Coordination of Chromosome Alignment and Mitotic Progression Chromosome-Based Ran Signal

Mitotic spindle assembly and chromosome segregation are controlled by the cell cycle machinery and by the guanosine triphosphatase Ran (RanGTPase). We developed a spatial model that allows us to simulate RanGTP production with different degrees of chromosome alignment in mitosis. Aided by this model, we defined three factors that modulate mitotic RanGTP gradients and mitotic progression in somatic cells. First, the concentration of RanGTPtransport-receptor (represented by RanGTP-importin β) and its spatial distribution are very sensitive to the level of RanBP1. Reduction of RanBP1 leads to an elevated RanGTP-transport receptor concentration throughout the cell, which disrupts spindle assembly and weakens spindle checkpoint control. Second, the completion of chromosome alignment at the metaphase plategenerates highest local RanGTP concentrations on chromosomes that could lead to spindle checkpoint silencing and metaphase-anaphase transition. Finally, chromosomal RanGTP production could be dampened by a reduction of RCC1 phosphorylation in mitosis. Our spatialsimulation of RanGTP production using individual chromosomes should provide means to further understand how the Ran system and the cell cycle machinery coordinately regulate mitosis.