Model scenarios for evolution of the eukaryotic cell cycle

Progress through the division cycle of present day eukaryotic cells is cont rolled by a complex network consisting of(i) cyclin-dependent kinases (CDKs ) and their associated cyclins, (ii) kinases and phosphatases that regulate CDK activity, and (iii) stoichiometric inhibitors that sequester cyclin-CD K dimers. Presumably regulation of cell division in the earliest ancestors of eukaryotes was a considerably simpler affair. Nasmyth (1995) recently pr oposed a mechanism for control of a putative, primordial, eukaryotic cell c ycle, based on antagonistic interactions between a cyclin-CDK and the anaph ase promoting complex (APC) that labels the cyclin subunit for proteolysis. We recast this idea in mathematical form and show that the model exhibits hysteretic behaviour between alternative steady states: a G1-like state (AP C on, CDK activity low, DNA unreplicated and replication complexes assemble d) and an S/M-like state (APC off, CDK activity high,:DNA replicated and re plication complexes disassembled). In our model, the transition from G1 to S/M ('Start') is driven by cell growth, and the reverse transition ('Finish ') is driven by completion of DNA synthesis and proper alignment of chromos omes on the metaphase plate. This simple and effective mechanism for coupli ng growth and division and for accurately copying and partitioning a genome consisting of numerous chromosomes, each with multiple origins of replicat ion, could represent the core of the eukaryotic cell cycle. Furthermore, we show how other controls could be added to this core and speculate on the r easons why stoichiometric inhibitors and CDK inhibitory phosphorylation mig ht have been appended to the primitive alternation between cyclin accumulat ion and degradation.