Regulation of Mitotic Checkpoint Complex by Anaphase-Promoting Complex/Cyclosome

Univ Of North Carolina Chapel Hill, Chapel Hill NC

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Abstract

ABSTRACT Understanding cell division is critical to understanding and treating cancer. The spindle assembly checkpoint (SAC) is a critical junction delaying aberrant mitosis to enable complete chromosome segregation and ensure proper mitotic progression. Activation of the SAC signaling pathway results in the inhibition of the 1.2 MDa ubiquitin ligase Anaphase-Promoting Complex/Cyclosome (APC) by the four-protein Mitotic Checkpoint Complex (MCC). However, the SAC barrier to cell division is deactivated by the poorly described MCC disassembly process once all sister chromatids achieve correct bipolar orientation. Dismantling MCC is an energy-dependent activity that requires the APC ubiquitination machinery, its associated proteins, and additional checkpoint-silencing factors. MCC ablation permits APC to trigger the ubiquitin-dependent proteasomal destruction of several key regulators of mitosis, such as Cyclin B and Securin, resulting in anaphase onset. As I pursue an independent research career examining how APC activity is modulated throughout the cell cycle, I will use a hybrid technological approach involving enzyme kinetics, crosslinking, electron microscopy, NMR, crystallography, and cell-based assays to dissect the biochemical (Aim 1) and structural (Aim 2) mechanisms of MCC disassembly by APC-mediated ubiquitination and other checkpoint termination factors. These results will have important implications for the fundamental understanding of cell cycle regulation and may enable the development of therapeutics for numerous cancers.