Journal articles: 'Centriole to centrosome conversion'

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Fong, Chii Shyang, Kanako Ozaki, and Meng-Fu Bryan Tsou. "PPP1R35 ensures centriole homeostasis by promoting centriole-to-centrosome conversion." Molecular Biology of the Cell 29, no. 23 (November 15, 2018): 2801–8. http://dx.doi.org/10.1091/mbc.e18-08-0525.

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Centriole-to-centrosome conversion (CCC) safeguards centriole homeostasis by coupling centriole duplication with segregation, and is essential for stabilization of mature vertebrate centrioles naturally devoid of the geometric scaffold or the cartwheel. Here we identified PPP1R35, a putative regulator of the protein phosphatase PP1, as a novel centriolar protein required for CCC. We found that PPP1R35 is enriched at newborn daughter centrioles in S or G2 phase. In the absence of PPP1R35, centriole assembly initiates normally in S phase, but none of the nascent centrioles can form active centrosomes or recruit CEP295, an essential factor for CCC. Instead, all PPP1R35-null centrioles, although stable during their birth in interphase, become disintegrated after mitosis upon cartwheel removal. Surprisingly, we found that neither the centriolar localization nor the function of PPP1R35 in CCC requires the putative PP1-interacting motif. PPP1R35 is thus acting upstream of CEP295 to induce CCC for proper centriole maintenance.

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Fu, Jingyan, Zoltan Lipinszki, Hélène Rangone, Mingwei Min, Charlotte Mykura, Jennifer Chao-Chu, Sandra Schneider, et al. "Conserved molecular interactions in centriole-to-centrosome conversion." Nature Cell Biology 18, no. 1 (November 23, 2015): 87–99. http://dx.doi.org/10.1038/ncb3274.

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Wang, Won-Jing, Rajesh Kumar Soni, Kunihiro Uryu, and Meng-Fu Bryan Tsou. "The conversion of centrioles to centrosomes: essential coupling of duplication with segregation." Journal of Cell Biology 193, no. 4 (May 16, 2011): 727–39. http://dx.doi.org/10.1083/jcb.201101109.

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Centrioles are self-reproducing organelles that form the core structure of centrosomes or microtubule-organizing centers (MTOCs). However, whether duplication and MTOC organization reflect innate activities of centrioles or activities acquired conditionally is unclear. In this paper, we show that newly formed full-length centrioles had no inherent capacity to duplicate or to organize pericentriolar material (PCM) but acquired both after mitosis through a Plk1-dependent modification that occurred in early mitosis. Modified centrioles initiated PCM recruitment in G1 and segregated equally in mitosis through association with spindle poles. Conversely, unmodified centrioles segregated randomly unless passively tethered to modified centrioles. Strikingly, duplication occurred only in centrioles that were both modified and disengaged, whereas unmodified centrioles, engaged or not, were “infertile,” indicating that engagement specifically blocks modified centrioles from reduplication. These two requirements, centriole modification and disengagement, fully exclude unlimited duplication in one cell cycle. We thus uncovered a Plk1-dependent mechanism whereby duplication and segregation are coupled to maintain centriole homeostasis.

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Izquierdo, Denisse, Won-Jing Wang, Kunihiro Uryu, and Meng-Fu Bryan Tsou. "Stabilization of Cartwheel-less Centrioles for Duplication Requires CEP295-Mediated Centriole-to-Centrosome Conversion." Cell Reports 8, no. 4 (August 2014): 957–65. http://dx.doi.org/10.1016/j.celrep.2014.07.022.

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Kobayashi, Tetsuo, and Brian D. Dynlacht. "Regulating the transition from centriole to basal body." Journal of Cell Biology 193, no. 3 (May 2, 2011): 435–44. http://dx.doi.org/10.1083/jcb.201101005.

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The role of centrioles changes as a function of the cell cycle. Centrioles promote formation of spindle poles in mitosis and act as basal bodies to assemble primary cilia in interphase. Stringent regulations govern conversion between these two states. Although the molecular mechanisms have not been fully elucidated, recent findings have begun to shed light on pathways that regulate the conversion of centrioles to basal bodies and vice versa. Emerging studies also provide insights into how defects in the balance between centrosome and cilia function could promote ciliopathies and cancer.

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Lee, Kyung S., Jung-Eun Park, Jong Il Ahn, Zhuang Wei, and Liang Zhang. "A self-assembled cylindrical platform for Plk4-induced centriole biogenesis." Open Biology 10, no. 8 (August 2020): 200102. http://dx.doi.org/10.1098/rsob.200102.

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The centrosome, a unique membraneless multiprotein organelle, plays a pivotal role in various cellular processes that are critical for promoting cell proliferation. Faulty assembly or organization of the centrosome results in abnormal cell division, which leads to various human disorders including cancer, microcephaly and ciliopathy. Recent studies have provided new insights into the stepwise self-assembly of two pericentriolar scaffold proteins, Cep63 and Cep152, into a near-micrometre-scale higher-order structure whose architectural properties could be crucial for proper execution of its biological function. The construction of the scaffold architecture appears to be centrally required for tight control of a Ser/Thr kinase called Plk4, a key regulator of centriole duplication, which occurs precisely once per cell cycle. In this review, we will discuss a new paradigm for understanding how pericentrosomal scaffolds are self-organized into a new functional entity and how, on the resulting structural platform, Plk4 undergoes physico-chemical conversion to trigger centriole biogenesis.

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Marshall, Wallace F. "No centriole, no centrosome." Trends in Cell Biology 9, no. 3 (March 1999): 94. http://dx.doi.org/10.1016/s0962-8924(99)01520-2.

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Cizmecioglu, Onur, Marc Arnold, Ramona Bahtz, Florian Settele, Lena Ehret, Uta Haselmann-Weiß, Claude Antony, and Ingrid Hoffmann. "Cep152 acts as a scaffold for recruitment of Plk4 and CPAP to the centrosome." Journal of Cell Biology 191, no. 4 (November 8, 2010): 731–39. http://dx.doi.org/10.1083/jcb.201007107.

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Both gain and loss of function studies have identified the Polo-like kinase Plk4/Sak as a crucial regulator of centriole biogenesis, but the mechanisms governing centrosome duplication are incompletely understood. In this study, we show that the pericentriolar material protein, Cep152, interacts with the distinctive cryptic Polo-box of Plk4 via its N-terminal domain and is required for Plk4-induced centriole overduplication. Reduction of endogenous Cep152 levels results in a failure in centriole duplication, loss of centrioles, and formation of monopolar mitotic spindles. Interfering with Cep152 function prevents recruitment of Plk4 to the centrosome and promotes loss of CPAP, a protein required for the control of centriole length in Plk4-regulated centriole biogenesis. Our results suggest that Cep152 recruits Plk4 and CPAP to the centrosome to ensure a faithful centrosome duplication process.

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Loukil, Abdelhalim, Kati Tormanen, and Christine Sütterlin. "The daughter centriole controls ciliogenesis by regulating Neurl-4 localization at the centrosome." Journal of Cell Biology 216, no. 5 (April 6, 2017): 1287–300. http://dx.doi.org/10.1083/jcb.201608119.

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The two centrioles of the centrosome differ in age and function. Although the mother centriole mediates most centrosome-dependent processes, the role of the daughter remains poorly understood. A recent study has implicated the daughter centriole in centriole amplification in multiciliated cells, but its contribution to primary ciliogenesis is unclear. We found that manipulations that prevent daughter centriole formation or induce its separation from the mother abolish ciliogenesis. This defect was caused by stabilization of the negative ciliogenesis regulator CP110 and was corrected by CP110 depletion. CP110 dysregulation may be caused by effects on Neurl-4, a daughter centriole–associated ubiquitin ligase cofactor, which was required for ciliogenesis. Centrosome-targeted Neurl-4 was sufficient to restore ciliogenesis in cells with manipulated daughter centrioles. Interestingly, early during ciliogenesis, Neurl-4 transiently associated with the mother centriole in a process that required mother–daughter centriole proximity. Our data support a model in which the daughter centriole promotes ciliogenesis through Neurl-4–dependent regulation of CP110 levels at the mother centriole.

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Wu, Jun, Hyekyung P. Cho, David B. Rhee, Dabney K. Johnson, John Dunlap, Yie Liu, and Yisong Wang. "Cdc14B depletion leads to centriole amplification, and its overexpression prevents unscheduled centriole duplication." Journal of Cell Biology 181, no. 3 (May 5, 2008): 475–83. http://dx.doi.org/10.1083/jcb.200710127.

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Centrosome duplication is tightly controlled in coordination with DNA replication. The molecular mechanism of centrosome duplication remains unclear. Previous studies found that a fraction of human proline-directed phosphatase Cdc14B associates with centrosomes. However, Cdc14B's involvement in centrosome cycle control has never been explored. Here, we show that depletion of Cdc14B by RNA interference leads to centriole amplification in both HeLa and normal human fibroblast BJ and MRC-5 cells. Induction of Cdc14B expression through a regulatable promoter significantly attenuates centriole amplification in prolonged S phase–arrested cells and proteasome inhibitor Z-L3VS–treated cells. This inhibitory function requires centriole-associated Cdc14B catalytic activity. Together, these results suggest a potential function for Cdc14B phosphatase in maintaining the fidelity of centrosome duplication cycle.

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Mahen, Robert. "cNap1 bridges centriole contact sites to maintain centrosome cohesion." PLOS Biology 20, no. 10 (October 25, 2022): e3001854. http://dx.doi.org/10.1371/journal.pbio.3001854.

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Centrioles are non-membrane-bound organelles that participate in fundamental cellular processes through their ability to form physical contacts with other structures. During interphase, two mature centrioles can associate to form a single centrosome—a phenomenon known as centrosome cohesion. Centrosome cohesion is important for processes such as cell migration, and yet how it is maintained is unclear. Current models indicate that pericentriolar fibres termed rootlets, also known as the centrosome linker, entangle to maintain centriole proximity. Here, I uncover a centriole–centriole contact site and mechanism of centrosome cohesion based on coalescence of the proximal centriole component cNap1. Using live-cell imaging of endogenously tagged cNap1, I show that proximal centrioles form dynamic contacts in response to physical force from the cytoskeleton. Expansion microscopy reveals that cNap1 bridges between these contact sites, physically linking proximal centrioles on the nanoscale. Fluorescence correlation spectroscopy (FCS)-calibrated imaging shows that cNap1 accumulates at nearly micromolar concentrations on proximal centrioles, corresponding to a few hundred protein copy numbers. When ectopically tethered to organelles such as lysosomes, cNap1 forms viscous and cohesive assemblies that promote organelle spatial proximity. These results suggest a mechanism of centrosome cohesion by cNap1 at the proximal centriole and illustrate how a non-membrane-bound organelle forms organelle contact sites.

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Hori, Akiko, Christopher J. Peddie, Lucy M. Collinson, and Takashi Toda. "Centriolar satellite– and hMsd1/SSX2IP-dependent microtubule anchoring is critical for centriole assembly." Molecular Biology of the Cell 26, no. 11 (June 2015): 2005–19. http://dx.doi.org/10.1091/mbc.e14-11-1561.

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Centriolar satellites are numerous electron-dense granules dispersed around the centrosome. Mutations in their components are linked to various human diseases, but their molecular roles remain elusive. In particular, the significance of spatial communication between centriolar satellites and the centrosome is unknown. hMsd1/SSX2IP localizes to both the centrosome and centriolar satellites and is required for tethering microtubules to the centrosome. Here we show that hMsd1/SSX2IP-mediated microtubule anchoring is essential for proper centriole assembly and duplication. On hMsd1/SSX2IP knockdown, the centriolar satellites become stuck at the microtubule minus end near the centrosome. Intriguingly, these satellites contain many proteins that normally localize to the centrosome. Of importance, microtubule structures, albeit not being anchored properly, are still required for the emergence of abnormal satellites, as complete microtubule depolymerization results in the disappearance of these aggregates from the vicinity of the centrosome. We highlighted, using superresolution and electron microscopy, that under these conditions, centriole structures are faulty. Remarkably, these cells are insensitive to Plk4 overproduction–induced ectopic centriole formation, yet they accelerate centrosome reduplication upon hydroxyurea arrest. Finally, the appearance of satellite aggregates is cancer cell specific. Together our findings provide novel insights into the mechanism of centriole assembly and microtubule anchoring.

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Schatten, Heide, Vanesa Y. Rawe, and Qing-Yuan Sun. "The Sperm Centrosome: Its Role and Significance in Nature and Human Assisted Reproduction." Journal of Reproductive and Stem Cell Biotechnology 2, no. 2 (December 2011): 121–27. http://dx.doi.org/10.1177/205891581100200206.

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In humans and other non-rodent mammalian species, the sperm's centriole-centrosome complex is an essential component for successful fertilization and serves as template for all centrioles during subsequent cell divisions, embryo development, divisions of most adult somatic cells, as well as in primary cilia formation and functions. Dysfunctions of this complex can be causes for infertility, developmental disorders, and play a role in various adulthood diseases. While assisted reproductive technology (ART) has been able to overcome sperm motility dysfunctions by employing intracytoplasmic sperm injection (ICSI), we currently do not yet have therapies to overcome dysfunctions of the centriole-centrosome complex although several lines of investigations have addressed the causes for centriole-centrosome dysfunctions and implications for sperm aster formation and union of the parental genomes. The present review highlights the importance of the centriole-centrosome complex and its significance for fertilization and embryo development.

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Vidwans, Smruti J., Mei Lie Wong, and Patrick H. O'Farrell. "Mitotic Regulators Govern Progress through Steps in the Centrosome Duplication Cycle." Journal of Cell Biology 147, no. 7 (December 27, 1999): 1371–78. http://dx.doi.org/10.1083/jcb.147.7.1371.

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Centrosome duplication is marked by discrete changes in centriole structure that occur in lockstep with cell cycle transitions. We show that mitotic regulators govern steps in centriole replication in Drosophila embryos. Cdc25string, the expression of which initiates mitosis, is required for completion of daughter centriole assembly. Cdc20fizzy, which is required for the metaphase-anaphase transition, is required for timely disengagement of mother and daughter centrioles. Stabilization of mitotic cyclins, which prevents exit from mitosis, blocks assembly of new daughter centrioles. Common regulation of the nuclear and centrosome cycles by mitotic regulators may ensure precise duplication of the centrosome.

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Zou, Chaozhong, Jun Li, Yujie Bai, William T. Gunning, David E. Wazer, Vimla Band, and Qingshen Gao. "Centrobin." Journal of Cell Biology 171, no. 3 (November 7, 2005): 437–45. http://dx.doi.org/10.1083/jcb.200506185.

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In mammalian cells, the centrosome consists of a pair of centrioles and amorphous pericentriolar material. The pair of centrioles, which are the core components of the centrosome, duplicate once per cell cycle. Centrosomes play a pivotal role in orchestrating the formation of the bipolar spindle during mitosis. Recent studies have linked centrosomal activity on centrioles or centriole-associated structures to cytokinesis and cell cycle progression through G1 into the S phase. In this study, we have identified centrobin as a centriole-associated protein that asymmetrically localizes to the daughter centriole. The silencing of centrobin expression by small interfering RNA inhibited centriole duplication and resulted in centrosomes with one or no centriole, demonstrating that centrobin is required for centriole duplication. Furthermore, inhibition of centriole duplication by centrobin depletion led to impaired cytokinesis.

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Sillibourne, James E., Frederik Tack, Nele Vloemans, An Boeckx, Sathiesan Thambirajah, Pascal Bonnet, Frans C. S. Ramaekers, Michel Bornens, and Thierry Grand-Perret. "Autophosphorylation of Polo-like Kinase 4 and Its Role in Centriole Duplication." Molecular Biology of the Cell 21, no. 4 (February 15, 2010): 547–61. http://dx.doi.org/10.1091/mbc.e09-06-0505.

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Centrosome duplication occurs once every cell cycle in a strictly controlled manner. Polo-like kinase 4 (PLK4) is a key regulator of this process whose kinase activity is essential for centriole duplication. Here, we show that PLK4 autophosphorylation of serine S305 is a consequence of kinase activation and enables the active fraction to be identified in the cell. Active PLK4 is detectable on the replicating mother centriole in G1/S, with the proportion of active kinase increasing through interphase to reach a maximum in mitosis. Activation of PLK4 at the replicating daughter centriole is delayed until G2, but a level equivalent to the replicating mother centriole is achieved in M phase. Active PLK4 is regulated by the proteasome, because either proteasome inhibition or mutation of the degron motif of PLK4 results in the accumulation of S305-phosphorylated PLK4. Autophosphorylation probably plays a role in the process of centriole duplication, because mimicking S305 phosphorylation enhances the ability of overexpressed PLK4 to induce centriole amplification. Importantly, we show that S305-phosphorylated PLK4 is specifically sequestered at the centrosome contrary to the nonphosphorylated form. These data suggest that PLK4 activity is restricted to the centrosome to prevent aberrant centriole assembly and sustained kinase activity is required for centriole duplication.

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Schwarz, Anna, Prabhu Sankaralingam, Kevin O’Connell, and Thomas Müller-Reichert. "Revisiting Centrioles in Nematodes—Historic Findings and Current Topics." Cells 7, no. 8 (August 8, 2018): 101. http://dx.doi.org/10.3390/cells7080101.

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Theodor Boveri is considered as the “father” of centrosome biology. Boveri’s fundamental findings have laid the groundwork for decades of research on centrosomes. Here, we briefly review his early work on centrosomes and his first description of the centriole. Mainly focusing on centriole structure, duplication, and centriole assembly factors in C. elegans, we will highlight the role of this model in studying germ line centrosomes in nematodes. Last but not least, we will point to future directions of the C. elegans centrosome field.

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Uzbekov, R. E., D. B. Maurel, P. C. Aveline, S. Pallu, C. L. Benhamou, and G. Y. Rochefort. "Centrosome Fine Ultrastructure of the Osteocyte Mechanosensitive Primary Cilium." Microscopy and Microanalysis 18, no. 6 (November 21, 2012): 1430–41. http://dx.doi.org/10.1017/s1431927612013281.

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AbstractThe centrosome is the principal microtubule organization center in cells, giving rise to microtubule-based organelles (e.g., cilia, flagella). The aim was to study the osteocyte centrosome morphology at an ultrastructural level in relation to its mechanosensitive function. Osteocyte centrosomes and cilia in tibial cortical bone were explored by acetylated alpha-tubulin (AαTub) immunostaining under confocal microscopy. For the first time, fine ultrastructure and spatial orientation of the osteocyte centrosome were explored by transmission electron microscopy on serial ultrathin sections. AαTub-positive staining was observed in 94% of the osteocytes examined (222/236). The mother centriole formed a short primary cilium and was longer than the daughter centriole due to an intermediate zone between centriole and cilium. The proximal end of the mother centriole was connected with the surface of daughter centriole by striated rootlets. The mother centriole exhibited distal appendages that interacted with the cell membrane and formed a particular structure called “cilium membrane prolongation.” The primary cilium was mainly oriented perpendicular to the long axis of bone. Mother and daughter centrioles change their original mutual orientation during the osteocyte differentiation process. The short primary cilium is hypothesized as a novel type of fluid-sensing organelle in osteocytes.

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Rattner, J. B., and D. P. Bazett-Jones. "Electron spectroscopic imaging of the centrosome in cells of the Indian muntjac." Journal of Cell Science 91, no. 1 (September 1, 1988): 5–11. http://dx.doi.org/10.1242/jcs.91.1.5.

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Specific antibody labelling indicates that phosphoproteins are present at microtubule-organizing centres, including the centrosome. We have employed electron spectroscopic imaging techniques that permit high-resolution elemental analysis of thin sections of intact cells to investigate the precise distribution of phosphorus and therefore phosphoproteins at the centrosome of Indian muntjac cells. We report that these proteins are localized to both the pericentriolar matrix and the centriole. The matrix contains an abundance of phosphorus and is associated with microtubule elements. Within the mature centriole, major structures including the nine triplet blades and linking elements that connect adjacent blades are composed of phosphorylated proteins. In addition, phosphoproteins are abundant at the ends of the centriole, at the interface between the centriole lumen and the pericentriolar environment. From these observations we suggest that phosphoproteins may play both a structural and a functional role within the centrosome region.

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Hatch, Emily M., Anita Kulukian, Andrew J. Holland, Don W. Cleveland, and Tim Stearns. "Cep152 interacts with Plk4 and is required for centriole duplication." Journal of Cell Biology 191, no. 4 (November 8, 2010): 721–29. http://dx.doi.org/10.1083/jcb.201006049.

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Centrioles are microtubule-based structures that organize the centrosome and nucleate cilia. Centrioles duplicate once per cell cycle, and duplication requires Plk4, a member of the Polo-like kinase family; however, the mechanism linking Plk4 activity and centriole formation is unknown. In this study, we show in human and frog cells that Plk4 interacts with the centrosome protein Cep152, the orthologue of Drosophila melanogaster Asterless. The interaction requires the N-terminal 217 residues of Cep152 and the crypto Polo-box of Plk4. Cep152 and Plk4 colocalize at the centriole throughout the cell cycle. Overexpression of Cep152 (1–217) mislocalizes Plk4, but both Cep152 and Plk4 are able to localize to the centriole independently of the other. Depletion of Cep152 prevents both normal centriole duplication and Plk4-induced centriole amplification and results in a failure to localize Sas6 to the centriole, an early step in duplication. Cep152 can be phosphorylated by Plk4 in vitro, suggesting that Cep152 acts with Plk4 to initiate centriole formation.

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Ou, Young, Meifeng Zhang, and Jerome B. Rattner. "The centrosome: The centriole-PCM coalition." Cell Motility and the Cytoskeleton 57, no. 1 (2003): 1–7. http://dx.doi.org/10.1002/cm.10154.

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Ganapathi Sankaran, Divya, Alexander J. Stemm-Wolf, and Chad G. Pearson. "CEP135 isoform dysregulation promotes centrosome amplification in breast cancer cells." Molecular Biology of the Cell 30, no. 10 (May 2019): 1230–44. http://dx.doi.org/10.1091/mbc.e18-10-0674.

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The centrosome, composed of two centrioles surrounded by pericentriolar material, is the cell’s central microtubule-organizing center. Centrosome duplication is coupled with the cell cycle such that centrosomes duplicate once in S phase. Loss of such coupling produces supernumerary centrosomes, a condition called centrosome amplification (CA). CA promotes cell invasion and chromosome instability, two hallmarks of cancer. We examined the contribution of centriole overduplication to CA and the consequences for genomic stability in breast cancer cells. CEP135, a centriole assembly protein, is dysregulated in some breast cancers. We previously identified a short isoform of CEP135, CEP135mini, that represses centriole duplication. Here, we show that the relative level of full-length CEP135 (CEP135full) to CEP135mini (the CEP135full:mini ratio) is increased in breast cancer cell lines with high CA. Inducing expression of CEP135full in breast cancer cells increases the frequency of CA, multipolar spindles, anaphase-lagging chromosomes, and micronuclei. Conversely, inducing expression of CEP135mini reduces centrosome number. The differential expression of the CEP135 isoforms in vivo is generated by alternative polyadenylation. Directed genetic mutations near the CEP135mini alternative polyadenylation signal reduces the CEP135full:mini ratio and decreases CA. We conclude that dysregulation of CEP135 isoforms promotes centriole overduplication and contributes to chromosome segregation errors in breast cancer cells.

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Inanç, Burcu, Monika Pütz, Pierce Lalor, Peter Dockery, Ryoko Kuriyama, Fanni Gergely, and Ciaran G. Morrison. "Abnormal centrosomal structure and duplication in Cep135-deficient vertebrate cells." Molecular Biology of the Cell 24, no. 17 (September 2013): 2645–54. http://dx.doi.org/10.1091/mbc.e13-03-0149.

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Centrosomes are key microtubule-organizing centers that contain a pair of centrioles, conserved cylindrical, microtubule-based structures. Centrosome duplication occurs once per cell cycle and relies on templated centriole assembly. In many animal cells this process starts with the formation of a radially symmetrical cartwheel structure. The centrosomal protein Cep135 localizes to this cartwheel, but its role in vertebrates is not well understood. Here we examine the involvement of Cep135 in centriole function by disrupting the Cep135 gene in the DT40 chicken B-cell line. DT40 cells that lack Cep135 are viable and show no major defects in centrosome composition or function, although we note a small decrease in centriole numbers and a concomitant increase in the frequency of monopolar spindles. Furthermore, electron microscopy reveals an atypical structure in the lumen of Cep135-deficient centrioles. Centrosome amplification after hydroxyurea treatment increases significantly in Cep135-deficient cells, suggesting an inhibitory role for the protein in centrosome reduplication during S-phase delay. We propose that Cep135 is required for the structural integrity of centrioles in proliferating vertebrate cells, a role that also limits centrosome amplification in S-phase–arrested cells.

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Kodani, Andrew, Tyler Moyer, Allen Chen, Andrew Holland, Christopher A. Walsh, and Jeremy F. Reiter. "SFI1 promotes centriole duplication by recruiting USP9X to stabilize the microcephaly protein STIL." Journal of Cell Biology 218, no. 7 (June 13, 2019): 2185–97. http://dx.doi.org/10.1083/jcb.201803041.

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In mammals, centrioles participate in brain development, and human mutations affecting centriole duplication cause microcephaly. Here, we identify a role for the mammalian homologue of yeast SFI1, involved in the duplication of the yeast spindle pole body, as a critical regulator of centriole duplication in mammalian cells. Mammalian SFI1 interacts with USP9X, a deubiquitylase associated with human syndromic mental retardation. SFI1 localizes USP9X to the centrosome during S phase to deubiquitylate STIL, a critical regulator of centriole duplication. USP9X-mediated deubiquitylation protects STIL from degradation. Consistent with a role for USP9X in stabilizing STIL, cells from patients with USP9X loss-of-function mutations have reduced STIL levels. Together, these results demonstrate that SFI1 is a centrosomal protein that localizes USP9X to the centrosome to stabilize STIL and promote centriole duplication. We propose that the USP9X protection of STIL to facilitate centriole duplication underlies roles of both proteins in human neurodevelopment.

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Pimenta-Marques, A., I. Bento, C. A. M. Lopes, P. Duarte, S. C. Jana, and M. Bettencourt-Dias. "A mechanism for the elimination of the female gamete centrosome inDrosophila melanogaster." Science 353, no. 6294 (May 26, 2016): aaf4866. http://dx.doi.org/10.1126/science.aaf4866.

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An important feature of fertilization is the asymmetric inheritance of centrioles. In most species it is the sperm that contributes the initial centriole, which builds the first centrosome that is essential for early development. However, given that centrioles are thought to be exceptionally stable structures, the mechanism behind centriole disappearance in the female germ line remains elusive and paradoxical. We elucidated a program for centriole maintenance in fruit flies, led by Polo kinase and the pericentriolar matrix (PCM): The PCM is down-regulated in the female germ line during oogenesis, which results in centriole loss. Perturbing this program prevents centriole loss, leading to abnormal meiotic and mitotic divisions, and thus to female sterility. This mechanism challenges the view that centrioles are intrinsically stable structures and reveals general functions for Polo kinase and the PCM in centriole maintenance. We propose that regulation of this maintenance program is essential for successful sexual reproduction and defines centriole life span in different tissues in homeostasis and disease, thereby shaping the cytoskeleton.

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Dias Louro, Marco António, Mónica Bettencourt-Dias, and Claudia Bank. "Patterns of selection against centrosome amplification in human cell lines." PLOS Computational Biology 17, no. 5 (May 12, 2021): e1008765. http://dx.doi.org/10.1371/journal.pcbi.1008765.

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The presence of extra centrioles, termed centrosome amplification, is a hallmark of cancer. The distribution of centriole numbers within a cancer cell population appears to be at an equilibrium maintained by centriole overproduction and selection, reminiscent of mutation-selection balance. It is unknown to date if the interaction between centriole overproduction and selection can quantitatively explain the intra- and inter-population heterogeneity in centriole numbers. Here, we define mutation-selection-like models and employ a model selection approach to infer patterns of centriole overproduction and selection in a diverse panel of human cell lines. Surprisingly, we infer strong and uniform selection against any number of extra centrioles in most cell lines. Finally we assess the accuracy and precision of our inference method and find that it increases non-linearly as a function of the number of sampled cells. We discuss the biological implications of our results and how our methodology can inform future experiments.

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Bahe, Susanne, York-Dieter Stierhof, Christopher J. Wilkinson, Florian Leiss, and Erich A. Nigg. "Rootletin forms centriole-associated filaments and functions in centrosome cohesion." Journal of Cell Biology 171, no. 1 (October 3, 2005): 27–33. http://dx.doi.org/10.1083/jcb.200504107.

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After duplication of the centriole pair during S phase, the centrosome functions as a single microtubule-organizing center until the onset of mitosis, when the duplicated centrosomes separate for bipolar spindle formation. The mechanisms regulating centrosome cohesion and separation during the cell cycle are not well understood. In this study, we analyze the protein rootletin as a candidate centrosome linker component. As shown by immunoelectron microscopy, endogenous rootletin forms striking fibers emanating from the proximal ends of centrioles. Moreover, rootletin interacts with C-Nap1, a protein previously implicated in centrosome cohesion. Similar to C-Nap1, rootletin is phosphorylated by Nek2 kinase and is displaced from centrosomes at the onset of mitosis. Whereas the overexpression of rootletin results in the formation of extensive fibers, small interfering RNA–mediated depletion of either rootletin or C-Nap1 causes centrosome splitting, suggesting that both proteins contribute to maintaining centrosome cohesion. The ability of rootletin to form centriole-associated fibers suggests a dynamic model for centrosome cohesion based on entangling filaments rather than continuous polymeric linkers.

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Yaguchi, Kan, Takahiro Yamamoto, Ryo Matsui, Yuki Tsukada, Atsuko Shibanuma, Keiko Kamimura, Toshiaki Koda, and Ryota Uehara. "Uncoordinated centrosome cycle underlies the instability of non-diploid somatic cells in mammals." Journal of Cell Biology 217, no. 7 (April 30, 2018): 2463–83. http://dx.doi.org/10.1083/jcb.201701151.

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In animals, somatic cells are usually diploid and are unstable when haploid for unknown reasons. In this study, by comparing isogenic human cell lines with different ploidies, we found frequent centrosome loss specifically in the haploid state, which profoundly contributed to haploid instability through subsequent mitotic defects. We also found that the efficiency of centriole licensing and duplication changes proportionally to ploidy level, whereas that of DNA replication stays constant. This caused gradual loss or frequent overduplication of centrioles in haploid and tetraploid cells, respectively. Centriole licensing efficiency seemed to be modulated by astral microtubules, whose development scaled with ploidy level, and artificial enhancement of aster formation in haploid cells restored centriole licensing efficiency to diploid levels. The ploidy–centrosome link was observed in different mammalian cell types. We propose that incompatibility between the centrosome duplication and DNA replication cycles arising from different scaling properties of these bioprocesses upon ploidy changes underlies the instability of non-diploid somatic cells in mammals.

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Holland, Andrew J., Weijie Lan, Sherry Niessen, Heather Hoover, and Don W. Cleveland. "Polo-like kinase 4 kinase activity limits centrosome overduplication by autoregulating its own stability." Journal of Cell Biology 188, no. 2 (January 25, 2010): 191–98. http://dx.doi.org/10.1083/jcb.200911102.

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Accurate control of the number of centrosomes, the major microtubule-organizing centers of animal cells, is critical for the maintenance of genome integrity. Abnormalities in centrosome number can promote errors in spindle formation that lead to subsequent chromosome missegregation, and extra centrosomes are found in many cancers. Centrosomes are comprised of a pair of centrioles surrounded by amorphous pericentriolar material, and centrosome duplication is controlled by centriole replication. Polo-like kinase 4 (Plk4) plays a key role in initiating centriole duplication, and overexpression of Plk4 promotes centriole overduplication and the formation of extra centrosomes. Using chemical genetics, we show that kinase-active Plk4 is inherently unstable and targeted for degradation. Plk4 is shown to multiply self-phosphorylate within a 24–amino acid phosphodegron. Phosphorylation of multiple sites is required for Plk4 instability, indicating a requirement for a threshold level of Plk4 kinase activity to promote its own destruction. We propose that kinase-mediated, autoregulated instability of Plk4 self-limits Plk4 activity so as to prevent centrosome amplification.

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30

Fırat-Karalar, Elif Nur, and Tim Stearns. "The centriole duplication cycle." Philosophical Transactions of the Royal Society B: Biological Sciences 369, no. 1650 (September 5, 2014): 20130460. http://dx.doi.org/10.1098/rstb.2013.0460.

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Centrosomes are the main microtubule-organizing centre of animal cells and are important for many critical cellular and developmental processes from cell polarization to cell division. At the core of the centrosome are centrioles, which recruit pericentriolar material to form the centrosome and act as basal bodies to nucleate formation of cilia and flagella. Defects in centriole structure, function and number are associated with a variety of human diseases, including cancer, brain diseases and ciliopathies. In this review, we discuss recent advances in our understanding of how new centrioles are assembled and how centriole number is controlled. We propose a general model for centriole duplication control in which cooperative binding of duplication factors defines a centriole ‘origin of duplication’ that initiates duplication, and passage through mitosis effects changes that license the centriole for a new round of duplication in the next cell cycle. We also focus on variations on the general theme in which many centrioles are created in a single cell cycle, including the specialized structures associated with these variations, the deuterosome in animal cells and the blepharoplast in lower plant cells.

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31

Inanç, Burcu, Helen Dodson, and Ciaran G. Morrison. "A Centrosome-autonomous Signal That Involves Centriole Disengagement Permits Centrosome Duplication in G2 Phase after DNA Damage." Molecular Biology of the Cell 21, no. 22 (November 15, 2010): 3866–77. http://dx.doi.org/10.1091/mbc.e10-02-0124.

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DNA damage can induce centrosome overduplication in a manner that requires G2-to-M checkpoint function, suggesting that genotoxic stress can decouple the centrosome and chromosome cycles. How this happens is unclear. Using live-cell imaging of cells that express fluorescently tagged NEDD1/GCP-WD and proliferating cell nuclear antigen, we found that ionizing radiation (IR)-induced centrosome amplification can occur outside S phase. Analysis of synchronized populations showed that significantly more centrosome amplification occurred after irradiation of G2-enriched populations compared with G1-enriched or asynchronous cells, consistent with G2 phase centrosome amplification. Irradiated and control populations of G2 cells were then fused to test whether centrosome overduplication is allowed through a diffusible stimulatory signal, or the loss of a duplication-inhibiting signal. Irradiated G2/irradiated G2 cell fusions showed significantly higher centrosome amplification levels than irradiated G2/unirradiated G2 fusions. Chicken–human cell fusions demonstrated that centrosome amplification was limited to the irradiated partner. Our finding that only the irradiated centrosome can duplicate supports a model where a centrosome-autonomous inhibitory signal is lost upon irradiation of G2 cells. We observed centriole disengagement after irradiation. Although overexpression of dominant-negative securin did not affect IR-induced centrosome amplification, Plk1 inhibition reduced radiation-induced amplification. Together, our data support centriole disengagement as a licensing signal for DNA damage-induced centrosome amplification.

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Hoffmann, Ingrid. "Role of Polo-like Kinases Plk1 and Plk4 in the Initiation of Centriole Duplication—Impact on Cancer." Cells 11, no. 5 (February 24, 2022): 786. http://dx.doi.org/10.3390/cells11050786.

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Centrosomes nucleate and anchor microtubules and therefore play major roles in spindle formation and chromosome segregation during mitosis. Duplication of the centrosome occurs, similar to DNA, only once during the cell cycle. Aberration of the centrosome number is common in human tumors. At the core of centriole duplication is the conserved polo-like kinase 4, Plk4, and two structural proteins, STIL and Sas-6. In this review, I summarize and discuss developments in our understanding of the first steps of centriole duplication and their regulation.

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33

Vaughan, Sue, and Helen R. Dawe. "Common themes in centriole and centrosome movements." Trends in Cell Biology 21, no. 1 (January 2011): 57–66. http://dx.doi.org/10.1016/j.tcb.2010.09.004.

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34

Ross, L., and B. B. Normark. "Evolutionary problems in centrosome and centriole biology." Journal of Evolutionary Biology 28, no. 5 (May 2015): 995–1004. http://dx.doi.org/10.1111/jeb.12620.

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Korzeniewski, Nina, Rolando Cuevas, Anette Duensing, and Stefan Duensing. "Daughter Centriole Elongation Is Controlled by Proteolysis." Molecular Biology of the Cell 21, no. 22 (November 15, 2010): 3942–51. http://dx.doi.org/10.1091/mbc.e09-12-1049.

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The centrosome is the major microtubule-organizing center of most mammalian cells and consists of a pair of centrioles embedded in pericentriolar material. Before mitosis, the two centrioles duplicate and two new daughter centrioles form adjacent to each preexisting maternal centriole. After initiation of daughter centriole synthesis, the procentrioles elongate in a process that is poorly understood. Here, we show that inhibition of cellular proteolysis by Z-L3VS or MG132 induces abnormal elongation of daughter centrioles to approximately 4 times their normal length. This activity of Z-L3VS or MG132 was found to correlate with inhibition of intracellular protease-mediated substrate cleavage. Using a small interfering RNA screen, we identified a total of nine gene products that either attenuated (seven) or promoted (two) abnormal Z-L3VS–induced daughter centriole elongation. Our hits included known regulators of centriole length, including CPAP and CP110, but, interestingly, several proteins involved in microtubule stability and anchoring as well as centrosome cohesion. This suggests that nonproteasomal functions, specifically inhibition of cellular proteases, may play an important and underappreciated role in the regulation of centriole elongation. They also highlight the complexity of daughter centriole length control and provide a framework for future studies to dissect the molecular details of this process.

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36

Callaini, G., and M. G. Riparbelli. "Centriole and centrosome cycle in the early Drosophila embryo." Journal of Cell Science 97, no. 3 (November 1, 1990): 539–43. http://dx.doi.org/10.1242/jcs.97.3.539.

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Centriole and centrosome cycles were examined by indirect immunofluorescence and electron microscopy techniques in the early Drosophila embryo. The centrosomes, which are already divided at interphase, appear as compact spheres during prophase and metaphase, expand and flatten from anaphase to telophase and split into two units in late telophase. Centriole separation starts in late metaphase, becomes evident in anaphase and increases during telophase. Procentrioles appear during the following interphase.

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37

Sala, Roberta, KC Farrell, and Tim Stearns. "Growth disadvantage associated with centrosome amplification drives population-level centriole number homeostasis." Molecular Biology of the Cell 31, no. 24 (November 15, 2020): 2646–56. http://dx.doi.org/10.1091/mbc.e19-04-0195.

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The centriole duplication cycle normally maintains number at two centrioles per G1 cell. However, some circumstances can result in an aberrant increase in centriole number. Cells with extra centrioles display extended cell cycle arrest, longer interphase durations, and death, which result in a proliferative disadvantage relative to normal cells.

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38

Patel, Hetal, and Myrtle Y. Gordon. "Abnormal centrosome-centriole cycle in chronic myeloid leukaemia?" British Journal of Haematology 146, no. 4 (August 2009): 408–17. http://dx.doi.org/10.1111/j.1365-2141.2009.07772.x.

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39

Saladino, Chiara, Emer Bourke, Pauline C. Conroy, and Ciaran G. Morrison. "Centriole separation in DNA damage-induced centrosome amplification." Environmental and Molecular Mutagenesis 50, no. 8 (October 2009): 725–32. http://dx.doi.org/10.1002/em.20477.

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40

Mahjoub, Moe R., Zhigang Xie, and Tim Stearns. "Cep120 is asymmetrically localized to the daughter centriole and is essential for centriole assembly." Journal of Cell Biology 191, no. 2 (October 18, 2010): 331–46. http://dx.doi.org/10.1083/jcb.201003009.

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Centrioles form the core of the centrosome in animal cells and function as basal bodies that nucleate and anchor cilia at the plasma membrane. In this paper, we report that Cep120 (Ccdc100), a protein previously shown to be involved in maintaining the neural progenitor pool in mouse brain, is associated with centriole structure and function. Cep120 is up-regulated sevenfold during differentiation of mouse tracheal epithelial cells (MTECs) and localizes to basal bodies. Cep120 localizes preferentially to the daughter centriole in cycling cells, and this asymmetry between mother and daughter centrioles is relieved coincident with new centriole assembly. Photobleaching recovery analysis identifies two pools of Cep120, differing in their halftime at the centriole. We find that Cep120 is required for centriole duplication in cycling cells, centriole amplification in MTECs, and centriole overduplication in S phase–arrested cells. We propose that Cep120 is required for centriole assembly and that the observed defect in neuronal migration might derive from a defect in this process.

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41

Brownlee, Christopher W., Joey E. Klebba, Daniel W. Buster, and Gregory C. Rogers. "The Protein Phosphatase 2A regulatory subunit Twins stabilizes Plk4 to induce centriole amplification." Journal of Cell Biology 195, no. 2 (October 10, 2011): 231–43. http://dx.doi.org/10.1083/jcb.201107086.

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Centriole duplication is a tightly regulated process that must occur only once per cell cycle; otherwise, supernumerary centrioles can induce aneuploidy and tumorigenesis. Plk4 (Polo-like kinase 4) activity initiates centriole duplication and is regulated by ubiquitin-mediated proteolysis. Throughout interphase, Plk4 autophosphorylation triggers its degradation, thus preventing centriole amplification. However, Plk4 activity is required during mitosis for proper centriole duplication, but the mechanism stabilizing mitotic Plk4 is unknown. In this paper, we show that PP2A (Protein Phosphatase 2ATwins) counteracts Plk4 autophosphorylation, thus stabilizing Plk4 and promoting centriole duplication. Like Plk4, the protein level of PP2A’s regulatory subunit, Twins (Tws), peaks during mitosis and is required for centriole duplication. However, untimely Tws expression stabilizes Plk4 inappropriately, inducing centriole amplification. Paradoxically, expression of tumor-promoting simian virus 40 small tumor antigen (ST), a reported PP2A inhibitor, promotes centrosome amplification by an unknown mechanism. We demonstrate that ST actually mimics Tws function in stabilizing Plk4 and inducing centriole amplification.

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42

Haren, Laurence, Marie-Hélène Remy, Ingrid Bazin, Isabelle Callebaut, Michel Wright, and Andreas Merdes. "NEDD1-dependent recruitment of the γ-tubulin ring complex to the centrosome is necessary for centriole duplication and spindle assembly." Journal of Cell Biology 172, no. 4 (February 6, 2006): 505–15. http://dx.doi.org/10.1083/jcb.200510028.

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The centrosome is the major microtubule organizing structure in somatic cells. Centrosomal microtubule nucleation depends on the protein γ-tubulin. In mammals, γ-tubulin associates with additional proteins into a large complex, the γ-tubulin ring complex (γTuRC). We characterize NEDD1, a centrosomal protein that associates with γTuRCs. We show that the majority of γTuRCs assemble even after NEDD1 depletion but require NEDD1 for centrosomal targeting. In contrast, NEDD1 can target to the centrosome in the absence of γ-tubulin. NEDD1-depleted cells show defects in centrosomal microtubule nucleation and form aberrant mitotic spindles with poorly separated poles. Similar spindle defects are obtained by overexpression of a fusion protein of GFP tagged to the carboxy-terminal half of NEDD1, which mediates binding to γTuRCs. Further, we show that depletion of NEDD1 inhibits centriole duplication, as does depletion of γ-tubulin. Our data suggest that centriole duplication requires NEDD1-dependent recruitment of γ-tubulin to the centrosome.

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Galletta, Brian J., Katherine C. Jacobs, Carey J. Fagerstrom, and Nasser M. Rusan. "Asterless is required for centriole length control and sperm development." Journal of Cell Biology 213, no. 4 (May 16, 2016): 435–50. http://dx.doi.org/10.1083/jcb.201501120.

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Centrioles are the foundation of two organelles, centrosomes and cilia. Centriole numbers and functions are tightly controlled, and mutations in centriole proteins are linked to a variety of diseases, including microcephaly. Loss of the centriole protein Asterless (Asl), the Drosophila melanogaster orthologue of Cep152, prevents centriole duplication, which has limited the study of its nonduplication functions. Here, we identify populations of cells with Asl-free centrioles in developing Drosophila tissues, allowing us to assess its duplication-independent function. We show a role for Asl in controlling centriole length in germline and somatic tissue, functioning via the centriole protein Cep97. We also find that Asl is not essential for pericentriolar material recruitment or centrosome function in organizing mitotic spindles. Lastly, we show that Asl is required for proper basal body function and spermatid axoneme formation. Insights into the role of Asl/Cep152 beyond centriole duplication could help shed light on how Cep152 mutations lead to the development of microcephaly.

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Flanagan, Anne-Marie, Elena Stavenschi, Shivakumar Basavaraju, David Gaboriau, David A. Hoey, and Ciaran G. Morrison. "Centriole splitting caused by loss of the centrosomal linker protein C-NAP1 reduces centriolar satellite density and impedes centrosome amplification." Molecular Biology of the Cell 28, no. 6 (March 15, 2017): 736–45. http://dx.doi.org/10.1091/mbc.e16-05-0325.

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Duplication of the centrosomes is a tightly regulated process. Abnormal centrosome numbers can impair cell division and cause changes in how cells migrate. Duplicated centrosomes are held together by a proteinaceous linker made up of rootletin filaments anchored to the centrioles by C-NAP1. This linker is removed in a NEK2A kinase-dependent manner as mitosis begins. To explore C-NAP1 activities in regulating centrosome activities, we used genome editing to ablate it. C-NAP1–null cells were viable and had an increased frequency of premature centriole separation, accompanied by reduced density of the centriolar satellites, with reexpression of C-NAP1 rescuing both phenotypes. We found that the primary cilium, a signaling structure that arises from the mother centriole docked to the cell membrane, was intact in the absence of C-NAP1, although components of the ciliary rootlet were aberrantly localized away from the base of the cilium. C-NAP1–deficient cells were capable of signaling through the cilium, as determined by gene expression analysis after fluid flow–induced shear stress and the relocalization of components of the Hedgehog pathway. Centrosome amplification induced by DNA damage or by PLK4 or CDK2 overexpression was markedly reduced in the absence of C-NAP1. We conclude that centriole splitting reduces the local density of key centriolar precursors to impede overduplication.

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Guo, Jing, Zhenye Yang, Wei Song, Qi Chen, Fubin Wang, Qiangge Zhang, and Xueliang Zhu. "Nudel Contributes to Microtubule Anchoring at the Mother Centriole and Is Involved in Both Dynein-dependent and -independent Centrosomal Protein Assembly." Molecular Biology of the Cell 17, no. 2 (February 2006): 680–89. http://dx.doi.org/10.1091/mbc.e05-04-0360.

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The centrosome is the major microtubule-organizing center in animal cells. Although the cytoplasmic dynein regulator Nudel interacts with centrosomes, its role herein remains unclear. Here, we show that in Cos7 cells Nudel is a mother centriole protein with rapid turnover independent of dynein activity. During centriole duplication, Nudel targets to the new mother centriole later than ninein but earlier than dynactin. Its centrosome localization requires a C-terminal region that is essential for associations with dynein, dynactin, pericentriolar material (PCM)-1, pericentrin, and γ-tubulin. Overexpression of a mutant Nudel lacking this region, a treatment previously shown to inactivate dynein, dislocates centrosomal Lis1, dynactin, and PCM-1, with little influence on pericentrin and γ-tubulin in Cos7 and HeLa cells. Silencing Nudel in HeLa cells markedly decreases centrosomal targeting of all the aforementioned proteins. Silencing Nudel also represses centrosomal MT nucleation and anchoring. Furthermore, Nudel can interact with pericentrin independently of dynein. Our current results suggest that Nudel plays a role in both dynein-mediated centripetal transport of dynactin, Lis1, and PCM-1 as well as in dynein-independent centrosomal targeting of pericentrin and γ-tubulin. Moreover, Nudel seems to tether dynactin and dynein to the mother centriole for MT anchoring.

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46

Xie, Shuwei, James B. Reinecke, Trey Farmer, Kriti Bahl, Ivana Yeow, Benjamin J. Nichols, Tiffany A. McLamarrah, Naava Naslavsky, Gregory C. Rogers, and Steve Caplan. "Vesicular trafficking plays a role in centriole disengagement and duplication." Molecular Biology of the Cell 29, no. 22 (November 2018): 2622–31. http://dx.doi.org/10.1091/mbc.e18-04-0241.

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Centrosomes are the major microtubule-nucleating and microtubule-organizing centers of cells and play crucial roles in microtubule anchoring, organelle positioning, and ciliogenesis. At the centrosome core lies a tightly associated or “engaged” mother–daughter centriole pair. During mitotic exit, removal of centrosomal proteins pericentrin and Cep215 promotes “disengagement” by the dissolution of intercentriolar linkers, ensuring a single centriole duplication event per cell cycle. Herein, we explore a new mechanism involving vesicular trafficking for the removal of centrosomal Cep215. Using small interfering RNA and CRISPR/Cas9 gene-edited cells, we show that the endocytic protein EHD1 regulates Cep215 transport from centrosomes to the spindle midbody, thus facilitating disengagement and duplication. We demonstrate that EHD1 and Cep215 interact and show that Cep215 displays increased localization to vesicles containing EHD1 during mitosis. Moreover, Cep215-containing vesicles are positive for internalized transferrin, demonstrating their endocytic origin. Thus, we describe a novel relationship between endocytic trafficking and the centrosome cycle, whereby vesicles of endocytic origin are used to remove key regulatory proteins from centrosomes to control centriole duplication.

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47

Uetake, Yumi, Jadranka Lončarek, Joshua J. Nordberg, Christopher N. English, Sabrina La Terra, Alexey Khodjakov, and Greenfield Sluder. "Cell cycle progression and de novo centriole assembly after centrosomal removal in untransformed human cells." Journal of Cell Biology 176, no. 2 (January 15, 2007): 173–82. http://dx.doi.org/10.1083/jcb.200607073.

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How centrosome removal or perturbations of centrosomal proteins leads to G1 arrest in untransformed mammalian cells has been a mystery. We use microsurgery and laser ablation to remove the centrosome from two types of normal human cells. First, we find that the cells assemble centrioles de novo after centrosome removal; thus, this phenomenon is not restricted to transformed cells. Second, normal cells can progress through G1 in its entirety without centrioles. Therefore, the centrosome is not a necessary, integral part of the mechanisms that drive the cell cycle through G1 into S phase. Third, we provide evidence that centrosome loss is, functionally, a stress that can act additively with other stresses to arrest cells in G1 in a p38-dependent fashion.

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Sawant, Dwitiya B., Shubhra Majumder, Jennifer L. Perkins, Ching-Hui Yang, Patrick A. Eyers, and Harold A. Fisk. "Centrin 3 is an inhibitor of centrosomal Mps1 and antagonizes centrin 2 function." Molecular Biology of the Cell 26, no. 21 (November 2015): 3741–53. http://dx.doi.org/10.1091/mbc.e14-07-1248.

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Centrins are a family of small, calcium-binding proteins with diverse cellular functions that play an important role in centrosome biology. We previously identified centrin 2 and centrin 3 (Cetn2 and Cetn3) as substrates of the protein kinase Mps1. However, although Mps1 phosphorylation sites control the function of Cetn2 in centriole assembly and promote centriole overproduction, Cetn2 and Cetn3 are not functionally interchangeable, and we show here that Cetn3 is both a biochemical inhibitor of Mps1 catalytic activity and a biological inhibitor of centrosome duplication. In vitro, Cetn3 inhibits Mps1 autophosphorylation at Thr-676, a known site of T-loop autoactivation, and interferes with Mps1-dependent phosphorylation of Cetn2. The cellular overexpression of Cetn3 attenuates the incorporation of Cetn2 into centrioles and centrosome reduplication, whereas depletion of Cetn3 generates extra centrioles. Finally, overexpression of Cetn3 reduces Mps1 Thr-676 phosphorylation at centrosomes, and mimicking Mps1-dependent phosphorylation of Cetn2 bypasses the inhibitory effect of Cetn3, suggesting that the biological effects of Cetn3 are due to the inhibition of Mps1 function at centrosomes.

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Moyer, Tyler C., Kevin M. Clutario, Bramwell G. Lambrus, Vikas Daggubati, and Andrew J. Holland. "Binding of STIL to Plk4 activates kinase activity to promote centriole assembly." Journal of Cell Biology 209, no. 6 (June 22, 2015): 863–78. http://dx.doi.org/10.1083/jcb.201502088.

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Centriole duplication occurs once per cell cycle in order to maintain control of centrosome number and ensure genome integrity. Polo-like kinase 4 (Plk4) is a master regulator of centriole biogenesis, but how its activity is regulated to control centriole assembly is unclear. Here we used gene editing in human cells to create a chemical genetic system in which endogenous Plk4 can be specifically inhibited using a cell-permeable ATP analogue. Using this system, we demonstrate that STIL localization to the centriole requires continued Plk4 activity. Most importantly, we show that direct binding of STIL activates Plk4 by promoting self-phosphorylation of the activation loop of the kinase. Plk4 subsequently phosphorylates STIL to promote centriole assembly in two steps. First, Plk4 activity promotes the recruitment of STIL to the centriole. Second, Plk4 primes the direct binding of STIL to the C terminus of SAS6. Our findings uncover a molecular basis for the timing of Plk4 activation through the cell cycle–regulated accumulation of STIL.

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Mayor, Thibault, York-Dieter Stierhof, Kayoko Tanaka, Andrew M. Fry, and Erich A. Nigg. "The Centrosomal Protein C-Nap1 Is Required for Cell Cycle–Regulated Centrosome Cohesion." Journal of Cell Biology 151, no. 4 (November 13, 2000): 837–46. http://dx.doi.org/10.1083/jcb.151.4.837.

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Duplicating centrosomes are paired during interphase, but are separated at the onset of mitosis. Although the mechanisms controlling centrosome cohesion and separation are important for centrosome function throughout the cell cycle, they remain poorly understood. Recently, we have proposed that C-Nap1, a novel centrosomal protein, is part of a structure linking parental centrioles in a cell cycle–regulated manner. To test this model, we have performed a detailed structure–function analysis on C-Nap1. We demonstrate that antibody-mediated interference with C-Nap1 function causes centrosome splitting, regardless of the cell cycle phase. Splitting occurs between parental centrioles and is not dependent on the presence of an intact microtubule or microfilament network. Centrosome splitting can also be induced by overexpression of truncated C-Nap1 mutants, but not full-length protein. Antibodies raised against different domains of C-Nap1 prove that this protein dissociates from spindle poles during mitosis, but reaccumulates at centrosomes at the end of cell division. Use of the same antibodies in immunoelectron microscopy shows that C-Nap1 is confined to the proximal end domains of centrioles, indicating that a putative linker structure must contain additional proteins. We conclude that C-Nap1 is a key component of a dynamic, cell cycle–regulated structure that mediates centriole–centriole cohesion.

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Journal articles on the topic 'Centriole to centrosome conversion'

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