Timing of centrosome separation is important for accurate chromosome segregation

Silkworth, William T.; Nardi, Isaac K.; Paul, Raja; Mogilner, Alex; Cimini, Daniela

doi:10.1091/mbc.e11-02-0095

Cited by 148 publications

(162 citation statements)

References 59 publications

(99 reference statements)

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“…Cells containing too few or too many centrosomes exhibit transient anastral, mono-or multipolar spindles and frequent chromosome missegregation [53,61,62]. Chromosomal instability generates aneuploidy, which has a strong anti-proliferative effect owing to imbalanced gene expression [63].…”

Section: Centrosomes In Brain Developmentmentioning

confidence: 99%

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

Chavali

Pütz

Gergely

2014

Phil. Trans. R. Soc. B

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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Section: Centrosomes In Brain Developmentmentioning

confidence: 99%

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

Chavali

Pütz

Gergely

2014

Phil. Trans. R. Soc. B

140

111

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“…As the cell approaches mitosis, linker proteins are phosphorylated by the Plk1-Mst2-NIMArelated kinase 2 (NEK2) cascade (16,17), which in turn causes cleavage of Rootletin (14) and displacement of C-NAP1 from centrosomes (18). Interference with linker proteins or their phosphorylation has a drastic effect on cell division (19) and on genome integrity caused by chromosome segregation errors (20). Structural or numerical centrosomal abnormalities are linked to chromosomal instability, cancer progression, and various developmental diseases (7,21).…”

mentioning

confidence: 99%

Dishevelled is a NEK2 kinase substrate controlling dynamics of centrosomal linker proteins

Červenka

Valnohová

Bernatík

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Dishevelled (DVL) is a key scaffolding protein and a branching point in Wnt signaling pathways. Here, we present conclusive evidence that DVL regulates the centrosomal cycle. We demonstrate that DVL dishevelled and axin (DIX) domain, but not DIX domain-mediated multimerization, is essential for DVL's centrosomal localization. DVL accumulates during the cell cycle and associates with NIMA-related kinase 2 (NEK2), which is able to phosphorylate DVL at a multitude of residues, as detected by a set of novel phospho-specific antibodies. This creates interfaces for efficient binding to CDK5 regulatory subunitassociated protein 2 (CDK5RAP2) and centrosomal Nek2-associated protein 1 (C-NAP1), two proteins of the centrosomal linker. Displacement of DVL from the centrosome and its release into the cytoplasm on NEK2 phosphorylation is coupled to the removal of linker proteins, an event necessary for centrosomal separation and proper formation of the mitotic spindle. Lack of DVL prevents NEK2-controlled dissolution of loose centrosomal linker and subsequent centrosomal separation. Increased DVL levels, in contrast, sequester centrosomal NEK2 and mimic monopolar spindle defects induced by a dominant negative version of this kinase. Our study thus uncovers molecular crosstalk between centrosome and Wnt signaling.Wnt signaling | centrosome | Dishevelled | NEK2 | linker proteins

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“…Incomplete centrosome separation has recently been linked to merotelic attachment, the microtubule-kinetochore attachment defect that yields lagging chromosomes (25). Importantly, PLK1 is part of a signaling cascade that regulates centrosome separation (26).…”

Section: Discussionmentioning

confidence: 99%

Nuclear pore protein NUP88 activates anaphase-promoting complex to promote aneuploidy

Naylor¹,

Jeganathan²,

Cao³

et al. 2016

Journal of Clinical Investigation

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Timing of centrosome separation is important for accurate chromosome segregation

Cited by 148 publications

References 59 publications

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

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

Dishevelled is a NEK2 kinase substrate controlling dynamics of centrosomal linker proteins

Nuclear pore protein NUP88 activates anaphase-promoting complex to promote aneuploidy

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