Ubiquitin Signaling in the Control of Centriole Duplication

Autosomal recessive primary microcephaly (MCPH) is a complex neurodevelopmental disorder characterized by a small brain size with mild to moderate intellectual disability. We previously demonstrated that human microcephaly RTTN played an important role in regulating centriole duplication during interphase, but the role of RTTN in mitosis is not fully understood. Here, we show that RTTN is required for normal mitotic progression and correct spindle position. The depletion of RTTN induces the dispersion of the pericentriolar protein γ-tubulin and multiple mitotic abnormalities, including monopolar, abnormal bipolar, and multipolar spindles. Importantly, the loss of RTTN altered NuMA/p150Glued congression to the spindle poles, perturbed NuMA cortical localization, and reduced the number and the length of astral microtubules. Together, our results provide a new insight into how RTTN functions in mitosis.

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Drosophila Ana2 is a conserved centriole duplication factor

The Journal of Cell Biology ◽

10.1083/jcb.200910016 ◽

2010 ◽

Vol 188 (3) ◽

pp. 313-323 ◽

Cited By ~ 102

Author(s):

Naomi R. Stevens ◽

Jeroen Dobbelaere ◽

Kathrin Brunk ◽

Anna Franz ◽

Jordan W. Raff

Keyword(s):

Drosophila Melanogaster ◽

Caenorhabditis Elegans ◽

De Novo ◽

Protein Family ◽

Centriole Duplication

In Caenorhabditis elegans, five proteins are required for centriole duplication: SPD-2, ZYG-1, SAS-5, SAS-6, and SAS-4. Functional orthologues of all but SAS-5 have been found in other species. In Drosophila melanogaster and humans, Sak/Plk4, DSas-6/hSas-6, and DSas-4/CPAP—orthologues of ZYG-1, SAS-6, and SAS-4, respectively—are required for centriole duplication. Strikingly, all three fly proteins can induce the de novo formation of centriole-like structures when overexpressed in unfertilized eggs. Here, we find that of eight candidate duplication factors identified in cultured fly cells, only two, Ana2 and Asterless (Asl), share this ability. Asl is now known to be essential for centriole duplication in flies, but no equivalent protein has been found in worms. We show that Ana2 is the likely functional orthologue of SAS-5 and that it is also related to the vertebrate STIL/SIL protein family that has been linked to microcephaly in humans. We propose that members of the SAS-5/Ana2/STIL family of proteins are key conserved components of the centriole duplication machinery.

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Albatross/FBF1 contributes to both centriole duplication and centrosome separation

Genes to Cells ◽

10.1111/gtc.12648 ◽

2018 ◽

Vol 23 (12) ◽

pp. 1023-1042 ◽

Cited By ~ 1

Author(s):

Akihito Inoko ◽

Tomoki Yano ◽

Tatsuo Miyamoto ◽

Shinya Matsuura ◽

Tohru Kiyono ◽

...

Keyword(s):

Centriole Duplication ◽

Centrosome Separation

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CCDC57 Cooperates with Microtubules and Microcephaly Protein CEP63 and Regulates Centriole Duplication and Mitotic Progression

Cell Reports ◽

10.1016/j.celrep.2020.107630 ◽

2020 ◽

Vol 31 (6) ◽

pp. 107630 ◽

Cited By ~ 4

Author(s):

H. Kubra Gurkaslar ◽

Efraim Culfa ◽

Melis D. Arslanhan ◽

Mariana Lince-Faria ◽

Elif Nur Firat-Karalar

Keyword(s):

Mitotic Progression ◽

Centriole Duplication

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Centriole duplication in sand dollar eggs

Experimental Cell Research ◽

10.1016/s0014-4827(77)80010-4 ◽

1977 ◽

Vol 108 (1) ◽

pp. 63-73

Author(s):

H.A. Went

Keyword(s):

Sand Dollar ◽

Centriole Duplication

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TRIM37 prevents formation of condensate-organized ectopic spindle poles to ensure mitotic fidelity

The Journal of Cell Biology ◽

10.1083/jcb.202010180 ◽

2021 ◽

Vol 220 (7) ◽

Author(s):

Franz Meitinger ◽

Dong Kong ◽

Midori Ohta ◽

Arshad Desai ◽

Karen Oegema ◽

...

Keyword(s):

Chromosome Segregation ◽

Ubiquitin Ligase ◽

Spindle Pole ◽

Mitotic Entry ◽

Centriole Duplication ◽

Mulibrey Nanism ◽

Spindle Poles ◽

Pathological Mechanism ◽

Pericentriolar Material ◽

Centrosomal Proteins

Centrosomes are composed of a centriolar core surrounded by pericentriolar material that nucleates microtubules. The ubiquitin ligase TRIM37 localizes to centrosomes, but its centrosomal roles are not yet defined. We show that TRIM37 does not control centriole duplication, structure, or the ability of centrioles to form cilia but instead prevents assembly of an ectopic centrobin-scaffolded structured condensate that forms by budding off of centrosomes. In ∼25% of TRIM37-deficient cells, the condensate organizes an ectopic spindle pole, recruiting other centrosomal proteins and acquiring microtubule nucleation capacity during mitotic entry. Ectopic spindle pole–associated transient multipolarity and multipolar segregation in TRIM37-deficient cells are suppressed by removing centrobin, which interacts with and is ubiquitinated by TRIM37. Thus, TRIM37 ensures accurate chromosome segregation by preventing the formation of centrobin-scaffolded condensates that organize ectopic spindle poles. Mutations in TRIM37 cause the disorder mulibrey nanism, and patient-derived cells harbor centrobin condensate-organized ectopic poles, leading us to propose that chromosome missegregation is a pathological mechanism in this disorder.

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Plk4/SAK/ZYG-1 in the regulation of centriole duplication

F1000 Biology Reports ◽

10.3410/b2-58 ◽

2010 ◽

Vol 2 ◽

Cited By ~ 1

Author(s):

Chad G Pearson ◽

Mark Winey

Keyword(s):

Centriole Duplication

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Autoamplification and competition drive symmetry breaking: Initiation of centriole duplication by the PLK4-STIL network

10.1101/430264 ◽

2018 ◽

Author(s):

Marcin Leda ◽

Andrew J. Holland ◽

Andrew B. Goryachev

Keyword(s):

Symmetry Breaking ◽

Mammalian Cells ◽

Molecular Mechanisms ◽

Break Symmetry ◽

Biophysical Model ◽

Model Organisms ◽

Centriole Duplication ◽

Mother Centriole ◽

Autocatalytic Activation

SummarySymmetry breaking, a central principle of physics, has been hailed as the driver of self-organization in biological systems in general and biogenesis of cellular organelles in particular, but the molecular mechanisms of symmetry breaking only begin to become understood. Centrioles, the structural cores of centrosomes and cilia, must duplicate every cell cycle to ensure their faithful inheritance through cellular divisions. Work in model organisms identified conserved proteins required for centriole duplication and found that altering their abundance affects centriole number. However, the biophysical principles that ensure that, under physiological conditions, only a single procentriole is produced on each mother centriole remain enigmatic. Here we propose a mechanistic biophysical model for the initiation of procentriole formation in mammalian cells. We posit that interactions between the master regulatory kinase PLK4 and its activator-substrate STIL form the basis of the procentriole initiation network. The model faithfully recapitulates the experimentally observed transition from PLK4 uniformly distributed around the mother centriole, the “ring”, to a unique PLK4 focus, the “spot”, that triggers the assembly of a new procentriole. This symmetry breaking requires a dual positive feedback based on autocatalytic activation of PLK4 and enhanced centriolar anchoring of PLK4-STIL complexes by phosphorylated STIL. We find that, contrary to previous proposals,in situdegradation of active PLK4 is insufficient to break symmetry. Instead, the model predicts that competition between transient PLK4 activity maxima for PLK4-STIL complexes explains both the instability of the PLK4 ring and formation of the unique PLK4 spot. In the model, strong competition at physiologically normal parameters robustly produces a single procentriole, while increasing overexpression of PLK4 and STIL weakens the competition and causes progressive addition of procentrioles in agreement with experimental observations.

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