Wolfgang Zachariae - Control of cell division by proteolysis

Previous and current research

Cell proliferation depends on the duplication of chromosomes followed by the segregation of sister chromatids to opposite poles of the cell prior to cell division. The mechanisms coordinating these cell cycle events are key to the high fidelity with which genetic information is passed on from generation to generation. Mistakes in the control of these processes have disastrous consequences such as cancer and genetic diseases associated with abnormal karyotypes. We are interested in the basic mechanisms, which ensure that key cell cycle events occur in the right order. We use budding yeast as an experimental system taking advantage of the ease with which the yeast genome can be manipulated and the fact that the basic mechanisms of cell cycle control are evolutionary conserved from yeast to humans.
Early cell cycle events such as chromosome duplication and their subsequent attachment to the mitotic spindle are triggered by the activation of cyclin-dependent kinases whereas later events are largely controlled by ubiquitin-dependent proteolysis. Segregation of sister chromatids (anaphase) and cell division depend on the co-ordinated proteolysis of cell cycle regulators including anaphase inhibitors and mitotic cyclins. This proteolytic program is mediated by a multi-subunit particle, the anaphase-promoting complex or cyclosome (APC/C), which functions as a ubiquitin-protein ligase. We use biochemical and genetic approaches to unravel how APC/Cs activity is regulated during the cell cycle and what roles different APC/C components have in its catalytic mechanism.

Future prospects and goals

Our research plans include:

Reconstitution of the APC/C from recombinant its regulation
Analysing how the APC/C particle is assembled in the cell
Investigating the regulation of the APC/C by the mitotic checkpoint pathway, which ensures that the APC/C is only activated after all chromosomes have been captured by the mitotic spindle
Analysing the role of APC/C dependent proteolysis in meiosis
Identification and analysis of new regulatory pathways in mitosis

Selected publications

Zachariae, W., Shevchenko, A., Andrews, P. D., Galova, M., Stark, M. J., Mann, M. and Nasmyth, K. (1998): Mass spectrometric analysis of the anaphase-promoting complex from yeast: identification of a subunit related to cullins. Science 279, 1216-1219

Zachariae, W., Schwab, M., Nasmyth, K. and Seufert, W. (1998): Control of cylin ubiquitination by CDK-regulated binding of Hct1 to the anaphase promoting complex. Science 282, 1721-24

Zachariae, W., and Nasmyth, K. (1999): Whose end is destruction: cell division and the anaphase-promoting complex. Genes Dev., 13, 2039-2058

Camasses, A., Bogdanova, A., Shevchenko, A. and Zachariae, W. (2003): The CCT chaperonin promotes activation of the anaphase-promoting complex through the generation of functional Cdc20. Mol. Cell., 12, 87-100

Schwickart, M., Havlis, J., Habermann, B., Bogdanova, A., Camasses, A., Oelschlaegel, T., Shevchenko, A. and Zachariae, W. (2003): Swm1/Apc13 is an evolutionary conserved subunit of the anaphase-promoting complex stabilising the association of Cdc16 and Cdc27. Mol. Cell. Biol., 24, 3562-3576

Wolfgang Zachariae

1994: PhD at Heinrich-Heine University Düsseldorf

1994-1999: Postdoctoral fellow at the Institute of Molecular Pathology in Vienna

since 1999: Group Leader, Max Planck Institute of Molecular Cell Biology and Genetics, Dresden