The myxoma virus (MV) M-T5 gene encodes an ankyrin repeat protein that is important for virus replication in cells from several species. Insight was gained into the molecular mechanisms underlying the role of M-T5 as a host range determinant when the cell cycle regulatory protein cullin-1 (cul-1) was identified as a cellular binding partner of M-T5 and found to colocalize with the protein in both nuclear and cytosolic compartments. The strict dependence of viruses on host cellular metabolic processes for the machinery and precursors necessary to support each unique phase of their life cycle makes the availability of these resources a critical determinant of the outcome of a virus infection. Unlike viruses with smaller genomes and a limited coding capacity for proteins specifically devoted to DNA replication, poxviruses encode the majority of enzymes required for viral genome synthesis (30). This property enables poxviruses to replicate in the cytosol of infected cells independently of the host nuclear machinery, decreasing the dependence of virus replication on the status of the host cell cycle. However, the ability to successfully compete with the host cell for such resources as deoxynucleotides and replicative factors to ensure transcription and translation of viral genes remains a major obstacle that poxviruses must still overcome to efficiently replicate their genomes and generate progeny virions. This requirement necessitates that poxviruses also possess strategies to divert such essential resources and at least transiently create an environment in infected cells that favors virus replication.Progression through the cell cycle is a highly regulated process during which chromosomes are replicated (S) and then segregated during cytokinesis and mitosis (M) (reviewed in reference 32). These periods of activity are separated by gaps of preparation and dormancy (G 0 , G 1 , and G 2 ) that allow for tighter control of cell replication by providing regulatory checkpoints at major transition phases. These checkpoints include G 0 /G 1 , which regulates the entry of a quiescent cell back into the cycle, G 1 /S, which regulates initiation of DNA replication, and G 2 /M, which regulates mitosis. This control is largely exerted by the sequential activation of cyclins, which function as the regulatory subunits of the cyclin-dependent kinases (CDKs) to mediate the selective phosphorylation of subsets of regulatory molecules. Because CDKs are constitutively expressed, their activity is regulated positively by the relative abundance of cyclins and negatively by CDK inhibitors (CDK-I), such as p21/waf and p27/Kip. Thus, the key mechanism for controlling progression through the cell cycle is the regulated turnover of cyclins, CDK, and CDK-I through selective synthesis and degradation.The ubiquitin (Ub)-proteasome system is the primary cellular mechanism for maintaining protein abundance and, as such, is responsible for the selective degradation of regulatory proteins involved in a spectrum of biological functions, including ce...
