Date of Award

January 2016

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biochemistry

First Advisor

Mark C Hall

Committee Member 1

Xiaoqi Liu

Committee Member 2

Sandra Rossie

Committee Member 3

Clifford Weil

Abstract

Mitotic exit depends on the proper degradation of numerous cell cycle-regulated proteins, which is executed by an E3 ubiquitin ligase called the anaphase promoting complex (APC). APC adds polyubiquitin chains to numerous substrates, which leads to their subsequent degradation in late mitosis and G1 phase. The selective and timely recognition and degradation of APC substrates is essential for proper cell cycle progression and maintenance of genome stability. However, a key question is how APC specifically recognizes such a diversity of substrates. The activation of APC requires binding to one of its co-activators, Cdh1 or Cdc20. The co-activators directly facilitate APC enzymatic activity, but also contribute to the highly selective recognition of substrates via binding to degrons, such as the destruction box (D-box), KEN-box, and ABBA motif. However, not all substrates contain these degrons. Moreover, D- and KEN-box sequences are found in many proteins that are clearly not APC substrates, indicating that additional factors must contribute to recognition of these degrons.

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