title: A CEP215-HSET complex links centrosomes with spindle poles and drives centrosome clustering in cancer.
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.
authors.affiliation: Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Robinson Way, Cambridge CB2 0RE, UK.
authors.forename: Pavithra L
authors.initials: PL
authors.lastname: Chavali
authors.affiliation: Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Robinson Way, Cambridge CB2 0RE, UK.
authors.forename: Gayathri
authors.initials: G
authors.lastname: Chandrasekaran
authors.affiliation: Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Robinson Way, Cambridge CB2 0RE, UK.
authors.forename: Alexis R
authors.initials: AR
authors.lastname: Barr
authors.affiliation: Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Robinson Way, Cambridge CB2 0RE, UK.
authors.forename: Péter
authors.initials: P
authors.lastname: Tátrai
authors.affiliation: Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Robinson Way, Cambridge CB2 0RE, UK.
authors.forename: Chris
authors.initials: C
authors.lastname: Taylor
authors.affiliation: Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Robinson Way, Cambridge CB2 0RE, UK.
authors.forename: Evaggelia K
authors.initials: EK
authors.lastname: Papachristou
authors.affiliation: Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Hills Road, Cambridge CB2 0XY, UK.
authors.forename: C Geoffrey
authors.initials: CG
authors.lastname: Woods
authors.affiliation: MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK.
authors.forename: Sreenivas
authors.initials: S
authors.lastname: Chavali
authors.affiliation: Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Robinson Way, Cambridge CB2 0RE, UK.
authors.forename: Fanni
authors.initials: F
authors.lastname: Gergely
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins; D002460:Cell Line; D018385:Centrosome / Q000378:metabolism*; D002645:Chickens; D016000:Cluster Analysis; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000378:metabolism*; D016547:Kinesins / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D009154:Mutation / Q000235:genetics; D009369:Neoplasms / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D060066:Protein Interaction Maps; D017434:Protein Structure, Tertiary; D064047:Spindle Poles / Q000378:metabolism*
chemical_list: C405929:CDK5RAP2 protein, human; D018797:Cell Cycle Proteins; D047908:Intracellular Signaling Peptides and Proteins; C486566:KIFC1 protein, human; D009419:Nerve Tissue Proteins; D016547:Kinesins