Human cytomegalovirus infection leads to accumulation of geminin and inhibition of the licensing of cellular DNA replication.
Previous studies have shown that infection of G(0)-synchronized human fibroblasts by human cytomegalovirus (HCMV) results in a block to cellular DNA synthesis. In this study, we have examined the effect of viral infection on the formation of the host cell DNA prereplication complex (pre-RC). We found that the Cdc6 protein level was significantly upregulated in the virus-infected cells and that there was a delay in the expression of the Mcm family of proteins. The loading of the Mcm proteins onto the DNA pre-RC complex also appeared to be defective in the virus-infected cells. This inhibition of DNA replication licensing was associated with the accumulation of geminin, a replication inhibitor. Cdt1, which participates in the loading of the Mcm proteins, was also downregulated and modified differentially in the infected cells. Early viral gene expression was sufficient for the virus-induced alteration of the pre-RC, and the immediate-early protein IE1 was not required. These studies show that the inhibition of replication licensing in HCMV-infected cells is one of the multiple pathways by which the virus dysregulates the host cell cycle.
Biswas
Nilima
N
Molecular Biology Section and Center for Molecular Genetics, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0366, USA.
Sanchez
Veronica
V
Spector
Deborah H
DH
D018797:Cell Cycle Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D003587:Cytomegalovirus / Q000472:pathogenicity*; D004261:DNA Replication; D004268:DNA-Binding Proteins; D005347:Fibroblasts / Q000821:virology*; D064248:Geminin; D006801:Humans; D064111:Minichromosome Maintenance Complex Component 2; D064148:Minichromosome Maintenance Complex Component 4; D009687:Nuclear Proteins / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins
C066503:CDC6 protein, S cerevisiae; C467199:CDT1 protein, human; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C577995:GMNN protein, human; D064248:Geminin; D009687:Nuclear Proteins; D029701:Saccharomyces cerevisiae Proteins; C099243:MCM4 protein, human; D064111:Minichromosome Maintenance Complex Component 2; D064148:Minichromosome Maintenance Complex Component 4