Human cytomegalovirus requires cellular deoxycytidylate deaminase for replication in quiescent cells.
We have previously observed that the expression of two thymidylate biosynthesis enzymes, dihydrofolate reductase and thymidylate synthase (TS), is upregulated in quiescent human fibroblasts infected with human cytomegalovirus (HCMV). Here, we have demonstrated that HCMV increases expression of the cellular deoxycytidylate deaminase (dCMP deaminase), which provides the substrate for TS by converting dCMP to dUMP. We observed an increase in dCMP deaminase protein levels, whereas deoxyuridine triphosphatase (dUTPase), another cellular enzyme that may provide dUMP by hydrolysing dUTP, was undetectable. The essential requirement of cellular dCMP deaminase for productive HCMV replication was further emphasized by showing that a precursor of a potent dCMP deaminase inhibitor, zebularine, suppressed virus replication and DNA synthesis. These results suggest that HCMV exploits the host's dCMP deaminase activity to replicate in quiescent cells.
Gribaudo
Giorgio
G
Department of Public Health and Microbiology, University of Torino, Via Santena 9, 10126 Torino, Italy.
Riera
Ludovica
L
Department of Public Health and Microbiology, University of Torino, Via Santena 9, 10126 Torino, Italy.
Caposio
Patrizia
P
Department of Public Health and Microbiology, University of Torino, Via Santena 9, 10126 Torino, Italy.
Maley
Frank
F
Wadsworth Center for Laboratories and Research, New York State Department of Health, Albany, New York, USA.
Landolfo
Santo
S
Department of Public Health and Microbiology, University of Torino, Via Santena 9, 10126 Torino, Italy.
D002478:Cells, Cultured; D003562:Cytidine / Q000031:analogs & derivatives; D003564:Cytidine Deaminase; D003587:Cytomegalovirus / Q000187:drug effects / Q000254:growth & development / Q000472:pathogenicity* / Q000502:physiology*; D004279:DNA, Viral / Q000096:biosynthesis; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007399:Interphase; D009700:Nucleoside Deaminases / Q000037:antagonists & inhibitors / Q000502:physiology*; D011741:Pyrimidine Nucleosides / Q000494:pharmacology; D011755:Pyrophosphatases / Q000502:physiology; D014779:Virus Replication / Q000187:drug effects / Q000502:physiology*
D004279:DNA, Viral; D004791:Enzyme Inhibitors; D011741:Pyrimidine Nucleosides; D003562:Cytidine; C009131:pyrimidin-2-one beta-ribofuranoside; D009700:Nucleoside Deaminases; D003564:Cytidine Deaminase; C011530:deoxycytidine deaminase; D011755:Pyrophosphatases; C020020:dUTP pyrophosphatase