SAMHD1-mediated negative regulation of cellular dNTP levels: HIV-1, innate immunity, and cancers

Metabolic regulation of cellular 2'-deoxynucleoside triphosphates (dNTPs), which are the building blocks of DNA, have been extensively investigated, mainly for their positive/biosynthetic regulations. A series of cellular enzymes involved in dNTP biosynthesis including ribonucleotide reductase (RNR) and thymidine kinase (TK) were also well characterized for their enzymatic regulatory mechanisms. Recent studies revealed a novel negative regulatory mechanism of cellular dNTP levels operated by a key multifunctional cellular protein, sterile alpha motif (SAM) domain and histidine-aspartate domain (HD) containing protein 1, SAMHD1. SAMHD1 is a dNTP triphosphohydrolase that degrades dNTPs into 2'-deoxynucleosides (dNs) and triphosphates, and highly expressed mainly in nondividing cells such as differentiated myeloid cells, including macrophages. SAMHD1 downregulates cellular dNTP levels in nondividing cells, which are not requiring dNTPs due to their lack of cellular DNA replication. Recent publications have elucidated the structure-function and disease-relevance of SAMHD1. First, SAMHD1 serves as an anti-HIV host factor that restricts HIV reverse transcription primarily in nondividing macrophages by depleting cellular dNTPs. Second, many genetic mutations in the human SAMHD1 gene induce a rare genetic immune disorder, the Aicardi Goutieres Syndrome (AGS), that displays hyper-interferon responses without actual infection and severe neuro-developmental problems, supporting a tie between SAMHD1 and host innate immunity. Finally, recent studies have proposed that SAMHD1 can be a biomarker for predicting the sensitivity of cancer patients to anticancer nucleoside analogues because SAMHD1 can hydrolyze and inactivate some of the anticancer nucleotides in cancer cells. In this chapter, we review the currently available knowledge on SAMHD1 structure-function, SAMHD1 regulation, and SAMHD1-related human diseases.