Cells reproduce by duplicating their genomes and other components and then distributing these components equally into two daughter cells. The carefully orchestrated series of events that leads to cell duplication and division is called the cell cycle. Cell-cycle events are timed and coordinated by a network of regulatory proteins called the cell-cycle control system.

Our research goal is a detailed biochemical understanding of the proteins that make up the cell-cycle control system. Much of our work has focused on the cyclin-dependent protein kinases (Cdks). These highly conserved enzymes are activated at specific cell cycle stages and are directly responsible for triggering major cell cycle events such as DNA replication and mitosis.

We use a variety of different model systems, including budding yeast and mammalian cells, to address fundamental questions in the control of cell division by Cdks and other regulatory molecules. Major projects in the lab include the following:

Targets of the Cdks: Little is known about the mechanisms by which Cdks trigger cell-cycle events. It is generally assumed that Cdks, like other protein kinases, exert their effects by phosphorylating target proteins, but few of these target proteins have been identified. We are using a novel 'chemical genetic' approach, conceived by our UCSF colleague Kevan Shokat, to search the yeast and vertebrate proteomes for Cdk substrates.

Exit from mitosis: We are exploring the regulatory mechanisms that complete the cell cycle in late mitosis. Much of this work focuses on a mysterious multi-subunit enzyme called the Anaphase-promoting complex (APC). The APC is a ubiquitin-protein ligase that catalyzes the attachment of the protein ubiquitin to substrate proteins, thereby targeting these substrates for destruction. In late mitosis, the APC triggers the proteolytic destruction of several cell-cycle regulators, including cyclins. We are interested in the biochemical reactions catalyzed by the APC and in the regulatory systems that control these reactions.