Involvement of SAMHD1 in dNTP homeostasis and the maintenance of genomic integrity and oncotherapy (Review)

  • Authors:
    • Zhou Zhang
    • Lixia Zheng
    • Yang Yu
    • Jinying Wu
    • Fan Yang
    • Yingxi Xu
    • Qiqiang Guo
    • Xuan Wu
    • Sunrun Cao
    • Liu Cao
    • Xiaoyu Song
  • View Affiliations

  • Published online on: February 14, 2020     https://doi.org/10.3892/ijo.2020.4988
  • Pages: 879-888
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Abstract

Sterile alpha motif and histidine/aspartic acid domain‑containing protein 1 (SAMHD1), the only deoxynucleotide triphosphate (dNTP) hydrolase in eukaryotes, plays a crucial role in regulating the dynamic balance and ratio of cellular dNTP pools. Furthermore, SAMHD1 has been reported to be involved in the pathological process of several diseases. Homozygous SAMHD1 mutations have been identified in immune system disorders, such as autoimmune disease Aicardi‑Goutières syndrome (AGS), whose primary pathogenesis is associated with the abnormal accumulation and disproportion of dNTPs. SAMHD1 is also considered to be an intrinsic virus‑restriction factor by suppressing the viral infection process, including reverse transcription, replication, packaging and transmission. In addition, SAMHD1 has been shown to promote genome integrity during homologous recombination following DNA damage, thus being considered a promising candidate for oncotherapy applications. The present review summarizes the molecular mechanisms of SAMHD1 regarding the regulation of dNTP homeostasis and DNA damage response. Additionally, its potential effects on tumorigenesis and oncotherapy are reported.

1. Introduction

Deoxynucleotide triphosphates (dNTPs) are the raw materials for DNA replication and repair, rendering them indispensable components for transmitting genetic information in cells and maintaining genomic stability (1,2). Sterile alpha motif and histidine/aspartic acid domain-containing protein 1 (SAMHD1), the only dNTP hydrolase in eukaryotes, is involved in several pathological processes. SAMHD1 is well known for its vital role in the resistance to virus transcription and replication by limiting the volume of the dNTP pool, thus resulting in the protection of the host cellular genome integrity. It has been reported that SAMHD1 acetylation enhances its dNTP hydrolase (dNTPase) activity and regulates cancer cell proliferation (3). Moreobver, the dNTPase activity of SAMHD1 is dependent on the stability of the catalytic core tetramer, which can be inhibited by cyclin-dependent kinase phosphorylation on threonine 592 (T592) (4-8). In addition, viral protein kinases can also phosphorylate SAMHD1, thereby inhibiting its dNTPase activity (9,10). The transcriptional repression of Samhd1 is mediated by methylation of its promoter (11-13). It has been also reported that viral protein X (Vpx) interacts with SAMHD1, resulting in the proteasomal degradation of SAMHD1 and an increase in dNTP levels (14-17). Therefore, it is necessary to systematically summarize the modifications of SAMHD1 and reveal its related downstream functions.

In the present review, the current knowledge of the role of SAMHD1 in the dynamic regulation of dNTP cellular homeostasis and genomic stability is summarized. In addition, the potential role of SAMHD1 as a housekeeping protein in the maintenance of dNTP homeostasis and the prevention of tumorigenesis is discussed.

2. Overview of SAMHD1

The human SAMHD1 gene was first cloned in 2000 by Li et al via a human dendritic cell cDNA library (18) and it was identified as an effective interferon γ (IFN-γ)-induced protein (18,19). Based on its dNTPase activity, SAMHD1 is recognized as an intrinsic host restriction factor against human immunodeficiency virus 1 (HIV-1) (20). Additionally, SAMHD1 is also known as the AGS gene. Multipoint mutations in AGS induce severe familial autoimmune Aicardi-Goutières syndrome (AGS) (21-24).

Human SAMHD1 is 626 amino acids (aa) in length and contains an N-terminal nuclear localization domain 11KRPR14 followed by a conserved sterile alpha motif (SAM) and a histidine/aspartic acid (HD) domain (25,26). These domains are connected by a short linker and flanked by unstructured regions. The SAM domain (44-110 aa) is involved in protein-protein and protein-DNA/RNA interactions, whereas the HD domain is a conserved sequence containing 160-339 aa comprising an arrangement of alternating histidine/aspartic acid amino acids (27-29) (Fig. 1). HD is the main functional domain of SAMHD1 with antiviral activity, which is involved in nucleotide metabolism and exhibits dNTPase and ribonuclease (RNase) activity. However, the RNase activity of SAMHD1 is controversial. Ryoo et al (31) suggested that SAMHD1 restricted HIV-1 infection by cleaving the viral RNA genome via its RNase activity. In addition, the SAMHD1 phosphorylation at T592 negatively regulates its RNase activity in vivo and impedes HIV-1 restriction. By contrast, Antonucci et al (30) reported that SAMHD1 did not exhibit broad nuclease activity; however, they did not rule out a specific nucleolytic interaction between SAMHD1 and incoming HIV-1 genomic RNA (gRNA). Furthermore, Antonucci et al (30) demonstrated that both SAMHD1D137N (RNase-positive and dNTPase-negative) and SAMHD1Q548A (RNase-negative and dNTPase-positive) mutants were expressed at comparable levels with wild-type SAMHD1 and each efficiently restricted HIV-1 infection (30,31). Several studies have demonstrated that the C-terminus of SAMHD1 (600-626 aa) is included in the crystal structure of the GTP/dNTP-bound tetramer and forms a short alpha-helical structure with an extended loop (32-34). The C-terminus of SAMHD1 is required for the efficient depletion of dNTP pools and the inhibition of HIV-1 infection in monocytes (35). Although the C-terminal region contains conserved amino acid sequences, it extends interspersed with more divergent ones among vertebrate species (17). A recent study demonstrated that SAMHD1 catalytic activity is regulated by redox signaling. SAMHD1 is inactivated in a dose-dependent, yet reversible manner when treated with the oxidizing agent, H2O2 (36).

The oxidation of SAMHD1 has been demonstrated to inhibit tetramerization, and has been emphasized as a central regulatory mechanism for the regulation of SAMHD1 activity in vivo (37). Recent research has highlighted that rapid protein degradation is not mediated by SAMHD1 phosphorylation at T592. In addition, it has been documented that the dNTPase activity of SAMHD1 is not only retained during the G1 and G0 phases, but throughout the entire cell cycle, independent of phosphorylation at T592 (38). Other researchers have indicated that constructed mutant SAMHD1 fragments generated by deleting the HD domain and C-terminal segment inhibit the ability to restrict HIV-1 infection (39). In the absence of the dGTP co-factor, SAMHD1 exists as an inactive monomer or dimer in which the substrate-binding pocket is unable to bind dNTP, thus losing its dNTPase activity (27,35). Upon dGTP-Mg2+-dGTP binding at the allosteric sites, the catalytically inactive SAMHD1 dimers tetramerize, thereby inducing a large conformational change at the tetramer interface and the recovery of its catalytic activity. Therefore, the dNTPase activity of SAMHD1 is mainly dependent on its active tetramer structure (35,40). Taken together, the aforementioned features of SAMHD1 verify its ability to properly regulate dNTP levels, which are indispensable for the transcription and replication of viruses, such as herpes simplex virus (HSV) type 1 (41,42) and hepatitis B virus (HBV) (43,44), and the inhibition of HIV-1 reverse transcription. The structure of SAMHD1 forms the basis of its biological functions and may thus provide novel insight into the elucidatation of the internal regulatory mechanisms of immune disorders, viral infections, DNA damage responses and tumorigenesis (45).

3. Modifications of SAMHD1

SAMHD1 is subjected to a vast array of post-translational modifications, including phosphorylation, acetylation and methylation. It has been suggested that cyclin-dependent kinase 1 (CDK1)/cyclin A2 phosphorylates SAMHD1 at T592 only in proliferating cells and completely abolish its ability to resist viral infections (46). In addition, SAMHD1 has been shown to be phosphorylated at T592 in proliferating leukocytes in the G1/S and G2/M phase of the cell cycle by the key S-phase kinase complex, CDK2-cyclin A (38). The study by Pauls et al (47) suggested that the CDK6-dependent CDK2 phosphorylation of SAMHD1 inhibited its restriction activity against HIV-1 replication in primary cells. Therefore, the synergistic effect of CDK2 and CDK6 during cell cycle progression is essential for determining the susceptibility to HIV-1 infection by modulating viral dNTP access through SAMHD1. Notably, SAMHD1 is also phosphorylated at T592 from the G0 to G1 phase of the cell cycle through the activation of CDK2 and cyclin E expression, resulting in increased dNTP pools (47).

Furthermore, the levels of SAMHD1 phosphorylation at T592 may be reduced following treatment with type I IFN, reinforcing the link between the phosphorylation of SAMHD1 and its antiviral activity (46). Recently, several studies have suggested that the expression of p21Waf1/Cip1 (referred to as p21), a CDK inhibitor, may lead to reduced phosphorylation at T592 residue by CDKs. Thus, SAMHD1 antiviral activity is regulated by CDK1 phosphorylation at amino acid T592, and type I IFN renders Vpx unable to induce SAMHD1 degradation (48-50). Type II IFN can stimulate the transcription of SAMHD1 to degrade dNTP and to restrict viral infection positively (51,52) and type III IFN exhibits modest to undetectable activity (53). However, further research is required in this field to explore the underlying molecular biological mechanisms.

The folding of the SAMHD1 region is disrupted around T592E due to negative charge repulsion generated by a phosphomimetic mutation. Subsequently, this disruption leads to the substantial destabilization of the active tetrameric form of SAMHD1 and an approximately 3-fold decrease in its dNTPase activity. However, the T592V variant does not perturb the crystal structure of SAMHD1; thus, the available active SAMHD1 tetramers are not significantly decreased (54). In addition, the importance of SAMHD1 dephosphorylation has also been investigated. Thus, phosphatase PP2A-B55α is responsible for rendering the antiviral activity of SAMHD1. These results suggest that phosphorylation and dephosphorylation at T592, the key regulatory site of SAMHD1 protein, is responsible for the diverse physiological functions of SAMHD1 (55).

Although alanine substitution at T592 exerts only a minimal effect on the viral restriction ability of SAMHD1 in differentiated U937 cells, phosphomimetic substitution by aspartate and glutamate completely eliminates its antiviral effect. In addition, introducing a T592A alanine mutation does not rescue SAMHD1 restriction in cycling U937 cells, suggesting that the inhibition of phosphorylation is not sufficient to restore SAMHD1 in proliferating cells (5,39). However, the antiviral activity of SAMHD1 is limited to non-cycling cells. As previously mentioned, SAMHD1 is phosphorylated on residue T592 in cycling cells; however, the phosphorylation dissipates when cells are in a non-cycling state, thus modulating the ability of SAMHD1 to block retroviral infection without affecting its dNTPase activity (6).

Moreover, it has been reported that SAMHD1 is acetylated on K405 by the acetyltransferase arrest defective protein 1 (ARD1) and enhances its dNTPase activity in vitro. However, the non-acetylated arginine substitution mutant (K405R) does not exert a similar effect. Compared with cells expressing wild-type SAMHD1, cancer cells expressing K405R mutant exhibit an attenuated G1/S cell cycle transition and a decreased cell proliferation. SAMHD1 acetylation levels are increased during the G1 phase of the cell cycle. Collectively, these findings suggest that SAMHD1 acetylation enhances its ability to hydrolyze dNTPs and promote cancer cell proliferation. Therefore, SAMHD1 may be a potent effective target for cancer treatment (3).

Finally, it has been documented that promoter hypermethylation suppresses the transcriptional regulation of SAMHD1, thereby downregulating its protein expression and its tumori-genesis-related functions (11-13).

SAMHD1 activity demonstrates a significant association between dNTP homeostasis and disease progression. Thus, further research on the post-translational modifications of SAMHD1 is urgently required in order for its additional benefits to be fully elucidated.

4. Role of SAMHD1 in dNTP homeostasis

SAMHD1, as a dNTP hydrolytic enzyme, plays a key role in the maintenance of homeostasis of cellular dNTP pools (20,56,57) and it is essential for preserving genome integrity. It has been reported that dNTP pool imbalance caused by SAMHD1 deficiency may lead to DNA damage, accompanied by the activation of IFN signaling (57). In addition, the surplus of dNTPs induces mismatches and increases the mutation rate during cellular DNA replication (58), which is an important molecular mechanism of tumorigenesis (1). There is increasing evidence to suggest that imbalanced dNTP levels are associated with the rate of replication fork formation under DNA replication stress, leading to gene mutations, genomic instability and cancer development (59,60). Therefore, SAMHD1 is considered a key regulator involved in the maintenance of the dNTP pool and genome homeostasis. The role of SAMHD1 is illustrated in Fig. 2.

5. Role of SAMHD1 in DNA damage response

DNA damage in cells, mainly single-strand breaks, arises frequently (approximately 10,000 lesions per cell per day) by a variety of endogenous and exogenous stimuli (61,62). It has been well established that the DNA damage response (DDR) pathway detects lesions in DNA strands and activates the repair system (63). Subsequently, cell cycle checkpoints are activated, providing sufficient time to allow lesions to be repaired. However, an unrepaired or improperly repaired DNA response leads to cell death or abnormal cell mitosis, which may induce malignant transformation and proliferation (64,65). Additionally, inherited defects in DNA damage repair mechanisms are associated with cancer predisposition (66), immunodeficiency (67), neurodegenerative disorders (68), infertility (69) and premature aging, highlighting the critical role of DDR in human health.

Several studies have demonstrated that SAMHD1 participates in the DDR process. Thus, SAMHD1 promotes dNTPase-independent DNA end resection to facilitate DNA double-strand breaks (DSBs) repair by homologous recombination (HR) (70). In addition, SAMHD1 exhibits a hydrolase-independent function though its C-terminal recruitment of interacting proteins (CTIP) to DSB sites. These observations suggest that SAMHD1 may contribute to anticancer therapy (71). Clifford et al (72) investigated the expression of SAMHD1 in patients with chronic lymphocytic leukemia (CLL) in the UK and revealed that SAMHD1 affected cell proliferation and survival following DNA damage induction. More specifically, the overexpression of wild-type SAMHD1 inhibited proliferation and increased cell death following DSB treatment. Furthermore, SAMHD1 was co-localized with p53-binding protein 1 (53BP1) at the DNA DSB site in the nucleus, which further indicated that SAMHD1 is involved in the DDR process and related diseases (72). By contrast, SAMHD1 downregulation may cause excess dNTPs and a subsequent imbalance of dNTP pools, resulting in base mismatches and mutations during replication, eventually leading to the activation of the intrinsic interferon signal (57). These findings indicate a novel association between SAMHD1 and DDR process in the pathogenesis of several diseases.

6. Role of SAMHD1 in immune disorders and viral infections

SAMHD1 is widely expressed in the majority of tissues and cells, and its restrictive function in the innate immunity has been extensively reviewed since it was first discovered. The SAMHD1 gene mutation was detected in autoimmune AGS (22,73-75), which was first described by Jean Aicardi and Francoise Goutières in 1984 (76). The common clinical features of AGS overlap with the autoimmune disease systemic lupus erythematosus (SLE), including brain atrophy and severe sequelae (75,77,78). It has been reported that SAMHD1 mutations at residues 123, 143, 145, 201, 209, 254, 369 and 385 result in impaired endogenous SAMHD1 protein function and induce nucleotide metabolism disorders in myeloid cells (22). Abnormally increased dNTP pools in fibroblasts derived from patients with AGS are caused by the loss of functional SAMHD1. Subsequently, dNTP accumulation may induce the immune system to secrete excessive amount of antibodies, as it has been previously described (57). These results suggest that SAMHD1 is a key regulator of the immune system by maintaining nucleotide pool homeostasis.

Reverse transcription is a unique DNA synthesis process through which retroviruses and retrotransposons convert single stranded RNA genomes into double stranded DNA. This process is catalyzed by reverse transcriptase, which is a virally encoded DNA polymerase (79,80). Retroviruses consume cellular dNTPs regulated by SAMHD1 to convert their RNA genomes into proviral DNA through reverse transcription (81). DNTPs differ by only a single atom from ribonucleotide triphosphates (NTPs), yet are maintained at 10-1,000-fold lower concentrations (82). Ryoo et al also found that SAMHD1 restricted HIV-1 infection through its RNase activity by cleaving the viral RNA genome, and SAMHD1 associated with HIV-1 RNA and degraded it during the early phases of cell infection (31). The poor dNTP availability in macrophages infected with HIV infection mainly promotes viral mutagenesis induced by frequent rNMP and non-canonical dUMP incorporation (83,84). Finally, SAMHD1 may be a primitive cellular defense tool that was developed to effectively control the replication of dNTP-utilizing pathogens (81).

Human SAMHD1 is a key restriction factor against HIV-1 infection and is highly expressed in non-circulating cells, such as resting CD4+ T cells and terminally differentiated macrophages. SAMHD1 limits HIV-1 infection in non-dividing cells by reducing the levels of intracellular dNTPs during viral reverse transcription, which is indispensable for viral storage and incubation (85). Thus, the overexpression of wild-type SAMHD1 inhibits HIV-1 long terminal repeat (LTR)-driven gene expression at the transcriptional level. In addition, it has been well documented that non-phosphorylated (T592A) and dNTPase inactive [H206D R207N (HD/RN)] mutants of SAMHD1 fail to efficiently inhibit HIV-1 LTR-driven gene expression or the latent virus reactivation (85). SAMHD1 has been reported to be a potent inhibitor of LINE-1 retrotrans-position. SAMHD1 is a potent regulator of LINE-1 and LINE-1-mediated Alu/SVA reverse transcriptional transposon. It has also been found that the mutant of SAMHD1 has a defect in LINE-1 inhibition. At the same time, the ability of SAMHD1 to inhibit ORF2p-mediated LINE-1 RNP reverse transcription has been shown to be associated with SAMHD1-mediated LINE-1 inhibition (86). Furthermore, SAMHD1 attenuates IFN- and T-cell-mediated responses by suppressing the induction of virus-specific cytotoxic T-cells in vivo (87). Of note, HIV-2 and simian immunodeficiency viruses (SIVs) with Vpx or viral protein R (Vpr) can induce SAMHD1 degradation, by inhibiting SAMHD1 downregulation during viral infection (25,88-91). Additionally, it has been reported that SAMHD1 blocks feline immunodeficiency virus (FIV), bovine immunodeficiency virus (BIV), equine infectious anemia virus (EIAV), N-tropic murine leukemia virus (N-MLV) and B-tropic murine leukemia virus (B-MLV) infections (92). These findings indicate that SAMHD1 exerts inhibitory effects on infectious diseases.

7. Role of SAMHD1 in tumorigenesis and cancer treatment

Recently, SAMHD1 has been shown to be associated with the development of CLL (72,93). Thus, SAMHD1 gene mutations have been detected in leukemia cells, and SAMHD1 mRNA and protein expression levels have been found to be significantly and differentially downregulated. The loss-of-function mutation of SAMHD1 usually occurs early in the evolutionary stage of the molecular cloning of CLL and promotes the development of the disease. In addition, some SAMHD1 mutations are detected in both AGS and CLL, thus AGS patients with SAMHD1 mutations are more likely to suffer concomitant CLL (72).

Several studies have demonstrated that SAMHD1 is associated with the development of multiple types of cancer, such as lung and colon cancer. Thus, in lung adenocarcinoma, SAMHD1 mRNA and protein levels have been shown to be downregulated compared with those noted in adjacent normal tissues. In addition, it has been suggested that the SAMHD1 promoter is highly methylated in lung adenocarcinoma, resulting in a suppressed SAMHD1 expression (13). Similarly, frequent mutations in SAMHD1 in colon cancer cells induce SAMHD1 downregulation (94). The aforementioned results suggest that SAMHD1 is closely associated with an increased risk of both lung and colon cancer, and presumably with other types of cancer.

Recently, it was demonstrated that a low level of exogenous SAMHD1 expression can significantly reduce the growth, proliferation and colony formation of HuT78 cells by increasing apoptosis; thus, it may play a potential anticancer role in cutaneous T cell lymphoma (CTCL) (95). In view of the role of SAMHD1 in maintaining genomic stability, it may play an additional role in cells as a cancer suppressor enzyme.

Exogenous SAMHD1 expression in HuT78 cells has also been shown to result in increased spontaneous and Fas ligand (Fas-L)-induced apoptosis levels via the activation of the extrinsic pathway, including caspase-8, -3 and -7. Mechanistically, SAMHD1 expression in HuT78 cells leads to a significant reduction in the expression of cFLIPS, a key anti-apoptotic regulator that is commonly overexpressed in patients with CTCL (95-97).

The catalogue of somatic mutations in cancer (COSMOS) records 164 unique mutations in SAMHD1 found in samples from various cancer tissues (98). Widely expressed in several tissues, SAMHD1 mutations have also been detected in breast cancer, myeloma, pancreatic cancer and others. The mutation and modification sites of SAMHD1 in different types of cancer are presented in Tables ITable II (99-104) and II, respectively.

Table I

Modifications to SAMHD1 in various human diseases.

Table I

Modifications to SAMHD1 in various human diseases.

Type of diseaseModificationsModifications to SAMHD1
(Refs.)
Results
Breast cancerN.A.Reduction in protein(99)
Skin T-cell lymphomaMethylationReduction in protein and mRNA(95,100)
Lung cancerMethylationReduction in protein and mRNA(101,102)
Colorectal cancerN.A.N.A.(94,99,103)
Cervical cancerAcetylationN.A.(3)
HIV-1 PhosphorylationReduction in protein(19,53)
AGSN.A.Reduction in protein(104)
HBV PhosphorylationN.A.(43,44)
HSV-1 PhosphorylationN.A.(41,42)
EBV PhosphorylationN.A.(9)
HCMV PhosphorylationN.A.(10)

[i] N.A., no information available; SAMHD1, sterile alpha motif and histidine/aspartic acid domain-containing protein 1; HIV-1, human immunodeficiency virus 1; AGS, Aicardi-Goutières syndrome; HBV, hepatitis B virus; HSV-1, herpes simplex virus 1; EBV, Epstein-Barr virus; HCMV, human cytomegalovirus.

Table II

Mutations of SAMHD1 in different human cancers.

Table II

Mutations of SAMHD1 in different human cancers.

Type of cancersFrequency (%)Mutation typeMutations of SAMHD1
Results(Refs.)
DNA alterations
Skin cancer53.01Multipoint chr20:g.35551400G>AN.A.N.A.
Liver cancer24.42Multipoint chr20:g.35585008A>-Reduction in protein(43)
Blood cancer14.29Single point chr20:g.35559188C>AN.A.N.A.
Breast cancer12.13Multipoint chr20:g.35513711A>-Reduction in protein(99)
Lung cancer11.76Multipoint chr20:g.35518800T>CReduction in protein and mRNA(13)
Pancreatic cancer7.84Multipoint chr20:g.35519255C>TN.A.N.A.
Prostate cancer1.54Single point chr20:g.35517455T>AN.A.N.A.
Cervical cancer0.52Single point chr20:g.35515883C>GN.A.N.A.

[i] N.A., no information available; SAMHD1, sterile alpha motif and histidine/aspartic acid domain-containing protein 1.

The importance of SAMHD1 in dNTP metabolism and genome integrity has been well established; thus, strategies targeting SAMHD1 gene replication, post-translational modifications and protein expression have been evaluated for the treatment of cancer and autoimmune diseases (105). SAMHD1 acetylation enhances its dNTPase activity, and thereby, cancer cell arrest at the G1 phase to aid G1/S phase transition and promote cell cycle progression. This observation suggests that the acetylation level of SAMHD1 may be a potential therapeutic target for cancer treatment. In addition, this finding also unveils a potential method for therapeutically targeting SAMHD1 activity in cells through the use of small molecule inhibitors of acetyltransferases (3). Furthermore, SAMHD1 protects cancer cells from several antinucleoside metabolite treatments, such as cytarabine (Ara-C) which is mainly used in the treatment of acute myeloid leukemia (AML) (106-109). Combination therapy with an anthracycline (commonly doxorubicin or daunorubicin) and Ara-C is the standard treatment for AML (110). Ara-C is converted by the canonical dNTP synthesis pathway to Ara-CTP, the active triphosphate of Ara-C, which serves as a substrate of SAMHD1 (107). Herold et al (106) demonstrated that wild-type SAMHD1 reduced Ara-C treatment efficacy in vivo in an AML mouse model. In addition, THP-1 cells lacking a functional SAMHD1 gene have been shown to exhibit an increased sensitivity to antimetabolites, including fludarabine, decitabine, vidarabine and clofarabine (106). SAMHD1 downregulation or the inhibition of its post-translational modifications may be promising strategies with which overcome tumor resistance. Therefore, SAMHD1 is considered a potential biomarker for the stratification of patients with AML and a target for the treatment of Ara-C-refractory AML (109). The aforementioned findings suggest that the invention of a potent SAMHD1 inhibitor that enhances the efficiency of nucleotide analogues should perhaps be a top priority for researchers. Thus, high-throughput assays have already been established from several research groups (111,112). Such approaches seem to be particularly promising for future developments in this field.

8. Conclusions and future perspectives

Studies on the unique, natural viral restriction and dNTPase properties of SAMHD1 have demonstrated its involvement in the pathogenesis of several diseases and have provided guidance for progress in the development of clinical applications. More specifically, studies on the underlying mechanisms of antiviral agents to fight infection have revealed that SAMHD1 inhibits HIV-1 infection in non-dividing cells by restricting viral reverse transcription, resulting in decreased virus activity and storage (14,15,113,114). In addition, SAMHD1 inhibits SIV activity containing Vpx or Vpr (116-118).

The dNTPase activity of SAMHD1 maintains balanced cellular dNTP pools, thus preventing genomic instability and tumorigenesis. SAMHD1 loss-of-function mutations are associated with abnormal dNTP accumulation, which induces rapid cancer cell proliferation (37,105,119,120) and immune system disfunctions. On the other hand, SAMHD1 protects cancer cells from DNA replication inhibitors, such as pyrimidine antimetabolite antitumor agents (104,105).

Therefore, future studies on SAMHD1 may provide further insight into the clinical treatment of cancer and other severe diseases. Finally, strategies targeting SAMHD1 are expected to provide more effective health-related interventions.

Funding

This study was supported by the National Key R&D Program of China (2016YFC1302400), the Ministry of Education Innovation Team Development plan to LC(IRT_17R107), and the National Science Foundation of China to XS (31300963, LFWK201725, 2018225083) and QG (81502400).

Availability of data and materials

Not applicable.

Authors' contributions

XS and LC designed and conceived the general idea and context of this review article. XS, LC and ZZ conceived and wrote the Abstract. ZZ and YY conceived and wrote the Introduction and 'Overview of SAMHD1' sections. LZ and JW contributed to the 'Modifications of SAMHD1' and the 'Role of SAMHD1 in dNTP homeostasis' sections. FY, YX and QG conducted the writing of the 'Role of SAMHD1 in DNA damage response' and 'Role of SAMHD1 in immune disorders and viral infections' sections. XW and SC completed the 'Role of SAMHD1 in tumorigenesis and cancer treatment' sections. ZZ integrated all sections and relevant references of this manuscript. XS, LC and ZZ revised the manuscript. All authors read and approved the final manuscript.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Abbreviations:

AGS

Aicardi-Goutières syndrome

ARD1

acetyltransferase arrest defective protein 1

BIV

bovine immunodeficiency virus

B-MLV

B-tropic murine leukemia virus

CDK1

cyclin-dependent kinase 1

CLL

chronic lymphocytic leukemia

CTCL

cutaneous T cell lymphoma

CTIP

c-terminal binding protein interacting protein

DDR

DNA damage response

dNTP

deoxynucleotide triphosphate

DSBs

DNA double-strand breaks

EBV

Epstein-Barr virus

EIAV

equine infectious anemia virus

FIV

feline immunodeficiency virus

HBV

hepatitis B virus

HCMV

human cytomegalovirus

HIV

human immunodeficiency virus

HR

homologous recombination

HSV

herpes simplex virus

IFN-γ

interferon γ

N-MLV

N-tropic murine leukemia virus

RNase

ribonuclease

SAMHD1

sterile alpha motif and histidine-aspartic acid domain-containing protein 1

SIVs

simian immunodeficiency viruses

Vpr

viral protein R

Vpx

viral protein X

53BP1

p53-binding protein 1

Acknowledgments

Not applicable.

References

1 

Kunz BA, Kohalmi SE, Kunkel TA, Mathews CK, McIntosh EM and Reidy JA: International commission for protection against environmental mutagens and carcinogens. Deoxyribonucleoside triphosphate levels: A critical factor in the maintenance of genetic stability. Mutat Res. 318:1–64. 1994. View Article : Google Scholar : PubMed/NCBI

2 

Reichard P: Interactions between deoxyribonucleotide and DNA synthesis. Annu Rev Biochem. 57:349–374. 1988. View Article : Google Scholar : PubMed/NCBI

3 

Lee EJ, Seo JH, Park JH, Vo TTL, An S, Bae SJ, Le H, Lee HS, Wee HJ, Lee D, et al: SAMHD1 acetylation enhances its deoxy-nucleotide triphosphohydrolase activity and promotes cancer cell proliferation. Oncotarget. 8:68517–68529. 2017.PubMed/NCBI

4 

Koharudin LM, Wu Y, DeLucia M, Mehrens J, Gronenborn AM and Ahn J: Structural basis of allosteric activation of sterile α motif and histidine-aspartate domain-containing protein 1 (SAMHD1) by nucleoside triphosphates. J Biol Chem. 289:32617–32627. 2014. View Article : Google Scholar : PubMed/NCBI

5 

Welbourn S, Dutta SM, Semmes OJ and Strebel K: Restriction of virus infection but not catalytic dNTPase activity is regulated by phosphorylation of SAMHD1. J Virol. 87:11516–11524. 2013. View Article : Google Scholar : PubMed/NCBI

6 

White TE, Brandariz-Nunez A, Valle-Casuso JC, Amie S, Nguyen LA, Kim B, Tuzova M and Diaz-Griffero F: The retroviral restriction ability of SAMHD1, but not its deoxynucleotide triphosphohydrolase activity, is regulated by phosphorylation. Cell Host Microbe. 13:441–451. 2013. View Article : Google Scholar : PubMed/NCBI

7 

St Gelais C, de Silva S, Hach JC, White TE, Diaz-Griffero F, Yount JS and Wu L: Identification of cellular proteins interacting with the retroviral restriction factor SAMHD1. J Virol. 88:5834–5844. 2014. View Article : Google Scholar : PubMed/NCBI

8 

Ji X, Tang C, Zhao Q, Wang W and Xiong Y: Structural basis of cellular dNTP regulation by SAMHD1. Proc Natl Acad Sci USA. 111:E4305–E4314. 2014. View Article : Google Scholar : PubMed/NCBI

9 

Zhang K, Lv DW and Li R: Conserved herpesvirus protein kinases target SAMHD1 to facilitate virus replication. Cell Rep. 28:449–459 e445. 2019. View Article : Google Scholar : PubMed/NCBI

10 

Kim ET, Roche KL, Kulej K, Spruce LA, Seeholzer SH, Coen DM, Diaz-Griffero F, Murphy EA and Weitzman MD: SAMHD1 modulates early steps during human cytomegalovirus infection by limiting NF-kB activation. Cell Rep. 28:434–448 e436. 2019. View Article : Google Scholar

11 

de Silva S, Hoy H, Hake TS, Wong HK, Porcu P and Wu L: Promoter methylation regulates SAMHD1 gene expression in human CD4+ T cells. J Biol Chem. 288:9284–9292. 2013. View Article : Google Scholar : PubMed/NCBI

12 

de Silva S, Wang F, Hake TS, Porcu P, Wong HK and Wu L: Downregulation of SAMHD1 expression correlates with promoter DNA methylation in Sezary syndrome patients. J Invest Dermatol. 134:562–565. 2014. View Article : Google Scholar

13 

Wang JL, Lu FZ, Shen XY, Wu Y and Zhao LT: SAMHD1 is down regulated in lung cancer by methylation and inhibits tumor cell proliferation. Biochem Biophys Res Commun. 455:229–233. 2014. View Article : Google Scholar : PubMed/NCBI

14 

Laguette N, Sobhian B, Casartelli N, Ringeard M, Chable-Bessia C, Ségéral E, Yatim A, Emiliani S, Schwartz O and Benkirane M: SAMHD1 is the dendritic- and myeloid-cell-specific HIV-1 restriction factor counteracted by Vpx. Nature. 474:654–657. 2011. View Article : Google Scholar : PubMed/NCBI

15 

Hrecka K, Hao C, Gierszewska M, Swanson SK, Kesik-Brodacka M, Srivastava S, Florens L, Washburn MP and Skowronski J: Vpx relieves inhibition of HIV-1 infection of macrophages mediated by the SAMHD1 protein. Nature. 474:658–661. 2011. View Article : Google Scholar : PubMed/NCBI

16 

Berger A, Sommer AF, Zwarg J, Hamdorf M, Welzel K, Esly N, Panitz S, Reuter A, Ramos I, Jatiani A, et al: SAMHD1-deficient CD14+ cells from individuals with aicardigoutieres syndrome are highly susceptible to HIV-1 infection. PLoS Pathog. 7:e10024252011. View Article : Google Scholar

17 

Ahn J, Hao C, Yan J, DeLucia M, Mehrens J, Wang C, Gronenborn AM and Skowronski J: HIV/simian immunodeficiency virus (SIV) accessory virulence factor Vpx loads the host cell restriction factor SAMHD1 onto the E3 ubiquitin ligase complex CRL4DCAF1. J Biol Chem. 287:12550–12558. 2012. View Article : Google Scholar : PubMed/NCBI

18 

Li N, Zhang W and Cao X: Identification of human homologue of mouse IFN-gamma induced protein from human dendritic cells. Immunol Lett. 74:221–224. 2000. View Article : Google Scholar : PubMed/NCBI

19 

Kueck T, Cassella E, Holler J, Kim B and Bieniasz PD: The aryl hydrocarbon receptor and interferon gamma generate antiviral states via transcriptional repression. Elife. 7:e388672018. View Article : Google Scholar : PubMed/NCBI

20 

Goldstone DC, Ennis-Adeniran V, Hedden JJ, Groom HC, Rice GI, Christodoulou E, Walker PA, Kelly G, Haire LF, Yap MW, et al: HIV-1 restriction factor SAMHD1 is a deoxynucleoside triphosphate triphosphohydrolase. Nature. 480:379–382. 2011. View Article : Google Scholar : PubMed/NCBI

21 

Leshinsky-Silver E, Malinger G, Ben-Sira L, Kidron D, Cohen S, Inbar S, Bezaleli T, Levine A, Vinkler C, Lev D and Lerman-Sagie T: A large homozygous deletion in the SAMHD1 gene causes atypical aicardi-goutieres syndrome associated with mtDNA deletions. Eur J Hum Genet. 19:287–292. 2011. View Article : Google Scholar

22 

Rice GI, Bond J, Asipu A, Brunette RL, Manfield IW, Carr IM, Fuller JC, Jackson RM, Lamb T, Briggs TA, et al: Mutations involved in aicardi-goutieres syndrome implicate SAMHD1 as regulator of the innate immune response. Nat Genet. 41:829–832. 2009. View Article : Google Scholar : PubMed/NCBI

23 

Thiele H, du Moulin M, Barczyk K, George C, Schwindt W, Nürnberg G, Frosch M, Kurlemann G, Roth J, Nürnberg P and Rutsch F: Cerebral arterial stenoses and stroke: Novel features of Aicardi-Goutieres syndrome caused by the arg164X mutation in SAMHD1 are associated with altered cytokine expression. Hum Mutat. 31:E1836–E1850. 2010. View Article : Google Scholar : PubMed/NCBI

24 

Dale RC, Gornall H, Singh-Grewal D, Alcausin M, Rice GI and Crow YJ: Familial aicardi-goutieres syndrome due to SAMHD1 mutations is associated with chronic arthropathy and contractures. Am J Med Genet A. 152A:938–942. 2010. View Article : Google Scholar : PubMed/NCBI

25 

Brandariz-Nunez A, Valle-Casuso JC, White TE, Laguette N, Benkirane M, Brojatsch J and Diaz-Griffero F: Role of SAMHD1 nuclear localization in restriction of HIV-1 and SIVmac. Retrovirology. 9:492012. View Article : Google Scholar : PubMed/NCBI

26 

Hofmann H, Logue EC, Bloch N, Daddacha W, Polsky SB, Schultz ML, Kim B and Landau NR: The Vpx lentiviral accessory protein targets SAMHD1 for degradation in the nucleus. J Virol. 86:12552–12560. 2012. View Article : Google Scholar : PubMed/NCBI

27 

DeLucia M, Mehrens J, Wu Y and Ahn J: HIV-2 and SIVmac accessory virulence factor Vpx down-regulates SAMHD1 enzyme catalysis prior to proteasome-dependent degradation. J Biol Chem. 288:19116–19126. 2013. View Article : Google Scholar : PubMed/NCBI

28 

Kim CA and Bowie JU: SAM domains: Uniform structure, diversity of function. Trends Biochem Sci. 28:625–628. 2003. View Article : Google Scholar : PubMed/NCBI

29 

Laguette N and Benkirane M: How SAMHD1 changes our view of viral restriction. Trends Immunol. 33:26–33. 2012. View Article : Google Scholar

30 

Antonucci JM, St Gelais C, de Silva S, Yount JS, Tang C, Ji X, Shepard C, Xiong Y, Kim B and Wu L: SAMHD1-mediated HIV-1 restriction in cells does not involve ribonuclease activity. Nat Med. 22:1072–1074. 2016. View Article : Google Scholar : PubMed/NCBI

31 

Ryoo J, Choi J, Oh C, Kim S, Seo M, Kim SY, Seo D, Kim J, White TE, Brandariz-Nuñez A, et al: The ribonuclease activity of SAMHD1 is required for HIV-1 restriction. Nat Med. 20:936–941. 2014. View Article : Google Scholar : PubMed/NCBI

32 

Zhu CF, Wei W, Peng X, Dong YH, Gong Y and Yu XF: The mechanism of substrate-controlled allosteric regulation of SAMHD1 activated by GTP. Acta Crystallogr D Biol Crystallogr. 71:516–524. 2015. View Article : Google Scholar : PubMed/NCBI

33 

Li Y, Kong J, Peng X, Hou W, Qin X and Yu XF: Structural insights into the high-efficiency catalytic mechanism of the sterile α-motif/histidine-aspartate domain-containing protein. J Biol Chem. 290:29428–29437. 2015. View Article : Google Scholar : PubMed/NCBI

34 

Patra KK, Bhattacharya A and Bhattacharya S: Allosteric signal transduction in HIV-1 restriction factor SAMHD1 proceeds via reciprocal handshake across monomers. J Chem Inf Model. 57:2523–2538. 2017. View Article : Google Scholar : PubMed/NCBI

35 

Yan J, Kaur S, DeLucia M, Hao C, Mehrens J, Wang C, Golczak M, Palczewski K, Gronenborn AM, Ahn J and Skowronski J: Tetramerization of SAMHD1 is required for biological activity and inhibition of HIV infection. J Biol Chem. 288:10406–10417. 2013. View Article : Google Scholar : PubMed/NCBI

36 

Mauney CH, Rogers LC, Harris RS, Daniel LW, Devarie-Baez NO, Wu H, Furdui CM, Poole LB, Perrino FW and Hollis T: The SAMHD1 dNTP triphosphohydrolase is controlled by a redox switch. Antioxid Redox Signal. 27:1317–1331. 2017. View Article : Google Scholar : PubMed/NCBI

37 

Mauney CH and Hollis T: SAMHD1: Recurring roles in cell cycle, viral restriction, cancer, and innate immunity. Autoimmunity. 51:96–110. 2018. View Article : Google Scholar : PubMed/NCBI

38 

Tramentozzi E, Ferraro P, Hossain M, Stillman B, Bianchi V and Pontarin G: The dNTP triphosphohydrolase activity of SAMHD1 persists during S-phase when the enzyme is phosphorylated at T592. Cell Cycle. 17:1102–1114. 2018. View Article : Google Scholar : PubMed/NCBI

39 

Arnold LH, Groom HC, Kunzelmann S, Schwefel D, Caswell SJ, Ordonez P, Mann MC, Rueschenbaum S, Goldstone DC, Pennell S, et al: Phospho-dependent regulation of SAMHD1 oligomerisation couples catalysis and restriction. PLoS Pathog. 11:e10051942015. View Article : Google Scholar : PubMed/NCBI

40 

Ji X, Wu Y, Yan J, Mehrens J, Yang H, DeLucia M, Hao C, Gronenborn AM, Skowronski J, Ahn J and Xiong Y: Mechanism of allosteric activation of SAMHD1 by dGTP. Nat Struct Mol Biol. 20:1304–1309. 2013. View Article : Google Scholar : PubMed/NCBI

41 

Badia R, Angulo G, Riveira-Munoz E, Pujantell M, Puig T, Ramirez C, Torres-Torronteras J, Martí R, Pauls E, Clotet B, et al: Inhibition of herpes simplex virus type 1 by the CDK6 inhibitor PD-0332991 (palbociclib) through the control of SAMHD1. J Antimicrob Chemother. 71:387–394. 2016. View Article : Google Scholar :

42 

Kim ET, White TE, Brandariz-Nunez A, Diaz-Griffero F and Weitzman MD: SAMHD1 restricts herpes simplex virus 1 in macrophages by limiting DNA replication. J Virol. 87:12949–12956. 2013. View Article : Google Scholar : PubMed/NCBI

43 

Hu J, Qiao M, Chen Y, Tang H, Zhang W, Tang D, Pi S, Dai J, Tang N, Huang A and Hu Y: Cyclin E2-CDK2 mediates SAMHD1 phosphorylation to abrogate its restriction of HBV replication in hepatoma cells. FEBS Lett. 592:1893–1904. 2018. View Article : Google Scholar : PubMed/NCBI

44 

Sommer AF, Riviere L, Qu B, Schott K, Riess M, Ni Y, Shepard C, Schnellbächer E, Finkernagel M, Himmelsbach K, et al: Restrictive influence of SAMHD1 on Hepatitis B Virus life cycle. Sci Rep. 6:266162016. View Article : Google Scholar : PubMed/NCBI

45 

Li M, Zhang D, Zhu M, Shen Y, Wei W, Ying S, Korner H and Li J: Roles of SAMHD1 in antiviral defense, autoimmunity and cancer. Rev Med Virol. 27:2017. View Article : Google Scholar : PubMed/NCBI

46 

Cribier A, Descours B, Valadao AL, Laguette N and Benkirane M: Phosphorylation of SAMHD1 by Cyclin A2/CDK1 regulates its restriction activity toward HIV-1. Cell Rep. 3:1036–1043. 2013. View Article : Google Scholar : PubMed/NCBI

47 

Pauls E, Ruiz A, Badia R, Permanyer M, Gubern A, Riveira-Muñoz E, Torres-Torronteras J, Alvarez M, Mothe B, Brander C, et al: Cell cycle control and HIV-1 susceptibility are linked by CDK6-dependent CDK2 phosphorylation of SAMHD1 in myeloid and lymphoid cells. J Immunol. 193:1988–1997. 2014. View Article : Google Scholar : PubMed/NCBI

48 

Valle-Casuso JC, Allouch A, David A, Lenzi GM, Studdard L, Barré-Sinoussi F, Müller-Trutwin M, Kim B, Pancino G and Sáez-Cirión A: p21 Restricts HIV-1 in monocyte-derived dendritic cells through the reduction of deoxynucleoside triphos-phate biosynthesis and regulation of SAMHD1 antiviral activity. J Virol. 91:e01324–e01317. 2017. View Article : Google Scholar :

49 

Bloch N, O'Brien M, Norton TD, Polsky SB, Bhardwaj N and Landau NR: HIV type 1 infection of plasmacytoid and myeloid dendritic cells is restricted by high levels of SAMHD1 and cannot be counteracted by Vpx. AIDS Res Hum Retroviruses. 30:195–203. 2014. View Article : Google Scholar :

50 

Dragin L, Nguyen LA, Lahouassa H, Sourisce A, Kim B, Ramirez BC and Margottin-Goguet F: Interferon block to HIV-1 transduction in macrophages despite SAMHD1 degradation and high deoxynucleoside triphosphates supply. Retrovirology. 10:302013. View Article : Google Scholar : PubMed/NCBI

51 

Lafuse WP, Brown D, Castle L and Zwilling BS: Cloning and characterization of a novel cDNA that is IFN-gamma-induced in mouse peritoneal macrophages and encodes a putative GTP-binding protein. J Leukoc Biol. 57:477–483. 1995. View Article : Google Scholar : PubMed/NCBI

52 

Taylor GA, Jeffers M, Largaespada DA, Jenkins NA, Copeland NG and Vande Woude GF: Identification of a novel GTPase, the inducibly expressed GTPase, that accumulates in response to interferon gamma. J Biol Chem. 271:20399–20405. 1996. View Article : Google Scholar : PubMed/NCBI

53 

Szaniawski MA, Spivak AM, Cox JE, Catrow JL, Hanley T, Williams ESCP, Tremblay MJ, Bosque A and Planelles V: SAMHD1 phosphorylation coordinates the Anti-HIV-1 response by diverse interferons and tyrosine kinase inhibition. Mbio. 9:e00819–e00818. 2018. View Article : Google Scholar : PubMed/NCBI

54 

Tang C, Ji X, Wu L and Xiong Y: Impaired dNTPase activity of SAMHD1 by phosphomimetic mutation of Thr-592. J Biol Chem. 290:26352–26359. 2015. View Article : Google Scholar : PubMed/NCBI

55 

Schott K, Fuchs NV, Derua R, Mahboubi B, Schnellbächer E, Seifr ied J, Tondera C, Schm itz H, Shepa rd C, Brandariz-Nuñez A, et al: Dephosphorylation of the HIV-1 restriction factor SAMHD1 is mediated by PP2A-B55 α holoenzymes during mitotic exit. Nat Commun. 9:22272018. View Article : Google Scholar

56 

Franzolin E, Pontarin G, Rampazzo C, Miazzi C, Ferraro P, Palumbo E, Reichard P and Bianchi V: The deoxynucleotide triphosphohydrolase SAMHD1 is a major regulator of DNA precursor pools in mammalian cells. Proc Natl Acad Sci USA. 110:14272–14277. 2013. View Article : Google Scholar : PubMed/NCBI

57 

Kretschmer S, Wolf C, Konig N, Staroske W, Guck J, Häusler M, Luksch H, Nguyen LA, Kim B, Alexopoulou D, et al: SAMHD1 prevents autoimmunity by maintaining genome stability. Ann Rheum Dis. 74:e172015. View Article : Google Scholar :

58 

Mathews CK: DNA precursor metabolism and genomic stability. FASEB J. 20:1300–1314. 2006. View Article : Google Scholar : PubMed/NCBI

59 

Poli J, Tsaponina O, Crabbe L, Keszthelyi A, Pantesco V, Chabes A, Lengronne A and Pasero P: dNTP pools determine fork progression and origin usage under replication stress. EMBO J. 31:883–894. 2012. View Article : Google Scholar : PubMed/NCBI

60 

Coquel F, Silva MJ, Techer H, Zadorozhny K, Sharma S, Nieminuszczy J, Mettling C, Dardillac E, Barthe A, Schmitz AL, et al: SAMHD1 acts at stalled replication forks to prevent interferon induction. Nature. 557:57–61. 2018. View Article : Google Scholar : PubMed/NCBI

61 

Seo YR, Sweeney C and Smith ML: Selenomethionine induction of DNA repair response in human fibroblasts. Oncogene. 21:3663–3669. 2002. View Article : Google Scholar : PubMed/NCBI

62 

Lin Y, Ha A and Yan S: Methods for studying DNA single-strand break repair and signaling in xenopus laevis egg extracts. Methods Mol Biol. 1999:161–172. 2019. View Article : Google Scholar : PubMed/NCBI

63 

Hanawalt PC: Historical perspective on the DNA damage response. DNA Repair (Amst). 36:2–7. 2015. View Article : Google Scholar

64 

Chu G: Double strand break repair. J Biol Chem. 272:24097–24100. 1997. View Article : Google Scholar : PubMed/NCBI

65 

Rooney S, Chaudhuri J and Alt FW: The role of the non-homologous end-joining pathway in lymphocyte development. Immunol Rev. 200:115–131. 2004. View Article : Google Scholar : PubMed/NCBI

66 

Figueroa-Gonzalez G and Perez-Plasencia C: Strategies for the evaluation of DNA damage and repair mechanisms in cancer. Oncol Lett. 13:3982–3988. 2017. View Article : Google Scholar : PubMed/NCBI

67 

Morio T: Recent advances in the study of immunodeficiency and DNA damage response. Int J Hematol. 106:357–365. 2017. View Article : Google Scholar : PubMed/NCBI

68 

Barzilai A: DNA damage, neuronal and glial cell death and neurodegeneration. Apoptosis. 15:1371–1381. 2010. View Article : Google Scholar : PubMed/NCBI

69 

Brown JS and Jackson SP: Ubiquitylation, neddylation and the DNA damage response. Open Biol. 5:1500182015. View Article : Google Scholar : PubMed/NCBI

70 

Medeiros AC, Soares CS, Coelho PO, Vieira NA, Baqui MMA, Teixeira FR and Gomes MD: DNA damage response signaling does not trigger redistribution of SAMHD1 to nuclear foci. Biochem Biophys Res Commun. 499:790–796. 2018. View Article : Google Scholar : PubMed/NCBI

71 

Cabello-Lobato MJ, Wang S and Schmidt CK: SAMHD1 sheds moonlight on DNA double-strand break repair. Trends Genet. 33:895–897. 2017. View Article : Google Scholar : PubMed/NCBI

72 

Clifford R, Louis T, Robbe P, Ackroyd S, Burns A, Timbs AT, Wright Colopy G, Dreau H, Sigaux F, Judde JG, et al: SAMHD1 is mutated recurrently in chronic lymphocytic leukemia and is involved in response to DNA damage. Blood. 123:1021–1031. 2014. View Article : Google Scholar :

73 

Oh C, Ryoo J, Park K, Kim B, Daly MB, Cho D and Ahn K: A central role for PI3K-AKT signaling pathway in linking SAMHD1-deficiency to the type I interferon signature. Sci Rep. 8:842018. View Article : Google Scholar : PubMed/NCBI

74 

Martinez-Lopez A, Martin-Fernandez M, Buta S, Kim B, Bogunovic D and Diaz-Griffero F: SAMHD1 deficient human monocytes autonomously trigger type I interferon. Mol Immunol. 101:450–460. 2018. View Article : Google Scholar : PubMed/NCBI

75 

Ramantani G, Kohlhase J, Hertzberg C, Innes AM, Engel K, Hunger S, Borozdin W, Mah JK, Ungerath K, Walkenhorst H, et al: Expanding the phenotypic spectrum of lupus erythematosus in aicardi-goutieres syndrome. Arthritis Rheum. 62:1469–1477. 2010. View Article : Google Scholar : PubMed/NCBI

76 

Aicardi J and Goutieres F: A progressive familial encephalopathy in infancy with calcifications of the basal ganglia and chronic cerebrospinal fluid lymphocytosis. Ann Neurol. 15:49–54. 1984. View Article : Google Scholar : PubMed/NCBI

77 

Pendergraft WF III and Means TK: AGS, SLE, and RNASEH2 mutations: Translating insights into therapeutic advances. J Clin Invest. 125:102–104. 2015. View Article : Google Scholar :

78 

Ramantani G, Hausler M, Niggemann P, Wessling B, Guttmann H, Mull M, Tenbrock K and Lee-Kirsch MA: Aicardi-Goutieres syndrome and systemic lupus erythematosus (SLE) in a 12-year-old boy with SAMHD1 mutations. J Child Neurol. 26:1425–1428. 2011. View Article : Google Scholar : PubMed/NCBI

79 

Hu WS and Hughes SH: HIV-1 reverse transcription. Cold Spring Harb Perspect Med. 2:a0068822012. View Article : Google Scholar : PubMed/NCBI

80 

Sarafianos SG, Marchand B, Das K, Himmel DM, Parniak MA, Hughes SH and Arnold E: Structure and function of HIV-1 reverse transcriptase: Molecular mechanisms of polymerization and inhibition. J Mol Biol. 385:693–713. 2009. View Article : Google Scholar

81 

Amie SM, Noble E and Kim B: Intracellular nucleotide levels and the control of retroviral infections. Virology. 436:247–254. 2013. View Article : Google Scholar :

82 

Traut TW: Physiological concentrations of purines and pyrimidines. Mol Cell Biochem. 140:1–22. 1994. View Article : Google Scholar : PubMed/NCBI

83 

Kennedy EM, Amie SM, Bambara RA and Kim B: Frequent incorporation of ribonucleotides during HIV-1 reverse transcription and their attenuated repair in macrophages. J Biol Chem. 287:14280–14288. 2012. View Article : Google Scholar : PubMed/NCBI

84 

Kennedy EM, Gavegnano C, Nguyen L, Slater R, Lucas A, Fromentin E, Schinazi RF and Kim B: Ribonucleoside triphosphates as substrate of human immunodeficiency virus type 1 reverse transcriptase in human macrophages. J Biol Chem. 285:39380–39391. 2010. View Article : Google Scholar : PubMed/NCBI

85 

Antonucci JM, Kim SH, St Gelais C, Bonifati S, Li TW, Buzovetsky O, Knecht KM, Duchon AA, Xiong Y, Musier-Forsyth K and Wu L: SAMHD1 impairs HIV-1 gene expression and negatively modulates reactivation of viral latency in CD4(+) T cells. J Virol. 92:e00292–e00218. 2018. View Article : Google Scholar :

86 

Gao W, Li G, Bian X, Rui Y, Zhai C, Liu P, Su J, Wang H, Zhu C, Du Y, et al: Defective modulation of LINE-1 retrotransposition by cancer-associated SAMHD1 mutants. Biochem Biophys Res Commun. 519:213–219. 2019. View Article : Google Scholar : PubMed/NCBI

87 

Maelfait J, Bridgeman A, Benlahrech A, Cursi C and Rehwinkel J: Restriction by SAMHD1 limits cGAS/STING-dependent innate and adaptive immune responses to HIV-1. Cell Rep. 16:1492–1501. 2016. View Article : Google Scholar : PubMed/NCBI

88 

Baldauf HM, Stegmann L, Schwarz SM, Ambiel I, Trotard M, Martin M, Burggraf M, Lenzi GM, Lejk H, Pan X, et al: Vpx overcomes a SAMHD1-independent block to HIV reverse transcription that is specific to resting CD4 T cells. Proc Natl Acad Sci USA. 114:2729–2734. 2017. View Article : Google Scholar : PubMed/NCBI

89 

Miyakawa K, Matsunaga S, Yokoyama M, Nomaguchi M, Kimura Y, Nishi M, Kimura H, Sato H, Hirano H, Tamura T, et al: PIM kinases facilitate lentiviral evasion from SAMHD1 restriction via Vpx phosphorylation. Nat Commun. 10:18442019. View Article : Google Scholar : PubMed/NCBI

90 

Yurkovetskiy L, Guney MH, Kim K, Goh SL, McCauley S, Dauphin A, Diehl WE and Luban J: Primate immunodeficiency virus proteins Vpx and Vpr counteract transcriptional repression of proviruses by the HUSH complex. Nat Microbiol. 3:1354–1361. 2018. View Article : Google Scholar : PubMed/NCBI

91 

Reinhard C, Bottinelli D, Kim B and Luban J: Vpx rescue of HIV-1 from the antiviral state in mature dendritic cells is independent of the intracellular deoxynucleotide concentration. Retrovirology. 11:122014. View Article : Google Scholar : PubMed/NCBI

92 

White TE, Brandariz-Nunez A, Valle-Casuso JC, Amie S, Nguyen L, Kim B, Brojatsch J and Diaz-Griffero F: Contribution of SAM and HD domains to retroviral restriction mediated by human SAMHD1. Virology. 436:81–90. 2013. View Article : Google Scholar :

93 

Rossi D: SAMHD1: A new gene for CLL. Blood. 123:951–952. 2014. View Article : Google Scholar : PubMed/NCBI

94 

Rentoft M, Lindell K, Tran P, Chabes AL, Buckland RJ, Watt DL, Marjavaara L, Nilsson AK, Melin B, Trygg J, et al: Heterozygous colon cancer-associated mutations of SAMHD1 have functional significance. Proc Natl Acad Sci USA. 113:4723–4728. 2016. View Article : Google Scholar : PubMed/NCBI

95 

Kodigepalli KM, Li MH, Liu SL and Wu L: Exogenous expression of SAMHD1 inhibits proliferation and induces apoptosis in cutaneous T-cell lymphoma-derived HuT78 cells. Cell Cycle. 16:179–188. 2017. View Article : Google Scholar :

96 

Contassot E, Kerl K, Roques S, Shane R, Gaide O, Dupuis M, Rook AH and French LE: Resistance to FasL and tumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosis in Sezary syndrome T-cells associated with impaired death receptor and FLICE-inhibitory protein expression. Blood. 111:4780–4787. 2008. View Article : Google Scholar : PubMed/NCBI

97 

Zhang CL, Kamarashev J, Qin JZ, Burg G, Dummer R and Dobbeling U: Expression of apoptosis regulators in cutaneous T-cell lymphoma (CTCL) cells. J Pathol. 200:249–254. 2003. View Article : Google Scholar : PubMed/NCBI

98 

Forbes SA, Beare D, Boutselakis H, Bamford S, Bindal N, Tate J, Cole CG, Ward S, Dawson E, Ponting L, et al: COSMIC: Somatic cancer genetics at high-resolution. Nucleic Acids Res. 45:D777–D783. 2017. View Article : Google Scholar :

99 

Sjoblom T, Jones S, Wood LD, Parsons DW, Lin J, Barber TD, Mandelker D, Leary RJ, Ptak J, Silliman N, et al: The consensus coding sequences of human breast and colorectal cancers. Science. 314:268–274. 2006. View Article : Google Scholar : PubMed/NCBI

100 

Kohnken R, Kodigepalli KM, Mishra A, Porcu P and Wu L: MicroRNA-181 contributes to downregulation of SAMHD1 expression in CD4+T-cells derived from Sezary syndrome patients. Leuk Res. 52:58–66. 2017. View Article : Google Scholar

101 

Liu J, Lee W, Jiang Z, Chen Z, Jhunjhunwala S, Haverty PM, Gnad F, Guan Y, Gilbert HN, Stinson J, et al: Genome and transcriptome sequencing of lung cancers reveal diverse mutational and splicing events. Genome Res. 22:2315–2327. 2012. View Article : Google Scholar : PubMed/NCBI

102 

Shang Z, Qian L, Liu S, Niu X, Qiao Z, Sun Y, Zhang Y, Fan LY, Guan X, Cao CX and Xiao H: Graphene oxide-facilitated comprehensive analysis of cellular nucleic acid binding proteins for lung cancer. Acs Appl Mater Interfaces. 10:17756–17770. 2018. View Article : Google Scholar : PubMed/NCBI

103 

Yang CA, Huang HY, Chang YS, Lin CL, Lai IL and Chang JG: DNA-sensing and nuclease gene expressions as markers for colorectal cancer progression. Oncology. 92:115–124. 2017. View Article : Google Scholar

104 

Herrmann A, Wittmann S, Thomas D, Shepard CN, Kim B, Ferreirós N and Gramberg T: The SAMHD1-mediated block of LINE-1 retroelements is regulated by phosphorylation. Mob DNA. 9:112018. View Article : Google Scholar : PubMed/NCBI

105 

Kohnken R, Kodigepalli KM and Wu L: Regulation of deoxy-nucleotide metabolism in cancer: Novel mechanisms and therapeutic implications. Mol Cancer. 14:1762015. View Article : Google Scholar

106 

Herold N, Rudd SG, Sanjiv K, Kutzner J, Bladh J, Paulin CBJ, Helleday T, Henter JI and Schaller T: SAMHD1 protects cancer cells from various nucleoside-based antimetabolites. Cell Cycle. 16:1029–1038. 2017. View Article : Google Scholar : PubMed/NCBI

107 

Rudd SG, Schaller T and Herold N: SAMHD1 is a barrier to antimetabolite-based cancer therapies. Mol Cell Oncol. 4:e12875542017. View Article : Google Scholar : PubMed/NCBI

108 

Zhu KW, Chen P, Zhang DY, Yan H, Liu H, Cen LN, Liu YL, Cao S, Zhou G, Zeng H, et al: Association of genetic polymorphisms in genes involved in Ara-C and dNTP metabolism pathway with chemosensitivity and prognosis of adult acute myeloid leukemia (AML). J Transl Med. 16:902018. View Article : Google Scholar : PubMed/NCBI

109 

Schneider C, Oellerich T, Baldauf HM, Schwarz SM, Thomas D, Flick R, Bohnenberger H, Kaderali L, Stegmann L, Cremer A, et al: SAMHD1 is a biomarker for cytarabine response and a therapeutic target in acute myeloid leukemia. Nat Med. 23:250–255. 2017. View Article : Google Scholar

110 

Ossenkoppele G and Lowenberg B: How I treat the older patient with acute myeloid leukemia. Blood. 125:767–774. 2015. View Article : Google Scholar

111 

Arnold LH, Kunzelmann S, Webb MR and Taylor IA: A continuous enzyme-coupled assay for triphosphohydrolase activity of HIV-1 restriction factor SAMHD1. Antimicrob Agents Chemother. 59:186–192. 2015. View Article : Google Scholar :

112 

Seamon KJ and Stivers JT: A high-throughput enzyme-coupled assay for SAMHD1 dNTPase. J Biomol Screen. 20:801–809. 2015. View Article : Google Scholar : PubMed/NCBI

113 

Baldauf HM, Pan X, Erikson E, Schmidt S, Daddacha W, Burggraf M, Schenkova K, Ambiel I, Wabnitz G, Gramberg T, et al: SAMHD1 restricts HIV-1 infection in resting CD4(+) T cells. Nat Med. 18:1682–1687. 2012. View Article : Google Scholar : PubMed/NCBI

114 

Descours B, Cribier A, Chable-Bessia C, Ayinde D, Rice G, Crow Y, Yatim A, Schwartz O, Laguette N and Benkirane M: SAMHD1 restricts HIV-1 reverse transcription in quiescent CD4(+) T-cells. Retrovirology. 9:872012. View Article : Google Scholar : PubMed/NCBI

115 

Lahouassa H, Daddacha W, Hofmann H, Ayinde D, Logue EC, Dragin L, Bloch N, Maudet C, Bertrand M, Gramberg T, et al: SAMHD1 restricts the replication of human immunodeficiency virus type 1 by depleting the intracellular pool of deoxynucleo-side triphosphates. Nat Immunol. 13:223–228. 2012. View Article : Google Scholar : PubMed/NCBI

116 

Sakai Y, Doi N, Miyazaki Y, Adachi A and Nomaguchi M: Phylogenetic insights into the functional relationship between primate lentiviral reverse transcriptase and accessory proteins vpx/vpr. Front Microbiol. 7:16552016. View Article : Google Scholar : PubMed/NCBI

117 

Plitnik T, Sharkey ME, Mahboubi B, Kim B and Stevenson M: Incomplete suppression of hiv-1 by samhd1 permits efficient macrophage infection. Pathog Immun. 3:197–223. 2018. View Article : Google Scholar

118 

Mereby SA, Maehigashi T, Holler JM, Kim DH, Schinazi RF and Kim B: Interplay of ancestral non-primate lentiviruses with the virus-restricting SAMHD1 proteins of their hosts. J Biol Chem. 293:16402–16412. 2018. View Article : Google Scholar : PubMed/NCBI

119 

Wang Z, Bhattacharya A, Villacorta J, Diaz-Griffero F and Ivanov DN: Allosteric activation of SAMHD1 protein by deoxynucleotide triphosphate (dNTP)-dependent tetramerization requires dNTP concentrations that are similar to dNTP concentrations observed in cycling T cells. J Biol Chem. 291:21407–21413. 2016. View Article : Google Scholar : PubMed/NCBI

120 

Bonifati S, Daly MB, St Gelais C, Kim SH, Hollenbaugh JA, Shepard C, Kennedy EM, Kim DH, Schinazi RF, Kim B and Wu L: SAMHD1 controls cell cycle status, apoptosis and HIV-1 infection in monocytic THP-1 cells. Virology. 495:92–100. 2016. View Article : Google Scholar : PubMed/NCBI

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April-2020
Volume 56 Issue 4

Print ISSN: 1019-6439
Online ISSN:1791-2423

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Copy and paste a formatted citation
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Spandidos Publications style
Zhang Z, Zheng L, Yu Y, Wu J, Yang F, Xu Y, Guo Q, Wu X, Cao S, Cao L, Cao L, et al: Involvement of SAMHD1 in dNTP homeostasis and the maintenance of genomic integrity and oncotherapy (Review). Int J Oncol 56: 879-888, 2020
APA
Zhang, Z., Zheng, L., Yu, Y., Wu, J., Yang, F., Xu, Y. ... Song, X. (2020). Involvement of SAMHD1 in dNTP homeostasis and the maintenance of genomic integrity and oncotherapy (Review). International Journal of Oncology, 56, 879-888. https://doi.org/10.3892/ijo.2020.4988
MLA
Zhang, Z., Zheng, L., Yu, Y., Wu, J., Yang, F., Xu, Y., Guo, Q., Wu, X., Cao, S., Cao, L., Song, X."Involvement of SAMHD1 in dNTP homeostasis and the maintenance of genomic integrity and oncotherapy (Review)". International Journal of Oncology 56.4 (2020): 879-888.
Chicago
Zhang, Z., Zheng, L., Yu, Y., Wu, J., Yang, F., Xu, Y., Guo, Q., Wu, X., Cao, S., Cao, L., Song, X."Involvement of SAMHD1 in dNTP homeostasis and the maintenance of genomic integrity and oncotherapy (Review)". International Journal of Oncology 56, no. 4 (2020): 879-888. https://doi.org/10.3892/ijo.2020.4988