Classes of Ubiquitination Substrates ent has long settled and the wizened eye of history Ubiquitination substrates relevant to the cell cycle fall levels its gaze at the field of cell cycle regulation, what into two broad categories: those whose destruction is discovery will it view as the most seminal? With some required for cell cycle progression (eg, Sic1, Pds1, and debate, it is likely to be the discovery of cyclins and the B-type cyclins), and those whose destruction is not escyclin-dependent kinases (Cdks) they regulate. Cyclins sential but is important for cellular homeostasis (eg, are key regulators of cell cycle transitions whose abun-Cdc6, Cdc20, and G1 cyclins)(Figure 1A). As mentioned dance varies through a cell cycle. Not only did the union above, several proteins have temporally distinct positive of cyclins and Cdks unravel the long-standing mystery and negative roles and their destruction relieves the of mitotic entry and oocyte maturation and lead to the negative barriers they impose on cell division. In condiscovery of the Cdk inhibitors (CKI), but the very nature trast, destruction of strictly positively acting factors 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 Figure 1. Ubiquitination Pathways in the Cell Cycle the inhibitory barrier to allow the transition to the next(A) A diagram showing ubiquitination substrates from H. sapiens,