Abstract
Faithful chromosome segregation requires proper chromosome congression at prometaphase and dynamic maintenance of the aligned chromosomes at metaphase. Chromosome missegregation can result in aneuploidy, birth defects and cancer. The kinetochore-bound KMN network and the kinesin motor CENP-E are critical for kinetochore-microtubule attachment and chromosome stability. The linear ubiquitin chain assembly complex (LUBAC) attaches linear ubiquitin chains to substrates, with well-established roles in immune response. Here, we identify LUBAC as a key player of chromosome alignment during mitosis. LUBAC catalyzes linear ubiquitination of the kinetochore motor CENP-E, which is specifically required for the localization of CENP-E at attached kinetochores, but not unattached ones. KNL1 acts as a receptor of linear ubiquitin chains to anchor CENP-E at attached kinetochores in prometaphase and metaphase. Thus, linear ubiquitination promotes chromosome congression and dynamic chromosome alignment by coupling the dynamic kinetochore microtubule receptor CENP-E to the static one, the KMN network.
Highlights
Faithful chromosome segregation requires proper chromosome congression at prometaphase and dynamic maintenance of the aligned chromosomes at metaphase
We explored the possible involvement of proteins containing ubiquitin-binding domains (UBD) in mitosis, because these proteins control diverse cellular functions by recognizing various types of ubiquitin signals[20]
We transfected HeLa cells with an arrayed small interfering RNA library targeting the genes encoding UBD-containing proteins[20] (Supplementary Fig. 1a), and used high-content microscopy to screen for proteins required for mitosis by determining the percentage of mitotic cells (Supplementary Fig. 1b). siRNAs that resulted in the increase by at least 1.5-fold of the average mitotic index (4.2%) were defined as candidate genes
Summary
Faithful chromosome segregation requires proper chromosome congression at prometaphase and dynamic maintenance of the aligned chromosomes at metaphase. LUBAC catalyzes linear ubiquitination of the kinetochore motor CENP-E, which is required for the localization of CENP-E at attached kinetochores, but not unattached ones. KNL1 acts as a receptor of linear ubiquitin chains to anchor CENP-E at attached kinetochores in prometaphase and metaphase. Linear ubiquitination promotes chromosome congression and dynamic chromosome alignment by coupling the dynamic kinetochore microtubule receptor CENP-E to the static one, the KMN network. LUBAC catalyzes the linear ubiquitination of the kinesin motor CENP-E to anchor it at attached kinetochores on mono-oriented or bi-oriented chromosomes, promoting full chromosome congression, dynamic chromosome alignment and accurate chromosome segregation. Linear ubiquitin chains constitute a critical mechanism for chromosome congression and alignment by coupling the dynamic kinetochore microtubule motor CENP-E to the static one, the KMN network. We reveal the role of linear ubiquitin chains in mitosis, and establish this non-degradation ubiquitination system as a safeguard of chromosome segregation
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