Diagram of the Role of SAMHD1 in Cytarabine (ara-C) Metabolism. Upon entering cells, ara-C is converted into its active metabolite ara-C triphosphate (ara-CTP). Ara-CTP, in turn, results in lethal misincorporation into genomic DNA. The enzyme SAMHD1 limits ara-C cytotoxicity by hydrolyzing ara-CTP. Interestingly, an accessory protein, termed viral protein X (VPX), encoded by several viruses recruits SAMHD1 to a cullin4A-RING E3 ubiquitin ligase, targeting SAMHD1 for proteasomal degradation. Depletion of SAMHD1 in this method promotes sensitivity of cells to ara-CTP. The expression level of other proteins responsible for ara-C transport metabolism as shown in this figure do not correlate with response to ara-C mediated cell death. Abbreviations: cytidine deaminase (CDA), deoxycytidylate deaminase (DCTD), deoxycytidine kinase (DCK), 5'-nucleotidase-II (NT5C2).