Abstract
How the cell rapidly and completely reorganizes its architecture when it divides is a problem that has fascinated researchers for almost 150 yr. We now know that the core regulatory machinery is highly conserved in eukaryotes, but how these multiple protein kinases, protein phosphatases, and ubiquitin ligases are coordinated in space and time to remodel the cell in a matter of minutes remains a major question. Cyclin B1-Cdk is the primary kinase that drives mitotic remodeling; here we show that it is targeted to the nuclear pore complex (NPC) by binding an acidic face of the kinetochore checkpoint protein, MAD1, where it coordinates NPC disassembly with kinetochore assembly. Localized cyclin B1-Cdk1 is needed for the proper release of MAD1 from the embrace of TPR at the nuclear pore so that it can be recruited to kinetochores before nuclear envelope breakdown to maintain genomic stability.
Highlights
IntroductionMajor mitotic kinase in almost all organisms studied to date, and Elucidating how cyclin B1-Cdk activity is directed to the the concomitant inhibition of its antagonistic PP2A-B55δ phos- right substrate at the right time as cells enter mitosis is essential phatase (Castilho et al, 2009; Gharbi-Ayachi et al, 2010; to understand how cells are remodeled because cyclin B1-Cdk is Mochida et al, 2010)
The rapid and complete reorganization of a cell at mitosis is one minimal consensus sequence recognized by Cdk1
Cyclin B1 binds to MAD1 through the acidic face of a helix encoded by exon 4 We sought to understand what controls the highly dynamic behavior of cyclin B1-Cdk1 complexes as the cell enters mitosis; in particular, how cyclin B1 is recruited to specific places in the cell at specific times
Summary
Major mitotic kinase in almost all organisms studied to date, and Elucidating how cyclin B1-Cdk activity is directed to the the concomitant inhibition of its antagonistic PP2A-B55δ phos- right substrate at the right time as cells enter mitosis is essential phatase (Castilho et al, 2009; Gharbi-Ayachi et al, 2010; to understand how cells are remodeled because cyclin B1-Cdk is Mochida et al, 2010). Together, these drive the cell to enter both the essential trigger and the “workhorse” of mitosis. As the level of cyclin B1-Cdk activity rises in the cell, it dence for its role as the trigger of mitosis is that mouse embryos triggers different events at different times (Gavet and Pines, with a genetic deletion of cyclin B1 (Brandeis et al, 1998) stop
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