Shugoshin Prevents Dissociation of Cohesin from Centromeres During Mitosis in Vertebrate Cells (original) (raw)
Figure 9
Model for Sgo1 Function during Mitosis
(A) During an unperturbed mitosis (Wild Type), arm cohesin (red circles) is removed in a kinase-dependent manner during prophase/prometaphase. Sgo1 protects centromeric cohesin (brown circles) until the metaphase-anaphase transition. Once all chromosomes have successfully bi-oriented on the metaphase plate, Mad2 inhibition of the APC/C is relieved, allowing separase activation. Separase in turn removes cohesin remaining at centromeres through cleavage of the α kleisin Scc1 subunit, allowing the cell to enter anaphase. In the absence of Sgo1 (Sgo1 Depletion), cohesin is removed from the chromosome arms and at the centromere during prophase/prometaphase before chromosomes have properly bi-oriented and been attached to their full complement of spindles. Thus, Mad2 activity continues to maintain the spindle checkpoint, causing cells to arrest for a prolonged period in a prometaphase-like state with separated sister chromatids. Expression of nonphosphorylatable Scc3-SA2 (Sgo1 Depletion + Cohesin containing SA2–12xA) prevents the prophase removal of cohesin both from arms and centromeres, thus allowing cells to proceed through an apparently normal anaphase even in the absence of Sgo1 activity.
(B) The phosphorylation state of cohesin may be the result of a dynamic balance in which Sgo1 somehow functions to antagonize the activity of mitotic kinases, including Plk1 and Aurora B and, potentially, other as-yet unidentified kinases (Kinase X, Y). In this model, when the direction of the reaction is artificially sent towards the hyperphosphorylated state (following Sgo1 knockdown), cohesin efficiently dissociates from chromatin; when the opposite state is favoured (e.g., as a result of Plk1 depletion) cohesin remains tightly associated with chromatin.