The classical X shape of mitotic human chromosomes is the consequence of two 
distinct waves of cohesin removal. First, during prophase and prometaphase, the 
bulk of cohesin is driven from chromosome arms by the cohesin antagonist WAPL. 
This arm-specific cohesin removal is referred to as the prophase pathway [1-4]. 
The subsequent cleavage of the remaining centromeric cohesin by Separase is 
known to be the trigger for anaphase onset [5-7]. Remarkably the biological 
purpose of the prophase pathway is unknown. We find that this pathway is 
essential for two key mitotic processes. First, it is important to focus Aurora 
B at centromeres to allow efficient correction of erroneous 
microtubule-kinetochore attachments. In addition, it is required to facilitate 
the timely decatenation of sister chromatids. As a consequence, WAPL-depleted 
cells undergo anaphase with segregation errors, including both lagging 
chromosomes and catenanes, resulting in micronuclei and DNA damage. Stable WAPL 
depletion arrests cells in a p53-dependent manner but causes p53-deficient cells 
to become highly aneuploid. Our data show that the WAPL-dependent prophase 
pathway is essential for proper chromosome segregation and is crucial to 
maintain genomic integrity.