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. 2005 Oct;4(10):1435-9.
doi: 10.4161/cc.4.10.2077. Epub 2005 Oct 2.

Human cytomegalovirus inactivates the G0/G1-APC/C ubiquitin ligase by Cdh1 dissociation

Lüder Wiebusch  1 , Miriam Bach, Ralf Uecker, Christian Hagemeier
Affiliations

Human cytomegalovirus inactivates the G0/G1-APC/C ubiquitin ligase by Cdh1 dissociation

Lüder Wiebusch et al. Cell Cycle. 2005 Oct.

Abstract

The anaphase promoting complex/cyclosome (APC/C) is an E3 ubiquitin ligase that targets regulators of the cell division cycle for degradation by the 26S proteasome. Discovered as a key regulator of mitosis, the APC/C has more recently been recognized to also play a limiting role in the control of G(0) maintenance, G(1)/S-transition and DNA-replication. Human cytomegalovirus (HCMV) has been shown to interfere with cell cycle regulation at different levels. It can induce an S phase-prone proliferation program in quiescent cells but at the same time this virus directly inhibits competitive cellular DNA replication. Here we show, that human cytomegalovirus (HCMV) inactivates the G(0)/G(1) APC/C rapidly after infection of quiescent fibroblasts, resulting in the untimely stabilization of APC/C substrates. APC/C inactivation is caused by the dissociation of its positive regulator, Cdh1. Surprisingly, this dissociation is independent from known Cdh1 inhibitors, Emi1 and Cyclin A, suggesting that APC/C-Cdh1 inhibition by HCMV is directly caused by a viral protein or an intermediate cellular factor distinct from Emi1 and Cyclin A. Thus, upon infection of quiescent cells HCMV not only activates the E2F-dependent G(1)/S transcription program but also facilitates protein accumulation of APC/C substrates by rapid Cdh1 dissociation.

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