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

Cell Cycle. 2018;17(9):1102-1114. doi: 10.1080/15384101.2018.1480216. Epub 2018 Jul 24.


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.

Keywords: Deoxynucleotide metabolism; Sterile alpha motif and HD domain containing protein1 (SAMHD1); cell cycle.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • CDC2 Protein Kinase / metabolism
  • Cell Proliferation
  • Cyclin A2 / metabolism
  • Cyclin E / metabolism
  • Cyclin-Dependent Kinase 2 / metabolism
  • Dinucleoside Phosphates / metabolism*
  • Gene Knockout Techniques
  • Humans
  • Phosphorylation
  • Proteolysis
  • Ribonucleotide Reductases / metabolism
  • S Phase / drug effects
  • S Phase / physiology*
  • SAM Domain and HD Domain-Containing Protein 1 / genetics
  • SAM Domain and HD Domain-Containing Protein 1 / metabolism*
  • THP-1 Cells
  • Threonine / chemistry*


  • Cyclin A2
  • Cyclin E
  • Dinucleoside Phosphates
  • Threonine
  • Ribonucleotide Reductases
  • CDC2 Protein Kinase
  • CDK1 protein, human
  • CDK2 protein, human
  • Cyclin-Dependent Kinase 2
  • SAM Domain and HD Domain-Containing Protein 1
  • SAMHD1 protein, human