Deoxynucleoside triphosphate (dNTP) synthesis and destruction regulate the replication of both cell and virus genomes

Stillman, Bruce

doi:10.1073/pnas.1312901110

Cited by 39 publications

(28 citation statements)

References 21 publications

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“…Earlier, we suggested that T592 phosphorylation may be a signal for SAMHD1 degradation during S-phase [10,43]. Here we showed that SAMHD1 co-immunoprecipitates with Skp2 in a phosphorylation dependent manner but we could not detect an increase of SAMHD1 protein after inhibition of the proteasome or of protein neddylation.…”

Section: Discussioncontrasting

confidence: 67%

The dNTP triphosphohydrolase activity of SAMHD1 persists during S-phase when the enzyme is phosphorylated at T592

et al. 2018

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SAMHD1 is the major catabolic enzyme regulating the intracellular concentrations of DNA precursors (dNTPs). The S-phase kinase CDK2-cyclinA phosphorylates SAMHD1 at Thr-592. How this modification affects SAMHD1 function is highly debated. We investigated the role of endogenous SAMHD1 phosphorylation during the cell cycle. Thr-592 phosphorylation occurs first at the G1/S border and is removed during mitotic exit parallel with Thr-phosphorylations of most CDK1 targets. Differential sensitivity to the phosphatase inhibitor okadaic acid suggested different involvement of the PP1 and PP2 families dependent upon the time of the cell cycle. SAMHD1 turn-over indicates that Thr-592 phosphorylation does not cause rapid protein degradation. Furthermore, SAMHD1 influenced the size of the four dNTP pools independently of its phosphorylation. Our findings reveal that SAMHD1 is active during the entire cell cycle and performs an important regulatory role during S-phase by contributing with ribonucleotide reductase to maintain dNTP pool balance for proper DNA replication.

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Section: Discussioncontrasting

confidence: 67%

The dNTP triphosphohydrolase activity of SAMHD1 persists during S-phase when the enzyme is phosphorylated at T592

et al. 2018

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“…In mammalian cells, the cell cycle regulation of the enzymes controlling dNTP pool sizes, ribonucleotide reductases and SAMHD1, is adjusted to the requirements of DNA replication (1). Both dNTP synthesis and destruction regulate the replication of both cell and virus genomes (34). The virus replicative cycle is tightly linked to the cell cycle control of dNTP availability.…”

Section: Discussionmentioning

confidence: 99%

Cell Cycle Control and HIV-1 Susceptibility Are Linked by CDK6-Dependent CDK2 Phosphorylation of SAMHD1 in Myeloid and Lymphoid Cells

Pauls

Ruiz

Badía

et al. 2014

The Journal of Immunology

118

135

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Proliferating cells are preferentially susceptible to infection by retroviruses. Sterile α motif and HD domain–containing protein-1 (SAMHD1) is a recently described deoxynucleotide phosphohydrolase controlling the size of the intracellular deoxynucleotide triphosphate (dNTP) pool, a limiting factor for retroviral reverse transcription in noncycling cells. Proliferating (Ki67+) primary CD4+ T cells or macrophages express a phosphorylated form of SAMHD1 that corresponds with susceptibility to infection in cell culture. We identified cyclin-dependent kinase (CDK) 6 as an upstream regulator of CDK2 controlling SAMHD1 phosphorylation in primary T cells and macrophages susceptible to infection by HIV-1. In turn, CDK2 was strongly linked to cell cycle progression and coordinated SAMHD1 phosphorylation and inactivation. CDK inhibitors specifically blocked HIV-1 infection at the reverse transcription step in a SAMHD1-dependent manner, reducing the intracellular dNTP pool. Our findings identify a direct relationship between control of the cell cycle by CDK6 and SAMHD1 activity, which is important for replication of lentiviruses, as well as other viruses whose replication may be regulated by intracellular dNTP availability.

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“…Because the dNTP pool sizes reflect a steady state between dNTP synthesis by RNR and their degradation by SAMHD1, it is expected that SAMHD1 levels and/or activity be down-regulated in S phase (21,45). As cyclinA2-CDK is activated at G 1 /S transition and responsible for actual initiation of nuclear DNA synthesis, SAMHD1 Thr-592 phosphorylation by this kinase is a plausible candidate event triggering suppression of SAMHD1 in S phase (45).…”

Section: Di-hydrophobic Cyclina2-cdk-binding Motif In the Samhd1 C Tementioning

confidence: 99%

CyclinA2-Cyclin-dependent Kinase Regulates SAMHD1 Protein Phosphohydrolase Domain

Yan

Hao

DeLucia

et al. 2015

Journal of Biological Chemistry

123

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Background: Human sterile ␣ motif and histidine-aspartate domain-containing protein 1 (SAMHD1) is a deoxyribonucleoside triphosphate (dNTP) triphosphohydrolase that is phosphorylated by cyclinA2-dependent kinases. Results: SAMHD1 mutants defective for cyclinA2 binding disrupt S phase progression, and this is alleviated by Thr-592 phosphomimetic mutation. Conclusion: CyclinA2-dependent kinases regulate SAMHD1 activity. Significance: SAMHD1 dNTP phosphohydrolase activity is regulated during the cell cycle.

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Deoxynucleoside triphosphate (dNTP) synthesis and destruction regulate the replication of both cell and virus genomes

Cited by 39 publications

References 21 publications

The dNTP triphosphohydrolase activity of SAMHD1 persists during S-phase when the enzyme is phosphorylated at T592

The dNTP triphosphohydrolase activity of SAMHD1 persists during S-phase when the enzyme is phosphorylated at T592

Cell Cycle Control and HIV-1 Susceptibility Are Linked by CDK6-Dependent CDK2 Phosphorylation of SAMHD1 in Myeloid and Lymphoid Cells

CyclinA2-Cyclin-dependent Kinase Regulates SAMHD1 Protein Phosphohydrolase Domain

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