We are interested in the molecular mechanisms, which ensure that the events of the eukaryotic cell cycle occur at the right time and in the correct order. To approach this problem we study an ubiquitin ligase called the anaphase-promoting complex. Together with cyclin-dependent kinases, this enzyme is at the centre of the regulatory network concerned with cell cycle control. The APC triggers key cell cycle transitions and is itself controlled by cell cycle events. The APC is not only an enzyme but can be viewed as a signal integration device.

CDKs first trigger chromosome duplication and then prepare chromosomes for segregation in mitosis, i.e. they drive cells into metaphase. Further cell cycle progression depends on the degradation of regulators through ubiquitination by the APC. Degradation of the anaphase inhibitor Pds1 is required for sister chromatid separation at the onset of anaphase and proteolysis of cyclin B is required for exit form mitosis and cytokinesis. APC’s activity during the cell cycle is regulated by the binding of activator proteins, by mitotic kinases, and by different checkpoint pathways.

Remarkable progress has been made in our understanding of how the APC controls cell cycle events, at least in yeast. Nevertheless, several key questions remain unsolved.

For example, it is unclear how APC bound to its mitotic activator Cdc20 is suddenly switched on at the metaphase-to-anaphase transition and how the APC-Cdc20 holoenzyme is inhibited by various checkpoint mechanisms. Furthermore, very little is known about the molecular function of the APC itself, its assembly, catalytic mechanisms, and regulation. This is largely due to the unusual complexity of this ubiquitin ligase. It is therefore important to identify all of the subunits and to define the functions of individual subunits.

The mutual regulation between CDKs and the APC is thought to be crucial for the strict alternation between chromosome duplication (S phase) and chromosome segregation, which is essential for the maintenance of a constant karyotype during cell proliferation. During meiosis, however, this almost universal rule is broken: One round of chromosome duplication is followed by two consecutive rounds of chromosome segregation. Also the meiotic cell cycle is controlled by CDKs and the APC. We are interested in the mechanisms that change the regulatory properties of the APC to bring about one S phase followed by two nuclear divisions and a differentiation program for gamete production.

We mainly use budding yeast and recently also fission yeast because these organisms offer a unique possibility to manipulate their genomes and to perform a combination of genetic and biochemical approaches. Purification of protein complexes and the subsequent identification of their constituents by mass spectrometry (done in the lab of Andrej Shevchenko at MPI-CBG) is a major tool to identify novel molecules. From the yeast work we try to derive models relevant for cell cycle regulation in all eukaryotes including humans. To validate models and predictions, we perform experiments with human cells in culture and in C. elegans.