This proposal concerns the biochemical mechanisms regulated by the anaphase promoting complex (APC) and the role of protein degradation, mediated by APC from metaphase through the G1 of the next cell cycle. These mechanisms are central to our understanding of the fidelity of chromosome segregation and thus are important for understanding pathologies, such as cancer. As the regulatory machinery for the cell cycle becomes better characterized in all organisms, there is an increased urgency and opportunity to connect this regulatory machinery to the events that characterize the cell cycle, such as chromosome replication and segregation, cytokinesis, and decisions concerning differentiation and proliferation. Here we examine the detailed mechanisms of chromosome segregation and in particular the role of two proteins, securin and separin, which act downstream of APC. We ask how these function to carry out chromosome separation and how fidelity control mechanisms intervene. We also ask what other processes are controlled by APC during mitosis and G1 by examining the function of two recently identified substrates. We ask how APC recognizes substrates and temporally distinguishes among them. Finally we examine the diversity of APC regulators and begin to characterize the possible role of APC outside the cell cycle.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM039023-15
Application #
6327275
Study Section
Cell Development and Function Integrated Review Group (CDF)
Program Officer
Zatz, Marion M
Project Start
1993-09-01
Project End
2005-03-31
Budget Start
2001-04-01
Budget End
2002-03-31
Support Year
15
Fiscal Year
2001
Total Cost
$632,278
Indirect Cost
Name
Harvard University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
082359691
City
Boston
State
MA
Country
United States
Zip Code
02115
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Lee, Byung-Hoon; Lu, Ying; Prado, Miguel A et al. (2016) USP14 deubiquitinates proteasome-bound substrates that are ubiquitinated at multiple sites. Nature 532:398-401
Lu, Ying; Wang, Weiping; Kirschner, Marc W (2015) Specificity of the anaphase-promoting complex: a single-molecule study. Science 348:1248737
Lu, Ying; Lee, Byung-hoon; King, Randall W et al. (2015) Substrate degradation by the proteasome: a single-molecule kinetic analysis. Science 348:1250834
Wang, Weiping; Wu, Tao; Kirschner, Marc W (2014) The master cell cycle regulator APC-Cdc20 regulates ciliary length and disassembly of the primary cilium. Elife 3:e03083
Merbl, Yifat; Kirschner, Marc W (2014) Post-Translational Modification Profiling--a High-Content Assay for Identifying Protein Modifications in Mammalian Cellular Systems. Curr Protoc Protein Sci 77:27.8.1-13
Wan, Lixin; Tan, Mingjia; Yang, Jie et al. (2014) APC(Cdc20) suppresses apoptosis through targeting Bim for ubiquitination and destruction. Dev Cell 29:377-91
Zhao, Rui; Deibler, Richard W; Lerou, Paul H et al. (2014) A nontranscriptional role for Oct4 in the regulation of mitotic entry. Proc Natl Acad Sci U S A 111:15768-73
Thompson, Joel W; Nagel, Jane; Hoving, Sjouke et al. (2014) Quantitative Lys-?-Gly-Gly (diGly) proteomics coupled with inducible RNAi reveals ubiquitin-mediated proteolysis of DNA damage-inducible transcript 4 (DDIT4) by the E3 ligase HUWE1. J Biol Chem 289:28942-55
Fukushima, Hidefumi; Ogura, Kohei; Wan, Lixin et al. (2013) SCF-mediated Cdh1 degradation defines a negative feedback system that coordinates cell-cycle progression. Cell Rep 4:803-16

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