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Journal of Virology, October 2008, p. 10188-10198, Vol. 82, No. 20
0022-538X/08/$08.00+0     doi:10.1128/JVI.01212-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Cell Cycle-Independent Expression of Immediate-Early Gene 3 Results in G₁ and G₂ Arrest in Murine Cytomegalovirus-Infected Cells

Lüder Wiebusch,^* Anke Neuwirth, Linus Grabenhenrich, Sebastian Voigt, and Christian Hagemeier^*

Department of Pediatrics, Laboratory for Molecular Biology, Charité-Universitätsmedizin Berlin, Ziegelstr. 5-9, 10117 Berlin, Germany

Received 11 June 2008/ Accepted 22 July 2008

The infectious cycle of human cytomegalovirus (HCMV) is intricately linked to the host's cell cycle. Viral gene expression can be initiated only in G₀/G₁ phase. Once expressed, the immediate-early gene product IE2 prevents cellular DNA synthesis, arresting infected cells with a G₁ DNA content. This function is required for efficient viral replication in vitro. A prerequisite for addressing its in vivo relevance is the characterization of cell cycle-regulatory activities of CMV species for which animal models have been established. Here, we show that murine CMV (MCMV), like HCMV, has a strong antiproliferative capacity and arrests cells in G₁. Unexpectedly, and in contrast to HCMV, MCMV can also block cells that have passed through S phase by arresting them in G₂. Moreover, MCMV can also replicate in G₂ cells. This is made possible by the cell cycle-independent expression of MCMV immediate-early genes. Transfection experiments show that of several MCMV candidate genes, only immediate-early gene 3 (ie3), the homologue of HCMV IE2, exhibits cell cycle arrest activity. Accordingly, an MCMV ie3 deletion mutant has lost the ability to arrest cells in either G₁ or G₂. Thus, despite interspecies variations in the cell cycle dependence of viral gene expression, the central theme of HCMV IE2-induced cell cycle arrest is conserved in the murine counterpart, raising the possibility of studying its physiological relevance at the level of the whole organism.

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* Corresponding author. Mailing address: Ziegelstr. 5-9, D-10117 Berlin, Germany. Phone for Christian Hagemeier: 49 30 450 566041. Fax: 49 30 450 566913. E-mail: christian.hagemeier{at}charite.de. Phone for Lüder Wiebusch: 49 30 450 566157. Fax: 49 30 450 566913. E-mail: lueder.wiebusch{at}charite.de

Published ahead of print on 30 July 2008.

Present address: Division of Hematology/Oncology, Children's Hospital Boston, 300 Longwood Ave., Boston, MA 02115.

Present address: Prof-Hess-Childrens' Hospital, Klinikum Bremen-Mitte, St. Jürgen-Str. 1, 28177 Bremen, Germany.

Present address: Division of Viral Infections, Robert Koch Institute, Nordufer 20, 13353 Berlin, Germany.

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Journal of Virology, October 2008, p. 10188-10198, Vol. 82, No. 20
0022-538X/08/$08.00+0     doi:10.1128/JVI.01212-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

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