclear SAMHD1 in Feline Lymphocytes

Sterile α motif and histidine-aspartate domain–containing protein 1 (SAMHD1) is a multifunctional protein that limits cellular dNTP availability, interacts with specific retroviral proteins to induce degradation. Regulation of dNTP availability is crucial for cell cycle regulation and DNA stability. Demethylating agents such as azacytidine are in clinical use for cancer therapy, and reduce methylation of the SAMHD1 promoter and SAMHD1 gene expression. Here, we evaluated the effect of azacytidine on global DNA methylation in feline lymphocytes, and specifically on the abundance and cellular distribution of phosphorylated and non-phosphorylated SAMHD1. Azacytidine increased cellular and nuclear SAMHD1 but did not increase phosphorylated SAMHD1. Phosphorylation is essential for SAMHD1 stability and function but is unaffected by demethylation. The findings suggest that treatment with azacytidine could increase viral restriction, and they lend support to development of in vivo models utilizing azacytidine to modulate SAMHD1 activity.