UCSF

Proteolysis of cell cycle regulators is essential for transit through the cell cycle. Much of this proteolysis is mediated by a process called ubiquitination. Ubiquitination occurs via an enzyme cascade and culminates in the covalent attachment of ubiquitin moieties to a substrate molecule. Ubiquitin ligases are essential for ubiquitination and select the substrates for ubiquitination. An example of an Ubiquitin ligase involved in cell cycle control is the Anaphase Promoting Complex (APC). The APC is essential for the proteolysis of several distinct molecules at the transition from metaphase to anaphase. The destruction of these molecules initiates a series of events that result in the onset of anaphase. The APC is critical for cell cycle progression, and likely because of this evolution has created a myriad of ways to regulate its activity including; transcriptional regulation, proteolysis, localization, and post-translational modification. Work presented here discusses novel mechanisms for regulating the APC. The first chapter looks at how Cdc20 one of the APC's mitotic substrate adaptors is proteolysed during the cell cycle. This work shows that Cdc20 is turned over via an auto ubiquitination mechanism, and this mechanism is likely influenced by substrate concentration. Chapter 2 focuses on the DNA damage checkpoint and how it directly phosphorylates Apc1 a scaffolding subunit of the APC. Importantly work presented here suggests that this phosphorylation may inhibit APC activity during DNA damage helping to enforce the arrest in metaphase seen on DNA damage.