Abstract
The master regulators of the cell cycle are cyclin-dependent kinases (Cdks), which influence the function of a myriad of proteins via phosphorylation. Mitotic Cdk1 is activated by A-type, as well as B1- and B2-type, cyclins. However, the role of a third, conserved cyclin B family member, cyclin B3, is less well defined. Here, we show that Caenorhabditis elegans CYB-3 has essential and distinct functions from cyclin B1 and B2 in the early embryo. CYB-3 is required for the timely execution of a number of cell cycle events including completion of the MII meiotic division of the oocyte nucleus, pronuclear migration, centrosome maturation, mitotic chromosome condensation and congression, and, most strikingly, progression through the metaphase-to-anaphase transition. Our experiments reveal that the extended metaphase delay in CYB-3–depleted embryos is dependent on an intact spindle assembly checkpoint (SAC) and results in salient defects in the architecture of holocentric metaphase chromosomes. Furthermore, genetically increasing or decreasing dynein activity results in the respective suppression or enhancement of CYB-3–dependent defects in cell cycle progression. Altogether, these data reveal that CYB-3 plays a unique, essential role in the cell cycle including promoting mitotic dynein functionality and alleviation of a SAC–dependent block in anaphase chromosome segregation.
Highlights
The eukaryotic cell cycle is driven by the temporally controlled activation of cyclin-dependent kinases (CDKs) in association with their requisite cofactors, the cyclins [1]
Each chromatid must be cleanly separated from its sister so that each daughter cell inherits the same DNA complement as the starting cell
We report that loss of an evolutionarily conserved cell cycle regulator, Cyclin B3/ CYB-3, results in an unusual and strikingly persistent spindle assembly checkpoint (SAC)– dependent delay in sister chromatid separation
Summary
The eukaryotic cell cycle is driven by the temporally controlled activation of cyclin-dependent kinases (CDKs) in association with their requisite cofactors, the cyclins [1]. As cells prepare to enter mitosis, cyclin B/Cdk complexes phosphorylate a host of substrates leading to chromosome condensation, centrosome maturation, and nuclear envelope breakdown [3]. During this period, the chromosome/microtubule interface, the kinetochore, is constructed from several protein complexes that are coordinately built at the centromere, an epigenetically defined chromosomal location [4]. Other organisms, including C. elegans, have holocentric chromosomes with kinetochores along their entire length [5] Despite these differences, all eukaryotic centromeres harbor specialized nucleosomes wherein the canonical histone H3 is replaced by the centromere-specific histone CENP-A/CenH3 [6]
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