One hundred years from now when the dust of the present has long settled and the wizened eye of history levels its gaze at the field of cell cycle regulation, what discovery will it view as the most seminal? With some debate, it is likely to be the discovery of cyclins and the cyclin-dependent kinases (Cdks) they regulate. Cyclins are key regulators of cell cycle transitions whose abundance varies through a cell cycle. Not only did the union of cyclins and Cdks unravel the long-standing mystery of mitotic entry and oocyte maturation and lead to the discovery of the Cdk inhibitors (CKI), but the very nature of cyclin periodicity held within itself the seeds of an equally significant discovery; the role of ubiquitin-mediated proteolysis in cell cycle control. It is now widely understood that cyclin/Cdks work hand-in-hand with ubiquitin-mediated proteolysis to provide the logical framework for cell cycle regulation. Not only are the levels of cyclins regulated by ubiquitination, but so are the levels of a host of other key cell cycle regulators.

To duplicate, cells must generally double their contents but precisely solve two specific problems: they must replicate their DNA once and only once per cell cycle, and they must segregate their chromosomes precisely to daughter cells. These are biochemically incompatible processes that are partitioned into temporally distinct cell cycle “states.” The general strategy employed to prevent improper transitions between these states is the use of inhibitory barriers that must be overcome in order for the transition to occur. Often, the same molecule is used both to promote one transition and to inhibit a subsequent transition. For example, in S. cerevisiae Sic1 promotes exit from mitosis by inhibiting Clb/Cdc28 kinases but acts as a barrier to S phase entry that must be overcome. Likewise, S phase cyclins promote initiation of DNA synthesis but prevent the reestablishment of new competent origins thus preventing rereplication, while mitotic cyclins promote entry into mitosis but inhibit mitotic exit. By coupling positive and negative regulators, the cell cycle ensures the maintenance of a single “state” that carries out one defined set of processes at a time. Once the “state” has accomplished its task, events are set in motion that overcome the inhibitory barrier to allow the transition to the next state.