FIG. 5.

Two models for coupling of circadian and cell cycles. (Top) Serial coupling. In this mode of synchronization of the two cycles, proteins or reactions belonging primarily to one cycle regulate the expression of genes controlling the other cycles. The circadian clock controls the cell cycle because, in part, it regulates the expression of Wee1 and c-myc cell cycle and proliferation genes. Conversely, the cell cycle may control the circadian cycle by shutting down cellular transcription activity during mitosis (broken lines), regardless of when mitosis takes place with regard to the phase of the circadian cycle, and as a consequence may shift the phase of the circadian cycle. Disruption of one cycle may or may not significantly affect the functioning of the other cycle depending on the strength of coupling and those of homeostatic mechanisms specific for the individual cycles. (Bottom) Direct coupling. In this mode a protein such as Tim directly participates in the molecular machineries of both cycles, and as a consequence elimination of such protein may result in collapse of both cycles. Note that the model for direct coupling is drawn to show the protein-protein interactions of Tim in carrying out its checkpoint and putative clock functions and does not imply a defined biochemical pathway or the presence of a supramolecular complex of clock-checkpoint proteins participating in the two cycles simultaneously or alternately.