Usp44^+/+ cells: Centrosomes separate in prophase to instruct the formation of a bipolar microtubule spindle apparatus. Chromosomes attach to microtubules of the mitotic spindle at their kinetochores. Unattached kinetochores create a diffusible mitotic checkpoint signal that culminates in the inhibition of the E3 ligase activity of APC^CDC20. At metaphase when all kinetochores are correctly attached to microtubules of the spindle, the mitotic checkpoint is turned off and APC^CDC20 ubiquitinates securin and cyclin B1 to target them for destruction by the 26S proteasome. Securin destruction promotes sister chromatid disjunction, while cyclin B1 destruction promotes mitotic exit. Usp44^–/– cells: Incomplete centrosome separation prior to nuclear envelope breakdown creates a spindle geometry that predisposes to the formation of improper kinetochore-microtubule interactions. The close positioning of the two centrosomes leads to an increase in the formation of merotelic kinetochore attachments (where a single kinetochore attaches to two different centrosomes) (14). These attachments persist into anaphase, resulting in lagging anaphase chromosomes and chromosome missegregation.