Spatial-Temporal Regulation of Spindle Assembly Checkpoint

Abstract

During mitosis, microtubule spindle organized by the two spindle poles (SP) need to properly capture and align chromosomes at the cell equator to ensure faithful chromosome segregation. Improper chromosome-spindle attachment will activate spindle assembly checkpoint proteins (SAC) emanated from this chromosome. Active SAC prevents cyclin B degradation in the cytoplasm and, consequently halts the progression of mitosis. Only after the last chromosome gets properly attached can chromosome segregation begin. Given the tens of chromosomes and everlasting fluctuations in the cell, it remains murky how the silencing of SAC faithfully couples with the last chromosome attachment. We established a theoretical model that describes the mitotic spindle structure (chromosomes, mitotic spindles, and spindle poles) as a coherent transport system. Depending on whether the chromosome is properly attached, SAC and cyclin B circulate within the transport system via dyneins, and exchange with the cytoplasm in accordance to their well-known biochemical regulations. The basis of such coherent transport is the compartmentalization underlied by direct and/or indirect protein binding affinities with these mitotic structures. Our model results show that such transport system recapitulates the observed spatial-temporal pattern of SAC and cyclin B. More importantly, the transport system establishes a robust and sensitive mechanism for silencing SAC activity in accordance with the status of chromosome-spindle attachments.