Abstract
Numerical centrosome aberrations underlie certain developmental abnormalities and may promote cancer. A cell maintains normal centrosome numbers by coupling centrosome duplication with segregation, which is achieved through sustained association of each centrosome with a mitotic spindle pole. Although the microcephaly- and primordial dwarfism-linked centrosomal protein CEP215 has been implicated in this process, the molecular mechanism responsible remains unclear. Here, using proteomic profiling, we identify the minus end-directed microtubule motor protein HSET as a direct binding partner of CEP215. Targeted deletion of the HSET-binding domain of CEP215 in vertebrate cells causes centrosome detachment and results in HSET depletion at centrosomes, a phenotype also observed in CEP215-deficient patient-derived cells. Moreover, in cancer cells with centrosome amplification, the CEP215–HSET complex promotes the clustering of extra centrosomes into pseudo-bipolar spindles, thereby ensuring viable cell division. Therefore, stabilization of the centrosome–spindle pole interface by the CEP215–HSET complex could promote survival of cancer cells containing supernumerary centrosomes.
Highlights
Numerical centrosome aberrations underlie certain developmental abnormalities and may promote cancer
We further show that cancer cells with centrosome amplification rely on the CEP215–HSET complex for centrosome clustering and survival
We found that depolymerization of actin in HSET knockout line (HSETKO) and CEP215DHBR cells by cytochalasin D reduced the incidence of centrosome detachment in both mutants (Supplementary Fig. 8b)
Summary
Numerical centrosome aberrations underlie certain developmental abnormalities and may promote cancer. HSET contributes to spindle elongation through crosslinking and sliding microtubules, functions dependent on its C-terminal motor domain and the additional microtubule-binding site in its N-terminal tail[15]. Both ncd and HSET have been implicated in survival of cells with centrosome amplification[16,17,18,19]. Deletion of centrosomin (cnn), its Drosophila orthologue, disruption of the CM1 domain of chicken CEP215 and depletion of CEP215 in HeLa cells all cause centrosome detachment from mitotic spindle poles[27,31,32]. We further show that cancer cells with centrosome amplification rely on the CEP215–HSET complex for centrosome clustering and survival
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