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#spindle checkpoint

3 public questions tagged with this topic.

Cell Cycle Regulation

Which of the following prevents mitotic exit if chromosomes are not properly aligned?

Accurate mitosis demands anaphase initiation strictly after all chromosomes achieve stable amphitelic attachment generating tension. The spindle assembly checkpoint monitors this criterion. Unattached kinetochores catalyze assembly of Mitotic Checkpoint Complex composed of Mad2 locked as C-Mad2, BubR1 ortholog of yeast Mad3, Bub3 and Cdc20 coactivator of APC/C. Within MCC, BubR1 provides pseudosubstrate motif inserting KEN boxes into Cdc20 binding pockets plus direct inhibition of APC/C central cavity, thereby preventing ubiquitination of securin and cyclin B. BubR1 also functions as protein k

Ref: Musacchio, Spindle Assembly Checkpoint Structure of BubR1-MCC, Curr Biol 2015; NCBI Bookshelf, SAC component BubR1.

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Cell Cycle Regulation

What is the function of p31 comet in checkpoint silencing?

The spindle assembly checkpoint generates the Mitotic Checkpoint Complex containing closed Mad2, BubR1, Bub3 and Cdc20, which potently inhibits APC/C until all kinetochores attach. Checkpoint silencing requires active disassembly of this inhibitor once alignment completes. p31comet, also called MAD2L1BP and Trip13 adaptor, functions as dedicated MCC antagonist. Structurally mimicking Mad2, p31comet selectively binds the closed conformation of Mad2, termed C-Mad2, occupying the same interface that normally contacts BubR1 and therefore competitively extracting BubR1 from MCC. Together with AAA+

Ref: Alfieri et al., TRIP13-p31comet mechanism in MCC disassembly, Nature Communications 2018; Musacchio, SAC silencing, Curr Biol.

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Cell Cycle Regulation

Which protein complex silences the spindle checkpoint once all chromosomes are attached?

Silencing of spindle assembly checkpoint once all chromosomes achieve correct bi-orientation requires active disassembly of mitotic checkpoint complex and removal of checkpoint proteins from attached kinetochores. Central regulator is p31comet, also called MAD2L1BP, adaptor that binds closed conformation of Mad2 within MCC and recruits ATPase TRIP13 (Pch2 in yeast). TRIP13 uses ATP hydrolysis to convert closed Mad2 back to open inactive form, promoting disassociation of BubR1-Bub3-Cdc20 complex and freeing Cdc20 to activate APC/C. p31comet also competes with Mad1 for Mad2 binding, preventing n

Ref: Mapelli & Musacchio, EMBO J 2007, p31comet and TRIP13; Eytan et al., PNAS 2014, MCC Disassembly.

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