Regulating S Phase: CDKs, Licensing and Proteolysis

Jé rô me Wuarin and Paul Nurse replication. Thus the control acting over S-phase onset Imperial Cancer Research Fund can be considered in two steps. The first, associated Cell Cycle Laboratory with the absence of CDK activity, makes the chromatin 44 Lincoln's Inn Fields permissive for DNA replication, and the second, associ-London WC2A 3PX UK ated with the presence of CDK activity, leads to the initiation of DNA replication. There are a number of overall S-phase controls which An interesting consequence of this two step model is regulate the initiation of DNA replication and couple that it can explain not only why there is only one S-phase this process to progression through the cell cycle. One per cell cycle but also why a particular DNA segment is ensures that there is only one S-phase in each cell cycle, only replicated once during each S-phase. If onset of and as a consequence of this control only G1 cells are S-phase requires first a period when CDK activity is able to initiate DNA replication. A second guarantees absent to make chromatin permissive, which is then that each DNA segment making up the genome repli-followed by a period of CDK activity to initiate replica-cates only once during each S-phase. These two con-tion, then once initiation has occurred, that region of trols contribute to the maintenance of genome integrity the chromatin cannot be made permissive again until which is necessary if the two cells formed at the end CDK activity falls. This would not normally occur until of each cell cycle are to receive a full complement of mitosis has been completed. Therefore the CDK cycle chromosomes of unchanged ploidy. A third control de-would ensure both that there is only one S-phase per termines the length of the G1-phase and thus the cell cell cycle and that each DNA segment is only replicated cycle timing of S-phase. Because in many, although once during each S-phase. not all cell types, onset of S-phase occurs only after a In complex eukaryotes different CDK complexes act minimal cell mass is attained, this control ensures that at different times during the cell cycle. However, in bud-the cytoplasmic mass supported by the genome never ding yeast there is much overlap in function between becomes too large. Work using a variety of different the different CDK complexes, and in fission yeast it is systems and approaches has begun to make …