'Braking' the cycle: Mechanism of cytokinesis inhibition by the E3 ubiquitin ligase Dma1

Abstract

Cell division requires proper coordination of chromosome segregation and cytokinesis. Mitotic checkpoints enforce proper coordination of these two events by stalling the core cell cycle machinery when unforeseen mistakes arise. This thesis aims to define the role of the fission yeast E3 ubiquitin ligase Dma1 in a mitotic checkpoint program that inhibits cytokinesis when chromosomes fail to separate. I found that Dma1 antagonizes the pro-cytokinesis factor Polo-like kinase Plo1 by ubiquitinating its mitotic scaffold Sid4. Sid4 ubiquitination impedes Plo1 recruitment to spindle-pole bodies (SPBs), where Plo1 activates a conserved signaling pathway called the septation initiation network (SIN) that triggers cytokinesis. I further show that Casein kinase I (CK1) recruits Dma1 to Sid4 when a checkpoint is stimulated and that Dma1 functions as an obligate dimer. Taken together, these studies reveal a novel signaling pathway that inhibits cytokinesis when cells encounter mitotic stress and contribute to our general understanding of cytokinesis regulation.