SAMHD1: Recurring roles in cell cycle, viral restriction, cancer, and innate immunity

Mauney, Christopher H.; Hollis, Thomas

doi:10.1080/08916934.2018.1454912

Cited by 39 publications

(54 citation statements)

References 221 publications

(303 reference statements)

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“…Nelarabine is metabolised into AraG, which is then triphosphorylated by cellular kinases into the active form [Curbo and Karlsson, 2006]. SAMHD1 is a deoxynucleotide triphosphate (dNTP) hydrolase that cleaves and inactivates triphosphorylated nucleoside analogues including triphosphorylated AraG [Hollenbaugh et al, 2017;Knecht et al, 2018;Mauney and Hollis, 2018;Oellerich et al, 2019]. Moreover, T-ALL cells were characterised by substantially lower SAMHD1 levels than B-ALL cells.…”

Section: Discussionmentioning

confidence: 99%

“…SAMHD1 is a deoxynucleotide triphosphate (dNTP) hydrolase that cleaves physiological dNTPs and triphosphorylated nucleoside analogues [Arnie et al, 2013;Ballana et al, 2014;Hollenbaugh et al, 2017;Knecht et al, 2018;Mauney and Hollis, 2018]. It was previously shown to interfere with the activity of anti-cancer nucleoside analogues including nelarabine [Herold et al, 2017;Hollenbaugh et al, 2017;Knecht et al, 2018].…”

Section: Samhd1 Expression Levels Correlate With Resistance To Nelaramentioning

confidence: 99%

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SAMHD1 is a key regulator of the lineage-specific response of acute lymphoblastic leukaemias to nelarabine

Rothenburger

McLaughlin

Herold

et al. 2019

Preprint

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The nucleoside analogue nelarabine, the prodrug of arabinosylguanine (AraG), has been known for decades to be effective against acute lymphoblastic leukaemias of T-cell (T-ALL), but not of B-cell (B-ALL) origin. The mechanisms underlying this lineage-specific drug sensitivity have remained elusive. Data from pharmacogenomics studies and from a panel of ALL cell lines revealed an inverse correlation of SAMHD1 expression and nelarabine sensitivity. SAMHD1 can hydrolyse and thus inactivate triphosphorylated nucleoside analogues. Transcriptomic and protein expression profiling of cell lines and patient-derived leukaemic blasts revealed lower SAMHD1 abundance in T-ALL than in B-ALL. Mechanistically, SAMHD1 promoter methylation strongly correlated with suppressed SAMHD1 expression, while T-ALL cells did not display increased global DNA methylation. Targeted SAMHD1 degradation using virus-like particles containing Vpx sensitised B-ALL cells to AraG, while ectopic SAMHD1 expression in SAMHD1-null T-ALL cells induced AraG resistance. SAMHD1had a larger impact on cytarabine activity than on nelarabine/ AraG activity in acute myeloid leukaemia (AML) cells, but more strongly affected nelarabine/ AraG activity in ALL cells. This indicates a critical role of the cancer entity. In conclusion, lineagespecific differences in SAMHD1 promoter methylation and, in turn, SAMHD1 expression levels determine ALL cell response to nelarabine. SAMHD1 is a potential biomarker for the identification of ALL patients likely to benefit from nelarabine therapy and a therapeutic target to overcome nelarabine resistance.Philadelphia chromosome-like acute lymphoblastic leukemia frequently have IGH-CRLF2 and JAK2 mutations, persistence of minimal residual disease and poor prognosis.

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Section: Discussionmentioning

confidence: 99%

Section: Samhd1 Expression Levels Correlate With Resistance To Nelaramentioning

confidence: 99%

SAMHD1 is a key regulator of the lineage-specific response of acute lymphoblastic leukaemias to nelarabine

Rothenburger

McLaughlin

Herold

et al. 2019

Preprint

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“…An upregulation of SAMHD1 by LPS induced acute lung injury in as early as 6 h of post-stimulation and was thought to be one of the early cellular responses and an effector of innate immunity after infection (83). This particular gene plays an important role in the regulation of innate immune response via type 1 interferons (84). These interferons also activate JAK/STAT signaling pathways.…”

Section: Sex Differences In Gene Expressionmentioning

confidence: 99%

Sex-Specific Regulation of Gene Expression Networks by Surfactant Protein A (SP-A) Variants in Alveolar Macrophages in Response to Klebsiella pneumoniae

et al. 2020

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Surfactant protein A (SP-A) in addition to its surfactant-related functions interacts with alveolar macrophages (AM), the guardian cells of innate immunity in the lungs, and regulates many of its functions under basal condition and in response to various pressures, such as infection and oxidative stress. The human SPA locus consists of two functional genes, SFTPA1 and SFTPA2, and one pseudogene. The functional genes encode human SP-A1 and SP-A2 proteins, respectively, and each has been identified with several genetic variants. SPA variants differ in their ability to regulate lung function mechanics and survival in response to bacterial infection. Here, we investigated the effect of hSP-A variants on the AM gene expression profile in response to Klebsiella pneumoniae infection. We used four humanized transgenic (hTG) mice that each carried SP-A1 (6A 2 , 6A 4) or SP-A2 (1A 0 , 1A 3), and KO. AM gene expression profiling was performed after 6 h post-infection. We found: (a) significant sex differences in the expression of AM genes; (b) in response to infection, 858 (KO), 196 (6A 2), 494 (6A 4), 276 (1A 0), and 397 (1A 3) genes were identified (P < 0.05) and some of these were differentially expressed with ≥2 fold, specific to either males or females; (c) significant SP-A1 and SP-A2 variant-specific differences in AM gene expression; (d) via Ingenuity Pathway Analysis (IPA), key pathways and molecules were identified that had direct interaction with TP53, TNF, and cell cycle signaling nodes; (e) of the three pathways (TNF, TP-53, and cell cycle signaling nodes) studied here, all variants except SP-A2 (1A 3) female, showed significance for at least 2 of these pathways, and KO male showed significance for all three pathways; (f) validation of key molecules exhibited variant-specific significant differences in the expression between sexes and a similarity in gene expression profile was observed between KO and SP-A1. These results reveal for the first time a Thorenoor et al. AM Gene Regulation by SPA Variants large number of biologically relevant functional pathways influenced in a sex-specific manner by SPA variants in response to infection. These data may assist in studying molecular mechanisms of SPA mediated AM gene regulation and potentially identify novel therapeutic targets for K. pneumoniae infection.

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“…In particular, mutations affecting its enzymatic activity are associated with Aicardi-Goutières syndrome (AGS), a genetic disorder characterized by a chronic inflammatory response, with increased production of type I interferons and signs of autoimmunity, mimicking a chronic viral infection [ 29 ]. Moreover, SAMHD1 is frequently mutated in a variety of cancers, implying a role of this protein in both cellular and viral growth [ 30 – 32 ].…”

Section: Introductionmentioning

confidence: 99%

SAMHD1 phosphorylation and cytoplasmic relocalization after human cytomegalovirus infection limits its antiviral activity

et al. 2020

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SAMHD1 is a host restriction factor that functions to restrict both retroviruses and DNA viruses, based on its nuclear deoxynucleotide triphosphate (dNTP) hydrolase activity that limits availability of intracellular dNTP pools. In the present study, we demonstrate that SAMHD1 expression was increased following human cytomegalovirus (HCMV) infection, with only a modest effect on infectious virus production. SAMHD1 was rapidly phosphorylated at residue T592 after infection by cellular cyclin-dependent kinases, especially Cdk2, and by the viral kinase pUL97, resulting in a significant fraction of phosho-SAMHD1 being relocalized to the cytoplasm of infected fibroblasts, in association with viral particles and dense bodies. Thus, our findings indicate that HCMV-dependent SAMHD1 cytoplasmic delocalization and inactivation may represent a potential novel mechanism of HCMV evasion from host antiviral restriction activities.

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SAMHD1: Recurring roles in cell cycle, viral restriction, cancer, and innate immunity

Cited by 39 publications

References 221 publications

SAMHD1 is a key regulator of the lineage-specific response of acute lymphoblastic leukaemias to nelarabine

SAMHD1 is a key regulator of the lineage-specific response of acute lymphoblastic leukaemias to nelarabine

Sex-Specific Regulation of Gene Expression Networks by Surfactant Protein A (SP-A) Variants in Alveolar Macrophages in Response to Klebsiella pneumoniae

SAMHD1 phosphorylation and cytoplasmic relocalization after human cytomegalovirus infection limits its antiviral activity

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