Two distinct pathways remove mammalian cohesin from chromosome arms in prophase and from centromeres in anaphase

In yeast, anaphase depends on cohesin cleavage. How anaphase is controlled in vertebrates is unknown because their cohesins dissociate from chromosome s before anaphase. We show that residual amounts of the cohesin SCC1 remain associated with human centromeres until the onset of anaphase when a simil arly small amount of SCC1 is cleaved. In Xenopus extracts, SCC1 cleavage de pends on the anaphase-promoting complex and separin. Separin immunoprecipit ates are sufficient to cleave SCC1, indicating that separin is associated w ith a protease activity. Separin activation coincides with securin destruct ion and partial separin cleavage, suggesting that several mechanisms regula te separin activity. We propose that in vertebrates, a cleavage-independent pathway removes cohesin from chromosome arms during prophase, whereas a se parin-dependent pathway cleaves centromeric cohesin at the metaphase-anapha se transition.