A primary microcephaly protein complex forms a ring around parental centrioles

Sir, Joo-Hee; Barr, Alexis R.; Nicholas, Adeline K.; Carvalho, Ofélia P.; Khurshid, Maryam; Sossick, Alex; Reichelt, Stefanie; D’Santos, Clive S.; Woods, C. Geoffrey; Gergely, Fanni

doi:10.1038/ng.971

Cited by 198 publications

(243 citation statements)

References 53 publications

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“…In these systems centrosome inactivation was consistently linked to impaired centrosomal MT-nucleation and the loss of centrosomal PCM components including c-tubulin and Cep63. In this current study, however, we failed to detect a loss of PCM components required for mitotic centrosome function and centrosomal spindle assembly in human cancer cells (Doxsey et al, 1994;Fong et al, 2008;Gomez-Ferreria et al, 2007;Graser et al, 2007;Haren et al, 2009;Sir et al, 2011;Smith et al, 2009;Zhu et al, 2008;Zimmerman et al, 2004). Instead, we consistently detected c-tubulin, Cep63, Pericentrin, Cep192 (the human ortholog of Drosophila SPD2) and Cep215 (the human ortholog of Drosophila centrosomin) at free mitotic centrosomes (Fig.…”

Section: Transient Detachment Of Individual Centrosomes From the Assementioning

confidence: 56%

Acentrosomal spindle organization renders cancer cells dependent on the kinesin HSET

Kleylein-Sohn

Pöllinger

Ohmer

et al. 2012

Journal of Cell Science

108

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SummaryCentrosomes represent the major microtubule organizing centers (MTOCs) of animal somatic cells and orchestrate bipolar spindle assembly during mitotic cell division. In meiotic cells, the kinesin HSET compensates for the lack of centrosomes by focusing acentrosomal MTOCs into two spindle poles. By clustering multiple centrosomes into two spindle poles, HSET also mediates bipolar mitosis in cancer cells with supernumerary centrosomes. However, although dispensable in non-transformed human cells, the role of HSET in cancer cells with two centrosomes has remained elusive. In this study, we demonstrate that HSET is required for proper spindle assembly, stable pole-focusing and survival of cancer cells irrespective of normal or supernumerary centrosome number. Strikingly, we detected pronounced acentrosomal MTOC structures in untreated mitotic cancer cells. While in most cancer cells these acentrosomal MTOCs were rapidly incorporated into the assembling bipolar spindle, some cells eventually established bipolar spindles with acentrosomal poles and free centrosomes. These observations demonstrate that acentrosomal MTOCs were functional and that both centrosomal and acentrosomal mechanisms were required for bipolar spindle organization. Our study shows that HSET is critical for clustering acentrosomal and centrosomal MTOCs during spindle formation in human cancer cells with two bona fide centrosomes. Furthermore, we show that in checkpoint-defective cancer cells, acentrosomal spindle formation and HSET-dependence are partially mediated by a constitutive activation of the DNA damage response. In summary, we propose that acentrosomal spindle assembly mechanisms are hyperactive in cancer cells and promote HSET, a key driver of acentrosomal spindle organization, as an attractive target for cancer therapy.

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Section: Transient Detachment Of Individual Centrosomes From the Assementioning

confidence: 56%

Acentrosomal spindle organization renders cancer cells dependent on the kinesin HSET

Kleylein-Sohn

Pöllinger

Ohmer

et al. 2012

Journal of Cell Science

108

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“…The depletion of PCM proteins cdk5rap2 or pericentrin, with the latter also genetically linked to primordial dwarfism with associated microcephaly, similarly altered neuroprogenitor division in embryonic mouse brains with reduced cell proliferation and enhanced cell cycle exit (Buchman et al, 2010;Lizarraga et al 2010). However, unlike MCPH proteins (cdk5rap2, CENPJ, STIL, Cep152, Cep135 and Cep63) with well characterized functions in centriole duplication (Barrera et al 2010;Delattre et al, 2004;Hatch et al, 2010;Hussain et al, 2012;Sir et al, 2011;Vulprecht et al, 2012), we have demonstrated that WDR62 is not principally a centrosome protein and its depletion did not obviously impact on centrosome number or structure during interphase. We cannot completely exclude WDR62 functions as an integral centrosomal protein.…”

Section: Discussionmentioning

confidence: 99%

WD40-repeat protein 62 is a JNK-phosphorylated spindle pole protein required for spindle maintenance and timely mitotic progression.

Bogoyevitch

Yeap

et al. 2012

Journal of Cell Science

120

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SummaryThe impact of aberrant centrosomes and/or spindles on asymmetric cell division in embryonic development indicates the tight regulation of bipolar spindle formation and positioning that is required for mitotic progression and cell fate determination. WD40-repeat protein 62 (WDR62) was recently identified as a spindle pole protein linked to the neurodevelopmental defect of microcephaly but its roles in mitosis have not been defined. We report here that the in utero electroporation of neuroprogenitor cells with WDR62 siRNAs induced their cell cycle exit and reduced their proliferative capacity. In cultured cells, we demonstrated cell-cycle-dependent accumulation of WDR62 at the spindle pole during mitotic entry that persisted until metaphase-anaphase transition. Utilizing siRNA depletion, we revealed WDR62 function in stabilizing the mitotic spindle specifically during metaphase. WDR62 loss resulted in spindle orientation defects, decreased the integrity of centrosomes displaced from the spindle pole and delayed mitotic progression. Additionally, we revealed JNK phosphorylation of WDR62 is required for maintaining metaphase spindle organization during mitosis. Our study provides the first functional characterization of WDR62 and has revealed requirements for JNK/WDR62 signaling in mitotic spindle regulation that may be involved in coordinating neurogenesis.

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“…It is thus possible that centrosomal PD proteins prevent centriole overduplication, for instance by promoting engagement between the mother centriole and its procentriole [38,103,104]. Recent studies suggest that ORC1 exercises centrosome copy number control by suppressing CDK2-cyclin E-dependent reduplication of centrioles, a function specifically disrupted by Meier-Gorlin mutations in ORC1 [91].…”

Section: Centrosomes and Body Size (A) Primordial Dwarfism Syndromesmentioning

confidence: 99%

Small organelle, big responsibility: the role of centrosomes in development and disease

Chavali

Pütz

Gergely

2014

Phil. Trans. R. Soc. B

Self Cite

140

111

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The centrosome, a key microtubule organizing centre, is composed of centrioles, embedded in a protein-rich matrix. Centrosomes control the internal spatial organization of somatic cells, and as such contribute to cell division, cell polarity and migration. Upon exiting the cell cycle, most cell types in the human body convert their centrioles into basal bodies, which drive the assembly of primary cilia, involved in sensing and signal transduction at the cell surface. Centrosomal genes are targeted by mutations in numerous human developmental disorders, ranging from diseases exclusively affecting brain development, through global growth failure syndromes to diverse pathologies associated with ciliary malfunction. Despite our much-improved understanding of centrosome function in cellular processes, we know remarkably little of its role in the organismal context, especially in mammals. In this review, we examine how centrosome dysfunction impacts on complex physiological processes and speculate on the challenges we face when applying knowledge generated from in vitro and in vivo model systems to human development.

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A primary microcephaly protein complex forms a ring around parental centrioles

Cited by 198 publications

References 53 publications

Acentrosomal spindle organization renders cancer cells dependent on the kinesin HSET

Acentrosomal spindle organization renders cancer cells dependent on the kinesin HSET

WD40-repeat protein 62 is a JNK-phosphorylated spindle pole protein required for spindle maintenance and timely mitotic progression.

Small organelle, big responsibility: the role of centrosomes in development and disease

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