Abstract
Accurate chromosome segregation relies on bioriented amphitelic attachments of chromosomes to microtubules of the mitotic spindle, in which sister chromatids are connected to opposite spindle poles. BUB-1 is a protein of the Spindle Assembly Checkpoint (SAC) that coordinates chromosome attachment with anaphase onset. BUB-1 is also required for accurate sister chromatid segregation independently of its SAC function, but the underlying mechanism remains unclear. Here we show that, in Caenorhabditis elegans embryos, BUB-1 accelerates the establishment of non-merotelic end-on kinetochore-microtubule attachments by recruiting the RZZ complex and its downstream partner dynein-dynactin at the kinetochore. In parallel, BUB-1 limits attachment maturation by the SKA complex. This activity opposes kinetochore-microtubule attachment stabilisation promoted by CLS-2CLASP-dependent kinetochore-microtubule assembly. BUB-1 is therefore a SAC component that coordinates the function of multiple downstream kinetochore-associated proteins to ensure accurate chromosome segregation.
Highlights
During mitosis, the microtubule-based spindle segregates sister chromatids by attaching to the macromolecular kinetochores assembled on centromeres
We confirmed by immunofluorescence the absence of BUB-1 and HCP1CENP-F after RNAi-treatment in the Dhcp-2 strain (Figure 1—figure supplement 2F). These results suggest that BUB-1 prevents chromosome biorientation, and that this activity is revealed in absence of HCP-1/2CENP-F or CLS-2CLASP
We focused on the BUB-1DKD and BUB1K718R ;D847N mutants, which are incapable of inhibiting chromosome biorientation, while promoting proper initial end-on attachment through kinetochore recruitment of RZZ and dyneindynactin
Summary
The microtubule-based spindle segregates sister chromatids by attaching to the macromolecular kinetochores assembled on centromeres. As BUB1 contributes to recruiting the RZZ complex to kinetochores in human cells (Caldas et al, 2015; Zhang et al, 2015), kinetochore-localized dynein-dynactin may be required downstream of BUB1 for establishing amphitelic attachments. The loss of BUB1-dependent kinetochore targeting of the RZZ complex is not sufficient to account for the lethality of SAC-deficient haploid (HAP1) cells upon BUB1 depletion (Raaijmakers et al, 2018) These observations suggest that BUB1 contributes to chromosome biorientation and alignment through one or several additional downstream activities that remain to be identified. By analysing BUB-1 during mitosis in the C. elegans one-cell embryo or zygotes, we show that it has multiple functions essential for proper chromosome biorientation Coordination of these activities by BUB-1 is required to prevent merotely and embryonic lethality. We propose that BUB-1 is a key regulator of kinetochore-microtubule interactions that ensures accurate chromosome biorientation and segregation
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
