Nuclease Activity of the Human SAMHD1 Protein Implicated in the Aicardi-Goutières Syndrome and HIV-1 Restriction

Beloglazova, Natalia; Flick, Robert; Tchigvintsev, Anatoli; Brown, Greg; Popović, Ana; Nocek, B.; Yakunin, Alexander F.

doi:10.1074/jbc.m112.431148

Cited by 199 publications

(223 citation statements)

References 39 publications

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“…SAMHD1 is a dual-function enzyme with both nuclease and deoxyribonucleoside triphosphate triphosphohydrolase (dNTPase) activities (21,22). Germ-line mutations in SAMHD1 have been associated with Aicardi-Goutieres syndrome, a congenital autoimmune disease (23), and more recently SAMHD1 was shown to be an HIV-1 restriction factor operating in nondividing blood cells (24,25).…”

mentioning

confidence: 99%

Heterozygous colon cancer-associated mutations of SAMHD1 have functional significance

Rentoft

Lindell

Tran

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

105

155

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Even small variations in dNTP concentrations decrease DNA replication fidelity, and this observation prompted us to analyze genomic cancer data for mutations in enzymes involved in dNTP metabolism. We found that sterile alpha motif and histidine-aspartate domain-containing protein 1 (SAMHD1), a deoxyribonucleoside triphosphate triphosphohydrolase that decreases dNTP pools, is frequently mutated in colon cancers, that these mutations negatively affect SAMHD1 activity, and that several SAMHD1 mutations are found in tumors with defective mismatch repair. We show that minor changes in dNTP pools in combination with inactivated mismatch repair dramatically increase mutation rates. Determination of dNTP pools in mouse embryos revealed that inactivation of one SAMHD1 allele is sufficient to elevate dNTP pools. These observations suggest that heterozygous cancer-associated SAMHD1 mutations increase mutation rates in cancer cells.

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mentioning

confidence: 99%

Heterozygous colon cancer-associated mutations of SAMHD1 have functional significance

Rentoft

Lindell

Tran

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

105

155

View full text Add to dashboard Cite

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“…The catalytic His-206 and/or Asp-207 residues have also been implicated in two additional enzymatic activities of the SAMHD1 HD domain, nuclease and RNase (47,48). Whereas potential contributions from these activities to S phase perturbations induced by SAMHD1 variants should be considered, the RNase activity was found to be insensitive to the T592D phosphomimetic mutation (48).…”

Section: Discussionmentioning

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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“…The catalytic activity is regulated by nucleoside triphosphate binding at two allosteric sites, which induces the formation of a stable tetramer [1]. In addition to the well-established dNTPase activity, single stranded nucleic acid binding [2] and in vitro nuclease activity were reported [3,4]. However, later data attributed the nuclease activity to contaminants co-purifying with SAMHD1 and the question of SAMHD1 harboring multiple functions is still debated [5].…”

Section: Introductionmentioning

confidence: 99%

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.

show abstract

Nuclease Activity of the Human SAMHD1 Protein Implicated in the Aicardi-Goutières Syndrome and HIV-1 Restriction

Cited by 199 publications

References 39 publications

Heterozygous colon cancer-associated mutations of SAMHD1 have functional significance

Heterozygous colon cancer-associated mutations of SAMHD1 have functional significance

CyclinA2-Cyclin-dependent Kinase Regulates SAMHD1 Protein Phosphohydrolase Domain

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

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