SAMHD1

Last updated
SAMHD1
3u1n.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases SAMHD1 , CHBL2, DCIP, HDDC1, MOP-5, SBBI88, SAM and HD domain containing deoxynucleoside triphosphate triphosphohydrolase 1, hSAMHD1
External IDs OMIM: 606754 MGI: 1927468 HomoloGene: 9160 GeneCards: SAMHD1
Orthologs
SpeciesHumanMouse
Entrez

25939

56045

Ensembl

ENSG00000101347

ENSMUSG00000027639

UniProt

Q9Y3Z3

Q60710

RefSeq (mRNA)

NM_015474
NM_001363729
NM_001363733

NM_001139520
NM_018851
NM_001370610

RefSeq (protein)

NP_056289
NP_001350658
NP_001350662

NP_001132992
NP_061339
NP_001357539

Location (UCSC) Chr 20: 36.89 – 36.95 Mb Chr 2: 156.94 – 156.98 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

SAM domain and HD domain-containing protein 1 is a protein that in humans is encoded by the SAMHD1 gene. SAMHD1 is a cellular enzyme, responsible for blocking replication of HIV in dendritic cells, [5] macrophages, [6] monocytes [7] and resting CD4+ T lymphocytes. [8] It is an enzyme that exhibits phosphohydrolase activity, [9] [10] converting deoxynucleoside triphosphates (dNTPs) to inorganic phosphate (iPPP) and a 2'-deoxynucleoside (i.e. deoxynucleosides without a phosphate group). In doing so, SAMHD1 depletes the pool of dNTPs available to a reverse transcriptase for viral cDNA synthesis and thus prevents viral replication. [11] SAMHD1 has also shown nuclease activity. [12] Although a ribonuclease activity was described to be required for HIV-1 restriction, [13] recent data confirmed that SAMHD1-mediated HIV-1 restriction in cells does not involve ribonuclease activity. [14]

Nomenclature

The SAMHD1 protein is also known as:

Gene

The gene encoding human SAMHD1 was originally identified in a human dendritic cell cDNA library as an orthologue of a mouse gene IFN-γ-induced gene Mg11. [16] The SAMHD1 gene is located on chromosome 20. 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. [17] [18] SAMHD1 expressed in both cycling and noncycling cells, but the antiviral activity of SAMHD1 is limited to noncycling cells. [19]

Structure

The SAMHD1 is 626 amino acids (aa) long and has 2 domains:

a. Sterile alpha motif (SAM) domain: residues 45 – 110 aa. [20] [21] 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. [22] [23]

b. Histidine- Aspartic (HD) domain-containing protein 1: residues 164 – 319 aa. [20] [21] 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. [22] [24]

A crystal structure of a SAMHD1 fragment comprising catalytic core reveals that the protein is dimeric. [10] Also studies have shown that SAMHD1 oligomerizes and forms tetramers. [25] SAMHD1 is phosphorylated on residue T592 in cycling cells but that this phosphorylation is lost when cells are in a noncycling state. [26]

Function

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”. [21] Monocytes isolated from individuals with AGS are highly susceptible to HIV-1. [7]

SAMHD1 was identified as a host protein that is bound and blocked by lentiviral protein, Vpx. Vpx promotes macrophage and DC infection by targeting SAMHD1. [27]

The human SAMHD1 protein has dNTP triphosphatase activity, specifically dGTP-stimulated dNTP triphosphohydrolase activity, and nuclease activity against single-stranded DNA and RNA which is associated with its HD domain. [12] [28] Other studies demonstrated that silencing SAMHD1 enhanced HIV-1 and SIV Δvpx infection of myeloid cells, also enhances HIV-1 infection of resting CD4+ T cells. [19] [28]

Role in disease

Aicardi-Goutieres syndrome

16 mutations in the SAMHD1 gene have been identified in patients with Aicardi-Goutieres syndrome. Mutations result in a SAMHD1 less functional protein. 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. [7] [21]

Restriction of viral infection

SAMHD1 was identified as the cellular protein responsible of the reverse transcription block to HIV-1 infection observed in myeloid cells as well as in quiescent CD4+ T cells. SAMHD1 inhibits HIV-1 infection in myeloid cells by limiting the intracellular pool of dNTPs. [27] The dNTP triphosphohydrolase activity of SAMHD1 has been proposed to reduce the intracellular dNTP level, restricting HIV-1 replication and preventing activation of the immune system, a nuclease activity against single-stranded (ss)DNAs and RNAs, as well as against RNA in DNA/RNA hybrids. [22] [27] Retroviral restriction ability of SAMHD1 is regulated by phosphorylation, for this purpose SAMHD1 associates with the cyclin A2/CDK1 complex that mediates its phosphorylation at threonine 592. Phosphorylated SAMHD1 has been observed to have minimal to no activity in cycling cells. Conversely, unphosphorylated SAMHD1 in non-cycling cells have potent restriction activity. [26]

Expression modulation and antimetabolite degradation in cancer cells

SAMHD1 protein expression can be influenced at four levels in cancer cells. First, mutations in the SAMHD1 gene can prevent SAMHD1 mRNA generation or a functional protein after translations. [29] Second, promoter methylation can prevent SAMHD1 mRNA transcription. [30] [31] Third, miRNA-155 and miRNA-181a can prevent the translation, thus preventing protein production. [32] [33] Finally, SAMHD1 degradation occurs during the S phase of the cell cycle. [34] Non-adherent tumor cell lines – B cells, T cells and myeloid cells can be rapidly dividing cells, have low to no detectable levels of SAMHD1 protein, as compared to adherent cells. Regulation of dNTP concentration by SAMHD1 in cancer cells might be an important mechanism with therapeutic implications. [35] Antimetabolites are anticancer nucleosides, nucleotides, and base analogs used as anticancer agents to promote cell death by several different mechanisms of action. [36] For some of these antimetabolites, the intracellular triphosphate form of the analog is the active compound. [36] SAMHD1 has been shown to be able to hydrolyze arabinose 5’-triphosphates. [37] SAMHD1 has been shown to be a biomarker and influence arabinose C (ara-C; cytarabine) responsiveness. [38] Viral protein x (Vpx) has been proposed to be potential therapy to improve cytarabine therapy for hematological malignancies. [39]

Related Research Articles

<span class="mw-page-title-main">HIV</span> Human retrovirus, cause of AIDS

The human immunodeficiency viruses (HIV) are two species of Lentivirus that infect humans. Over time, they cause acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive. Without treatment, the average survival time after infection with HIV is estimated to be 9 to 11 years, depending on the HIV subtype.

A restriction enzyme, restriction endonuclease, REase, ENase orrestrictase is an enzyme that cleaves DNA into fragments at or near specific recognition sites within molecules known as restriction sites. Restriction enzymes are one class of the broader endonuclease group of enzymes. Restriction enzymes are commonly classified into five types, which differ in their structure and whether they cut their DNA substrate at their recognition site, or if the recognition and cleavage sites are separate from one another. To cut DNA, all restriction enzymes make two incisions, once through each sugar-phosphate backbone of the DNA double helix.

<i>Simian immunodeficiency virus</i> Species of retrovirus

Simian immunodeficiency virus (SIV) is a species of retrovirus that cause persistent infections in at least 45 species of non-human primates. Based on analysis of strains found in four species of monkeys from Bioko Island, which was isolated from the mainland by rising sea levels about 11,000 years ago, it has been concluded that SIV has been present in monkeys and apes for at least 32,000 years, and probably much longer.

<span class="mw-page-title-main">Ribonuclease H</span> Enzyme family

Ribonuclease H is a family of non-sequence-specific endonuclease enzymes that catalyze the cleavage of RNA in an RNA/DNA substrate via a hydrolytic mechanism. Members of the RNase H family can be found in nearly all organisms, from bacteria to archaea to eukaryotes.

A nucleoside triphosphate is a nucleoside containing a nitrogenous base bound to a 5-carbon sugar, with three phosphate groups bound to the sugar. They are the molecular precursors of both DNA and RNA, which are chains of nucleotides made through the processes of DNA replication and transcription. Nucleoside triphosphates also serve as a source of energy for cellular reactions and are involved in signalling pathways.

<span class="mw-page-title-main">Clofarabine</span> Chemical compound

Clofarabine is a purine nucleoside antimetabolite marketed in the United States and Canada as Clolar. In Europe and Australia/New Zealand the product is marketed under the name Evoltra. It is FDA-approved for treating relapsed or refractory acute lymphoblastic leukaemia (ALL) in children after at least two other types of treatment have failed. Some investigations of effectiveness in cases of acute myeloid leukaemia (AML) and juvenile myelomonocytic leukaemia (JMML) have been carried out. Ongoing trials are assessing its efficacy for managing other cancers.

The genome and proteins of HIV (human immunodeficiency virus) have been the subject of extensive research since the discovery of the virus in 1983. "In the search for the causative agent, it was initially believed that the virus was a form of the Human T-cell leukemia virus (HTLV), which was known at the time to affect the human immune system and cause certain leukemias. However, researchers at the Pasteur Institute in Paris isolated a previously unknown and genetically distinct retrovirus in patients with AIDS which was later named HIV." Each virion comprises a viral envelope and associated matrix enclosing a capsid, which itself encloses two copies of the single-stranded RNA genome and several enzymes. The discovery of the virus itself occurred two years following the report of the first major cases of AIDS-associated illnesses.

<span class="mw-page-title-main">Drosha</span> Ribonuclease III enzyme

Drosha is a Class 2 ribonuclease III enzyme that in humans is encoded by the DROSHA gene. It is the primary nuclease that executes the initiation step of miRNA processing in the nucleus. It works closely with DGCR8 and in correlation with Dicer. It has been found significant in clinical knowledge for cancer prognosis and HIV-1 replication.

<span class="mw-page-title-main">ADAR</span> Mammalian protein found in Homo sapiens

The double-stranded RNA-specific adenosine deaminase enzyme family are encoded by the ADAR family genes. ADAR stands for adenosine deaminase acting on RNA. This article focuses on the ADAR proteins; This article details the evolutionary history, structure, function, mechanisms and importance of all proteins within this family.

<span class="mw-page-title-main">IFI16</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">TREX1</span> Protein-coding gene in the species Homo sapiens

Three prime repair exonuclease 1 is an enzyme that in humans is encoded by the TREX1 gene.

<span class="mw-page-title-main">USP18</span> Protein-coding gene in the species Homo sapiens

Ubiquitin specific peptidase 18 (USP18), also known as UBP43, is a type I interferon receptor repressor and an isopeptidase. In humans, it is encoded by the USP18 gene. USP18 is induced by the immune response to type I and III interferons, and serves as a negative regulator of type I interferon, but not type III interferon. Loss of USP18 results in increased responsiveness to type I interferons and life-threatening autoinflammatory disease in humans due to the negative regulatory function of USP18 in interferon signal transduction. Independent of this activity, USP18 is also a member of the deubiquitinating protease family of enzymes. It is known to remove ISG15 conjugates from a broad range of protein substrates, a process known as deISGylation.

<span class="mw-page-title-main">Vpr</span> Group of transport proteins

Vpr is a Human immunodeficiency virus gene and protein product. Vpr stands for "Viral Protein R". Vpr, a 96 amino acid 14-kDa protein, plays an important role in regulating nuclear import of the HIV-1 pre-integration complex, and is required for virus replication and enhanced gene expression from provirus in dividing or non-dividing cells such as T cells or macrophages. Vpr also induces G2 cell cycle arrest and apoptosis in proliferating cells, which can result in immune dysfunction.

<span class="mw-page-title-main">RNASEH2A</span> Protein-coding gene in the species Homo sapiens

Ribonuclease H2 subunit A, also known as RNase H2 subunit A, is an enzyme that in humans is encoded by the RNASEH2A gene.

<span class="mw-page-title-main">RNASEH2B</span> Protein-coding gene in the species Homo sapiens

Ribonuclease H2, subunit B is a protein in humans is encoded by the RNASEH2B gene. RNase H2 is composed of a single catalytic subunit (A) and two non-catalytic subunits, and degrades the RNA of RNA:DNA hybrids. The non-catalytic B subunit of RNase H2 is thought to play a role in DNA replication.

<span class="mw-page-title-main">Genome editing</span> Type of genetic engineering

Genome editing, or genome engineering, or gene editing, is a type of genetic engineering in which DNA is inserted, deleted, modified or replaced in the genome of a living organism. Unlike early genetic engineering techniques that randomly inserts genetic material into a host genome, genome editing targets the insertions to site-specific locations. The basic mechanism involved in genetic manipulations through programmable nucleases is the recognition of target genomic loci and binding of effector DNA-binding domain (DBD), double-strand breaks (DSBs) in target DNA by the restriction endonucleases, and the repair of DSBs through homology-directed recombination (HDR) or non-homologous end joining (NHEJ).

Vpx is a virion-associated protein encoded by human immunodeficiency virus type 2 HIV-2 and most simian immunodeficiency virus (SIV) strains, but that is absent from HIV-1. It is similar in structure to the protein Vpr that is carried by SIV and HIV-2 as well as HIV-1. Vpx is one of five accessory proteins carried by lentiviruses that enhances viral replication by inhibiting host antiviral factors.

<span class="mw-page-title-main">Aicardi–Goutières syndrome</span> Medical condition

Aicardi–Goutières syndrome (AGS), which is completely distinct from the similarly named Aicardi syndrome, is a rare, usually early onset childhood, inflammatory disorder most typically affecting the brain and the skin. The majority of affected individuals experience significant intellectual and physical problems, although this is not always the case. The clinical features of AGS can mimic those of in utero acquired infection, and some characteristics of the condition also overlap with the autoimmune disease systemic lupus erythematosus (SLE). Following an original description of eight cases in 1984, the condition was first referred to as 'Aicardi–Goutières syndrome' (AGS) in 1992, and the first international meeting on AGS was held in Pavia, Italy, in 2001.

<span class="mw-page-title-main">RNASEH2C</span> Protein-coding gene in the species Homo sapiens

Ribonuclease H2 subunit C is a protein that in humans is encoded by the RNASEH2C gene. RNase H2 is composed of a single catalytic subunit (A) and two non-catalytic subunits, and degrades the RNA of RNA:DNA hybrids.

Since antiretroviral therapy requires a lifelong treatment regimen, research to find more permanent cures for HIV infection is currently underway. It is possible to synthesize zinc finger nucleotides with zinc finger components that selectively bind to specific portions of DNA. Conceptually, targeting and editing could focus on host cellular co-receptors for HIV or on proviral HIV DNA.

References

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  37. ↑ Hollenbaugh JA, Shelton J, Tao S, Amiralaei S, Liu P, Lu X, Goetze RW, Zhou L, Nettles JH, Schinazi RF, Kim B (Jan 2017). "Substrates and Inhibitors of SAMHD1". PLOS ONE. 12 (1): e0169052. Bibcode:2017PLoSO..1269052H. doi: 10.1371/journal.pone.0169052 . PMC   5207538 . PMID   28046007.
  38. ↑ Schneider C, Oellerich T, Baldauf HM, Schwarz SM, Thomas D, Flick R, et al. (February 2017). "SAMHD1 is a biomarker for cytarabine response and a therapeutic target in acute myeloid leukemia" (PDF). Nature Medicine. 23 (2): 250–255. doi:10.1038/nm.4255. PMID   27991919. S2CID   205398095.
  39. ↑ Herold N, Rudd SG, Ljungblad L, Sanjiv K, Myrberg IH, Paulin CB, et al. (February 2017). "Targeting SAMHD1 with the Vpx protein to improve cytarabine therapy for hematological malignancies". Nature Medicine. 23 (2): 256–263. doi:10.1038/nm.4265. PMID   28067901. S2CID   22800252.

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