Proper chromosome segregation requires the attachment of sister kinetochores to microtubules from opposite spindle poles to form bi-oriented chromosomes on the metaphase spindle. The chromosome passenger complex containing Survivin and the kinase Aurora B regulates this process from the centromeres. We report that a de-ubiquitinating enzyme, hFAM, regulates chromosome alignment and segregation by controlling both the dynamic association of Survivin with centromeres and the proper targeting of Survivin and Aurora B to centromeres. Survivin is ubiquitinated in mitosis through both Lys 48 and Lys63 ubiquitin linkages. Lys63 de-ubiquitination mediated by hFAM is required for the dissociation of Survivin from centromeres, whereas Lys63 ubiquitination mediated by the ubiquitin binding protein Ufd1 is required for the association of survivin with centromeres. Thus, ubiquitination regulates dynamic protein-protein interactions and chromosome segregation independently of protein degradation.
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