BuGZ Is Required for Bub3 Stability, Bub1 Kinetochore Function, and Chromosome Alignment

Highlights•BuGZ is a kinetochore protein that binds to and stabilizes Bub3•BuGZ localizes to the kinetochore and binds to Bub3 through a conserved GLEBS domain•BuGZ depletion in transformed cells results in severe chromosome alignment defects•Inhibiting Bub3's GLEBS domain interactions may be a therapeutic strategy for GBMSummaryDuring mitosis, the spindle assembly checkpoint (SAC) monitors the attachment of kinetochores (KTs) to the plus ends of spindle microtubules (MTs) and prevents anaphase onset until chromosomes are aligned and KTs are under proper tension. Here, we identify a SAC component, BuGZ/ZNF207, from an RNAi viability screen in human glioblastoma multiforme (GBM) brain tumor stem cells. BuGZ binds to and stabilizes Bub3 during interphase and mitosis through a highly conserved GLE2p-binding sequence (GLEBS) domain. Inhibition of BuGZ results in loss of both Bub3 and its binding partner Bub1 from KTs, reduction of Bub1-dependent phosphorylation of centromeric histone H2A, attenuation of KT-based Aurora B kinase activity, and lethal chromosome congression defects in cancer cells. Phylogenetic analysis indicates that BuGZ orthologs are highly conserved among eukaryotes, but are conspicuously absent from budding and fission yeasts. These findings suggest that BuGZ has evolved to facilitate Bub3 activity and chromosome congression in higher eukaryotes.Graphical abstract