Abstract
Viral DNA replication is generally dependent upon circumventing host cell cycle control to force S phase entry in an otherwise quiescent cell. Here we describe novel attributes of the cyclin encoded by Human Herpesvirus 8 (K cyclin) that enable it to subvert the quiescent state. K cyclin is most similar to the mammalian D-type cyclins in primary sequence but displays properties more akin to those of cyclin E. K cyclin (like cyclin E) can autonomously couple with its cognate cdk subunit and localize to the nucleus. D-type cyclins require mitogen stimulated accessory factors (such as p21Cip1 and p27Kip1) to facilitate both of these processes. A striking difference between K cyclin and mammalian cyclins is that K cyclin binding to cdk6 can substantially activate the catalytic activity of the complex without the requirement for cyclin H/cdk7 phosphorylation of the cdk T-loop; this phosphorylation is obligatory for endogenous cyclin/cdk activity. However, K cyclin/cdk6 complexes are not totally immune from cell cycle control since CAK phosphorylation is necessary for complete activation. Thus, CAK phosphorylated K cyclin/cdk6 targets multiple sites in the retinoblastoma protein (pRb) whereas the unphosphorylated complex targets a single site. The restricted substrate specificity of the non-CAK phosphorylated K cyclin/cdk6 complex is insufficient to enable K cyclin-mediated S phase entry. Thus, the viral K cyclin is reliant upon endogenous CAK activity to subvert the quiescent state.
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Acknowledgements
We thank D Bentley, E Harlow, M Meyerson, D Morgan, G Peters and C Sherr for generously supplying reagents and N Jones, G Peters and H Laman for critical reading of the manuscript. We also thank D Davies for FACS analysis and I Kill for help with the fluorescence microscopy. This work was supported by the Cancer Research Campaign (DJ Mann).
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Child, E., Mann, D. Novel properties of the cyclin encoded by Human Herpesvirus 8 that facilitate exit from quiescence. Oncogene 20, 3311–3322 (2001). https://doi.org/10.1038/sj.onc.1204447
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DOI: https://doi.org/10.1038/sj.onc.1204447
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