SAMHD1 is a cellular enzyme, responsible for blocking replication of HIV in dendritic cells,[5] macrophages,[6] monocytes[7] and resting CD4+ T lymphocytes.

[14] In addition to its role in nucleotide metabolism, SAMHD1 also promotes DNA double-strand break (DSB) repair in a dNTPase-independent fashion.

SAMHD1 spans 59,532 bp of genomic sequence (chromosome 20:34,954,059–35,013,590) in 16 exons and encodes a 626 amino-acid (aa) protein with a molecular weight of 72.2 kDa.

[21][22] In general, SAM domains are known to function as protein–protein and protein–nucleic acid interactions in organisms from yeast to humans, docking sites for kinases, signal transduction and regulation of transcription.

[21][22] HD domains proteins are characterized by a doublet of histidine and aspartic acid catalytic residues, and have been shown to possess putative nuclease, dGTP triphosphatase, phosphatase or phosphodiesterase activities.

[23][25] A crystal structure of a SAMHD1 fragment comprising catalytic core reveals that the protein is dimeric.

[27] Mutations in SAMHD1 are found in Aicardi–Goutières syndrome (AGS), “a hereditary autoimmune encephalopathy that is characterized by aberrant production of type I interferon (IFN) and symptoms mimicking congenital viral infection”.

However, it is not known how this protein dysfunction leads to immune system abnormalities, inflammatory damage to the brain and skin, and other characteristics of this syndrome.

Regulation of dNTP concentration by SAMHD1 in cancer cells might be an important mechanism with therapeutic implications.