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Ubiquitin-driven cell cycle control
Adam Williamson '06, Graduate Student Researcher, University of California, Berkeley
Date: Monday, November 5th, 2012
Time: 3:30 pm
Duration: 1 hour
Location: Olin 141
Sponsored by: Biology
Contact: Lorie Tuma, x4884
Ubiquitylation, the attachment of the small protein ubiquitin to substrate proteins, is involved in nearly every aspect of cellular life, including protein trafficking, quality control, signaling, and cell cycle regulation. Mutations that affect ubiquitylation in these pathways have been linked to human diseases including neurodegeneration, developmental disorders, and cancer. In my seminar I will tell two stories that focus on the importance of ubiquitylation for cell cycle regulation.
Ubiquitylation is driven by an enzymatic cascade: E1, E2, and E3, which work together to form ubiquitin chains on substrate proteins. Ubiquitin chains are recognized by the 26S proteasome, which targets ubiquitin-modified proteins for degradation. Ubiquitin-dependent proteolysis of regulators is an effective way to drive cell cycle transitions since it is rapid and irreversible.
The first part of my seminar will focus on a well-studied enzyme, the Anaphase-Promoting Complex (APC). The human APC targets >100 proteins for degradation during mitosis, but must do so in an orderly fashion: some of its substrates must be degraded early for division to proceed, but other substrates must be present until cytokinesis to accomplish proper division. I will discuss how the APC balances its massive substrate workload with the necessity to order the ubiquitylation of its many substrates.
However, the cellular roles of most E3s are a mystery since we don't know their physiological substrates. In the second part of my talk I will discuss how I screened for E3 enzymes that are essential for proliferation under clinically relevant conditions and set up a method to determine their substrates. By coupling image-based screening with biochemical approaches I hope to uncover exciting new functions for ubiquitylation enzymes.