Whose end is destruction: cell division and the anaphase-promoting complex

Abstract

Cell proliferation depends on the duplication of chromosomes followed by the segregation of duplicates (sister chromatids) to opposite poles of the cell prior to cell division (cytokinesis).How cells ensure that chromosome duplication, chromosome segregation, and cell division occur in the correct order and form an immortal reproductive cycle is one of the most fundamental questions in cell biology.Without such coordination, cells would not maintain a constant chromosome number and sexual reproduction as we know and love it would not be possible. A halfhearted cell cycleThe discovery of cyclin-dependent kinases (CDKs) went some way to answering this question.Successive waves of S-and M-phase-promoting CDKs first trigger chromosome duplication (S phase)-then the attachment of the replicated chromosomes to a bipolar spindle (M phase).In animal cells, S phase is induced by Cdk2 bound to S-phase cyclins (E-and A-type) whereas M phase is triggered by Cdk1 associated with mitotic cyclins (A-and B-type).In both fission yeast and budding yeast, S and M phase are induced by a single CDK (Cdk1) bound to Sphase-and M-phase-specific B-type cyclins, respectively.We now understand many of the regulatory mechanisms that activate S-and M-CDKs in the correct order.We also have a robust hypothesis for how cells ensure that no genomic sequence is duplicated more than once during the interval between the onset of S and M phases.Initiation of DNA replication requires two distinct steps: first, prereplicative complexes (pre-RCs) are assembled at future origins of replication, a process that can occur only in the absence of CDK activity.The second step, origin unwinding and the recruitment of replication enzymes, is triggered by CDK activation.Because pre-RC assembly is inhibited by CDK activity, chromosome rereplication requires a CDK cycle, a period of low CDK activity followed by a period of high CDK activity.Having activated S-CDKs in late G 1 , cells maintain high