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Review
. 2020 Mar 31;12(4):382.
doi: 10.3390/v12040382.

SAMHD1 Functions and Human Diseases

Si'Ana A Coggins  1 , Bijan Mahboubi  1 , Raymond F Schinazi  1 , Baek Kim  1   2
Affiliations
Review

SAMHD1 Functions and Human Diseases

Si'Ana A Coggins et al. Viruses. .

Abstract

Deoxynucleoside triphosphate (dNTP) molecules are essential for the replication and maintenance of genomic information in both cells and a variety of viral pathogens. While the process of dNTP biosynthesis by cellular enzymes, such as ribonucleotide reductase (RNR) and thymidine kinase (TK), has been extensively investigated, a negative regulatory mechanism of dNTP pools was recently found to involve sterile alpha motif (SAM) domain and histidine-aspartate (HD) domain-containing protein 1, SAMHD1. When active, dNTP triphosphohydrolase activity of SAMHD1 degrades dNTPs into their 2'-deoxynucleoside (dN) and triphosphate subparts, steadily depleting intercellular dNTP pools. The differential expression levels and activation states of SAMHD1 in various cell types contributes to unique dNTP pools that either aid (i.e., dividing T cells) or restrict (i.e., nondividing macrophages) viral replication that consumes cellular dNTPs. Genetic mutations in SAMHD1 induce a rare inflammatory encephalopathy called Aicardi-Goutières syndrome (AGS), which phenotypically resembles viral infection. Recent publications have identified diverse roles for SAMHD1 in double-stranded break repair, genome stability, and the replication stress response through interferon signaling. Finally, a series of SAMHD1 mutations were also reported in various cancer cell types while why SAMHD1 is mutated in these cancer cells remains to investigated. Here, we reviewed a series of studies that have begun illuminating the highly diverse roles of SAMHD1 in virology, immunology, and cancer biology.

Keywords: Aicardi–Goutières syndrome; SAMHD1; cancers; dNTPs; viruses.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
SAMHD1 plays a variety of roles in virology, immunology, and cell biology. The dNTPase activity of SAMHD1 depletes intercellular dNTP pools in macrophages, restricting reverse transcription of HIV-1 in this cell type. Similarly, SAMHD1 has been found to restrict the viral replication of other DNA and RNA viruses. In addition to viral restriction, SAMHD1 facilitates replication fork progression, is implicated in cell proliferation and apoptosis, and is localized to sites of DNA damage. As a negative regulator of IFN I, SAMHD1 is commonly mutated in a disease that phenotypically resembles a congenital viral infection called AGS. The controversial exonuclease activity of SAMHD1 would negatively regulate host innate immunity as aberrant host and viral nucleic acids could serve as potential degradation targets. Figure 1, Figure 2 and Figure 3 were created with BioRender.com.
Figure 2
Figure 2
Key SAMHD1 domains, residues, and AGS mutants. SAMHD1 contains an N-terminal SAM domain, central catalytic HD domain, and C-terminus containing an 451RXL453 and 620LF621 cyclin-binding motif that is essential for recognition and subsequent phosphorylation of T592 by CDK1/2. SAMHD1 contains a classic NLS sequence (11-KRPR-14), a residue that can undergo acetylation (K405), and at least four residues that can undergo phosphorylation (S6, T21, S33, and well-known T592). Lastly, a triad of surface-exposed, oxidizable cysteines (C341, C350, and C522) have been found to influence protein function. SAMHD1 mutations identified in AGS patients are labeled and distributed along the top of the SAMHD1 schematic. In White et al. (2017), the dNTP concentrations of U937 cells were measured following the transduction of different SAMHD1 AGS mutants. Here, the mutants are summarized to have more (+) or no difference (ND) in dNTP pools relative to wildtype hSAMHD1. SAMHD1 mutants that do not have a symbol assigned represent the population that were not able to be tested. The mutant G209S (highlighted red) represents the only variant found to restrict HIV-1.
Figure 3
Figure 3
Host SAMHD1 restricts HIV-1 infection within macrophages at the reverse transcription, integration, and ERT steps of viral replication. Tetrameric SAMHD1 (orange), which can reside in the cytosol (beige) and nucleus (dark grey), restricts the HIV-1 lifecycle at three points during viral infection of a macrophage. The SAMHD1-mediated low dNTP pools in macrophages inhibit reverse transcription in the cytosol (red inhibition arrow 1), gap repair within the nucleus (red inhibition arrow 2), and ERT activity occurring extracellularly (red inhibition arrow 3).
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