Reversible centriole depletion with an inhibitor of Polo-like kinase 4

Wong, Yao Liang; Anzola, John V.; Davis, Robert L.; Yoon, Michelle; Motamedi, Amir; Kroll, Ashley V.; Seo, Chanmee P.; Hsia, Judy E.; Kim, Sun K.; Mitchell, Jennifer W.; Mitchell, Brian J.; Desai, Arshad; Gahman, Timothy C.; Shiau, Andrew K.; Oegema, Karen

doi:10.1126/science.aaa5111

Cited by 404 publications

(653 citation statements)

References 60 publications

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“…Therefore, we aimed to uncouple increased ploidy from increased centrosome numbers, two main events occurring concomitantly with cytokinesis failure (Holland and Cleveland 2009). To this end, we used centrinone, a Polo-like-kinase 4 (PLK4) inhibitor, leading to centriole depletion by blocking their duplication during S phase (Wong et al 2015). A 24-h cotreatment of A549 or U2OS cells with an agent triggering cytokinesis failure plus centrinone led to a measurable loss of centrioles without impinging on centrosome abundance (note that the two centrosomes per cell failing cytokinesis comprise either two centrioles each or only one centriole, depending on the presence or absence of centrinone, as opposed to one centrosome for each control cell) ( Fig.…”

Section: The Piddosome Limits Polyploidization During Liver Organogenmentioning

confidence: 99%

“…The following drugs were used alone or in combination: 0.5 µM reversine (Enzo Life Sciences, BML-SC104), 100 nM nocodazole (Sigma-Aldrich, M1404), 100 nM taxol (Sigma-Aldrich, T7191), 100 ng/mL doxorubicin (Sigma-Aldrich, D1515), 2 μM ZM447439 (Selleck Chemicals, S1103), 4 μM DHCB (Sigma-Aldrich, D1641), 125 nM centrinone (Wong et al 2015), 2 mM thymidine (Sigma-Aldrich, T1895), 1 μg/mL doxocycline (SigmaAldrich, D9891), and 5 μM nutlin-3 (Sigma-Aldrich, N6287).…”

Section: Drug Treatments and Synchronization Proceduresmentioning

confidence: 99%

“…This apparent controversy suggests that the oncogenic potential of extra centrosomes may vary depending on context or cell type, but all studies agree that tissues retaining functional p53 are nonpermissive to propagate supernumerary centrosomes (Coelho et al 2015;Kulukian et al 2015;Vitre et al 2015;Serçin et al 2016). Perturbations of the centrosome duplication cycle lead to p53 stabilization and p53-dependent cell cycle arrest (Holland et al 2012;Lambrus et al 2015;Wong et al 2015). Of note, while centrosome depletion (or increased mitotic duration) activates p53 via 53BP1 and USP28 (Fong et al 2016;Lambrus et al 2016;Meitinger et al 2016), the molecular machinery activating p53 upon cytokinesis failure or forced generation of extra centrosomes is not understood.…”

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confidence: 99%

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The PIDDosome activates p53 in response to supernumerary centrosomes

et al. 2017

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Centrosomes, the main microtubule-organizing centers in animal cells, are replicated exactly once during the cell division cycle to form the poles of the mitotic spindle. Supernumerary centrosomes can lead to aberrant cell division and have been causally linked to chromosomal instability and cancer. Here, we report that an increase in the number of mature centrosomes, generated by disrupting cytokinesis or forcing centrosome overduplication, triggers the activation of the PIDDosome multiprotein complex, leading to Caspase-2-mediated MDM2 cleavage, p53 stabilization, and p21-dependent cell cycle arrest. This pathway also restrains the extent of developmentally scheduled polyploidization by regulating p53 levels in hepatocytes during liver organogenesis. Taken together, the PIDDosome acts as a first barrier, engaging p53 to halt the proliferation of cells carrying more than one mature centrosome to maintain genome integrity.

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Section: The Piddosome Limits Polyploidization During Liver Organogenmentioning

confidence: 99%

Section: Drug Treatments and Synchronization Proceduresmentioning

confidence: 99%

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The PIDDosome activates p53 in response to supernumerary centrosomes

et al. 2017

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“…Cell cycle defects in Cp110 −/− MEFs Impairment in centrosome biogenesis leads to defects at cell cycle checkpoints, which prevent cells with damaged DNA from replication (G1/S checkpoint) or entering mitosis (G2/M checkpoint) (Lambrus et al, 2015;Wong et al, 2015). The reported role of CP110 in centrosome duplication (Chen et al, 2002) led us to hypothesize a cell cycle progression defect during DNA replication and chromosome segregation at anaphase in Cp110 −/− MEFs.…”

Section: Abnormal Distribution Of Rab11mentioning

confidence: 99%

Centrosomal protein CP110 controls maturation of the mother centriole during cilia biogenesis

Yadav¹,

Sharma²,

Liu³

et al. 2016

Journal of Cell Science

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Defects in cilia centrosomal genes cause pleiotropic clinical phenotypes, collectively called ciliopathies. Cilia biogenesis is initiated by the interaction of positive and negative regulators. Centriolar coiled coil protein 110 (CP110) caps the distal end of the mother centriole and is known to act as a suppressor to control the timing of ciliogenesis. Here, we demonstrate that CP110 promotes cilia formation in vivo, in contrast to findings in cultured cells. Cp110 −/− mice die shortly after birth owing to organogenesis defects as in ciliopathies. Shh signaling is impaired in null embryos and primary cilia are reduced in multiple tissues. We show that CP110 is required for anchoring of basal bodies to the membrane during cilia formation. CP110 loss resulted in an abnormal distribution of core components of subdistal appendages (SDAs) and of recycling endosomes, which may be associated with premature extension of axonemal microtubules. Our data implicate CP110 in SDA assembly and ciliary vesicle docking, two requisite early steps in cilia formation. We suggest that CP110 has unique context-dependent functions, acting as both a suppressor and a promoter of ciliogenesis.

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“…In contrast, human cells can assemble a mitotic spindle even in the absence of centrosomes because of centrosome-independent MT formation and the presence of spindle assembly pathways. Recent studies have shown that the ability of human cells to tolerate loss of centrosomes or centrosome overduplication is reliant upon the inactivation of the p53 tumor suppressor gene that otherwise arrests these abnormal cells in G 1 phase (6,7). How cells sense centrosome number defects is currently not understood.…”

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confidence: 99%

Duplication of the Yeast Spindle Pole Body Once per Cell Cycle

Rüthnick

Schiebel

2016

Molecular and Cellular Biology

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bThe yeast spindle pole body (SPB) is the functional equivalent of the mammalian centrosome. Centrosomes and SPBs duplicate exactly once per cell cycle by mechanisms that use the mother structure as a platform for the assembly of the daughter. The conserved Sfi1 and centrin proteins are essential components of the SPB duplication process. Sfi1 is an elongated molecule that has, in its center, 20 to 23 binding sites for the Ca 2؉ -binding protein centrin. In the yeast Saccharomyces cerevisiae, all Sfi1 N termini are in contact with the mother SPB whereas the free C termini are distal to it. During S phase and early mitosis, cyclin-dependent kinase 1 (Cdk1) phosphorylation of mainly serine residues in the Sfi1 C termini blocks the initiation of SPB duplication ("off" state). Upon anaphase onset, the phosphatase Cdc14 dephosphorylates Sfi1 ("on" state) to promote antiparallel and shifted incorporation of cytoplasmic Sfi1 molecules into the half-bridge layer, which thereby elongates into the bridge. The Sfi1 C termini of the two Sfi1 layers localize in the bridge center, whereas the N termini of the newly assembled Sfi1 molecules are distal to the mother SPB. These free Sfi1 N termini then assemble the new SPB in G 1 phase. Recruitment of Sfi1 molecules into the anaphase SPB and bridge formation were also observed in Schizosaccharomyces pombe, suggesting that the Sfi1 bridge cycle is conserved between the two organisms. Thus, restricting SPB duplication to one event per cell cycle requires only an oscillation between Cdk1 kinase and Cdc14 phosphatase activities. This clockwork regulates the "on"/"off" state of the Sfi1-centrin receiver.T he mammalian centrosome and the yeast spindle pole body (SPB) are both able to nucleate microtubules (MTs) from tubulin subunits and are therefore collectively named MT organizing centers (MTOCs). A second common feature is the duplication of the centrosome and SPB just once during each cell division cycle. In each case, it is the mother centrosome or SPB that provides the platform for the assembly of the daughter (1-3).In yeast, the SPB is absolutely critical for mitotic spindle formation and chromosome segregation. This is because alternative MT assembly pathways, such as the RCC1/Ran-GTP-or augmindependent MT nucleation pathways, are absent from yeast (4, 5). In contrast, human cells can assemble a mitotic spindle even in the absence of centrosomes because of centrosome-independent MT formation and the presence of spindle assembly pathways. Recent studies have shown that the ability of human cells to tolerate loss of centrosomes or centrosome overduplication is reliant upon the inactivation of the p53 tumor suppressor gene that otherwise arrests these abnormal cells in G 1 phase (6, 7). How cells sense centrosome number defects is currently not understood. Yet it is becoming clearer why such a surveillance mechanism is important. Centrosome overamplification may contribute to cell transformation or enhance the aggressive nature of already transformed cells (8, 9). It is therefore...

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Reversible centriole depletion with an inhibitor of Polo-like kinase 4

Cited by 404 publications

References 60 publications

The PIDDosome activates p53 in response to supernumerary centrosomes

The PIDDosome activates p53 in response to supernumerary centrosomes

Centrosomal protein CP110 controls maturation of the mother centriole during cilia biogenesis

Duplication of the Yeast Spindle Pole Body Once per Cell Cycle

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