Astrin is required for the maintenance of sister chromatid cohesion and centrosome integrity

Thein, Kerstin; Kleylein-Sohn, Julia; Nigg, Erich A.; Grüneberg, Ulrike

doi:10.1083/jcb.200701163

Cited by 163 publications

(248 citation statements)

References 29 publications

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“…32 It turns out that separase also mediates timely centriole licensing. 31,[33][34][35] The cell utilizes separase's protease activity to cleave the tight intercentriolar linker to license duplication, thereby coupling centriole duplication mechanistically to the onset of sister-chromatid separation. 34,36 These data engendered the hypothesis that cohesin forms the tight intercentriolar linker.…”

Section: Excess Baggage: How Cancer Cells Acquire Extra Centrosomesmentioning

confidence: 99%

Let's huddle to prevent a muddle: centrosome declustering as an attractive anticancer strategy

2012

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Nearly a century ago, cell biologists postulated that the chromosomal aberrations blighting cancer cells might be caused by a mysterious organelle-the centrosome-that had only just been discovered. For years, however, this enigmatic structure was neglected in oncologic investigations and has only recently reemerged as a key suspect in tumorigenesis. A majority of cancer cells, unlike healthy cells, possess an amplified centrosome complement, which they manage to coalesce neatly at two spindle poles during mitosis. This clustering mechanism permits the cell to form a pseudo-bipolar mitotic spindle for segregation of sister chromatids. On rare occasions this mechanism fails, resulting in declustered centrosomes and the assembly of a multipolar spindle. Spindle multipolarity consigns the cell to an almost certain fate of mitotic arrest or death. The catastrophic nature of multipolarity has attracted efforts to develop drugs that can induce declustering in cancer cells. Such chemotherapeutics would theoretically spare healthy cells, whose normal centrosome complement should preclude multipolar spindle formation. In search of the 'Holy Grail' of nontoxic, cancer cell-selective, and superiorly efficacious chemotherapy, research is underway to elucidate the underpinnings of centrosome clustering mechanisms. Here, we detail the progress made towards that end, highlighting seminal work and suggesting directions for future research, aimed at demystifying this riddling cellular tactic and exploiting it for chemotherapeutic purposes. We also propose a model to highlight the integral role of microtubule dynamicity and the delicate balance of forces on which cancer cells rely for effective centrosome clustering. Finally, we provide insights regarding how perturbation of this balance may pave an inroad for inducing lethal centrosome dispersal and death selectively in cancer cells.

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Section: Excess Baggage: How Cancer Cells Acquire Extra Centrosomesmentioning

confidence: 99%

Let's huddle to prevent a muddle: centrosome declustering as an attractive anticancer strategy

2012

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“…Thus, the centrosome must form a strong structure that can withstand the spindle microtubule-based tensions during mitosis. The loss of centriole cohesion and PCM factors, such as astrin [4], Kizuna [5] and tastin [6], leads to centriole disengagement and PCM fragmentation. The collapse of the centrosome yields new MTOCs and multiple spindle poles.…”

Section: Introductionmentioning

confidence: 99%

Cep57, a NEDD1-binding pericentriolar material component, is essential for spindle pole integrity

Zhou

et al. 2012

Cell Res

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Formation of a bipolar spindle is indispensable for faithful chromosome segregation and cell division. Spindle integrity is largely dependent on the centrosome and the microtubule network. Centrosome protein Cep57 can bundle microtubules in mammalian cells. Its related protein (Cep57R) in Xenopus was characterized as a stabilization factor for microtubule-kinetochore attachment. Here we show that Cep57 is a pericentriolar material (PCM) component. Its interaction with NEDD1 is necessary for the centrosome localization of Cep57. Depletion of Cep57 leads to unaligned chromosomes and a multipolar spindle, which is induced by PCM fragmentation. In the absence of Cep57, centrosome microtubule array assembly activity is weakened, and the spindle length and microtubule density decrease. As a spindle microtubule-binding protein, Cep57 is also responsible for the proper organization of the spindle microtubule and localization of spindle pole focusing proteins. Collectively, these results suggest that Cep57, as a NEDD1-binding centrosome component, could function as a spindle pole-and microtubule-stabilizing factor for establishing robust spindle architecture.

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“…Although it is known that Astrin recruits the outer KT resident motor protein Cenp-E and its partner Cenp-F for stable MT-KT interactions (26), precisely how it is targeted to KTs is unclear. Here, we show that Astrin phosphorylation at Ser-135 and Ser-249 by Cdk1 is essential not only for bipolar spindle formation but also for targeting it to KTs.…”

mentioning

confidence: 99%

“…Recently, microtubule-associated proteins, such as Astrin and Ska1, have been implicated in stable MT-KT attachment (25)(26)(27). Astrin, which contains two coiled coil domains in its C terminus, is associated with spindle MTs as early as prophase and functions in centrosome integrity, spindle formation prior to metaphase chromosome alignment, and chromosome segregation (28,29).…”

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confidence: 99%

Phosphorylation of Astrin Regulates Its Kinetochore Function

Chung

Park

Lee

et al. 2016

Journal of Biological Chemistry

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The error-free segregation of chromosomes, which requires the precisely timed search and capture of chromosomes by spindles during early mitotic and meiotic cell division, is responsible for genomic stability and is achieved by the spindle assembly checkpoint in the metaphase-anaphase transition. Mitotic kinases orchestrate M phase events, such as the reorganization of cell architecture and kinetochore (KT) composition with the exquisite phosphorylation of mitotic regulators, to ensure timely and temporal progression. However, the molecular mechanisms underlying the changes of KT composition for stable spindle attachment during mitosis are poorly understood. Here, we show that the sequential action of the kinase Cdk1 and the phosphatase Cdc14A control spindle attachment to KTs. During prophase, the mitotic spindle protein Spag5/Astrin is transported into centrosomes by Kinastrin and phosphorylated at Ser-135 and Ser-249 by Cdk1, which, in prometaphase, is loaded onto the spindle and targeted to KTs. We also demonstrate that Cdc14A dephosphorylates Astrin, and therefore the overexpression of Cdc14A sequesters Astrin in the centrosome and results in aberrant chromosome alignment. Mechanistically, Plk1 acts as an upstream kinase for Astrin phosphorylation by Cdk1 and targeting phospho-Astrin to KTs, leading to the recruitment of outer KT components, such as Cenp-E, and the stable attachment of spindles to KTs. These comprehensive findings reveal a regulatory circuit for protein targeting to KTs that controls the KT composition change of stable spindle attachment and chromosome integrity.The maintenance of genome integrity during mitosis is crucial for cell survival and organismal development. To generate two daughter cells with identical genetic information, each sister chromatid must be captured by spindle microtubules (MTs), 4 aligned at the mitotic equator, and segregated toward the spindle poles. Cells build a proteinaceous structure, known as the KT, at the centromere and form a bipolar spindle with an amphitelic spindle attachment to achieve accurate chromosome segregation (1). The KT is made up of protein complexes that control its localization on the chromosome, assembly, attachment to spindle MTs, and chromosome movements, such as congression and segregation (2). KTs lacking essential proteins for KT-MT attachment, such as Knl1, Mis12, and Ndc80 protein subcomplexes, are unable to attach to spindle MTs (3), which in turn results in chromosome loss and concurrent cell death (4).Entry into mitosis is controlled by the concerted action of several mitotic kinases, such as Cyclin-dependent kinase 1 (Cdk1), Polo-like kinase 1 (Plk1), and Aurora A, whose activities are regulated indirectly in a positive feedback loop (5). Plk1 activates Cdk1 by phosphorylating and activating Cdc25, which then removes inhibitory phosphorylation at the Thr-14 and Tyr-15 sites of Cdk1. Aurora A phosphorylates Thr-210 in the active loop of Plk1 with the aid of Bora (6). Cdk1 also activates Plk1 via Bora phosphorylation to promote mit...

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Astrin is required for the maintenance of sister chromatid cohesion and centrosome integrity

Cited by 163 publications

References 29 publications

Let's huddle to prevent a muddle: centrosome declustering as an attractive anticancer strategy

Let's huddle to prevent a muddle: centrosome declustering as an attractive anticancer strategy

Cep57, a NEDD1-binding pericentriolar material component, is essential for spindle pole integrity

Phosphorylation of Astrin Regulates Its Kinetochore Function

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