Browse
Submit Data
Databases
API
Help

Dataset Information

10 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

A non-canonical function for Centromere-associated protein-E controls centrosome integrity and orientation of cell division.

ABSTRACT: Centromere-associated protein-E (CENP-E) is a kinesin motor localizing at kinetochores. Although its mitotic functions have been well studied, it has been challenging to investigate direct consequences of CENP-E removal using conventional methods because CENP-E depletion resulted in mitotic arrest. In this study, we harnessed an auxin-inducible degron system to achieve acute degradation of CENP-E. We revealed a kinetochore-independent role for CENP-E that removes pericentriolar material 1 (PCM1) from centrosomes in late S/early G₂ phase. After acute loss of CENP-E, centrosomal Polo-like kinase 1 (Plk1) localization is abrogated through accumulation of PCM1, resulting in aberrant phosphorylation and destabilization of centrosomes, which triggers shortened astral microtubules and oblique cell divisions. Furthermore, we also observed centrosome and cell division defects in cells from a microcephaly patient with mutations in CENPE. Orientation of cell division is deregulated in some microcephalic patients, and our unanticipated findings provide additional insights into how microcephaly can result from centrosomal defects.

SUBMITTER: Owa M

PROVIDER: S-EPMC7979751 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

FBXO38 Ubiquitin Ligase Controls Centromere Integrity via ZXDA/B Stability.

Project description:Alterations in the gene encoding the E3 ubiquitin ligase substrate receptor FBXO38 have been associated with several diseases, including early-onset motor neuronopathy. However, the cellular processes affected by the enzymatic action of FBXO38 are not yet known. Here, we identify the zinc finger proteins ZXDA/B as its interaction partners. FBXO38 controls the stability of ZXDA/B proteins via ubiquitination and proteasome-dependent degradation. We show that ZXDA/B proteins associate with the centromeric protein CENP-B and that the interaction between ZXDA/B and FBXO38 or CENP-B is mutually exclusive. Functionally, ZXDA/B factors control the protein level of chromatin-associated CENP-B. Furthermore, their inappropriate stabilization leads to upregulation of CENP-A and CENP-B positive centromeric chromatin. Thus we demonstrate a previously unknown role of cullin-dependent protein degradation in the control of centromeric chromatin integrity.

| S-EPMC9260856 | biostudies-literature

Non-visual arrestins are constitutively associated with the centrosome and regulate centrosome function.

Project description:In addition to regulating receptor activity, non-visual arrestins function as scaffolds for numerous intracellular signaling cascades and as regulators of gene transcription. Here we report that the two non-visual arrestins, arrestin2 and arrestin3, localize to the centrosome, a key organelle involved in microtubule nucleation and bipolar mitotic spindle assembly. Both arrestins co-localized with the centrosomal marker gamma-tubulin during interphase and mitosis and were found in purified centrosome preparations. In vitro binding assays demonstrated that both arrestins directly interact with gamma-tubulin. Knockdown of either arrestin by RNA interference resulted in multinucleation, centrosome amplification, and mitotic defects, although only the loss of arrestin2 triggered aberrant microtubule nucleation. Importantly, overexpression of wild type arrestin rescued the multinucleation phenotype and restored normal centrosome number in arrestin siRNA-transfected cells. Moreover, overexpression of arrestin2 or -3 rescued the multinucleation defect observed in MDA-MB-231 breast cancer cells. Taken together, our data reveal that non-visual arrestins are novel centrosomal components and regulate normal centrosome function.

| S-EPMC2832982 | biostudies-literature

Constitutive centromere-associated network controls centromere drift in vertebrate cells.

Project description:Centromeres are specified by sequence-independent epigenetic mechanisms, and the centromere position may drift at each cell cycle, but once this position is specified, it may not be frequently moved. Currently, it is unclear whether the centromere position is stable. To address this question, we systematically analyzed the position of nonrepetitive centromeres in 21 independent clones isolated from a laboratory stock of chicken DT40 cells using chromatin immunoprecipitation combined with massive parallel sequencing analysis with anti-CENP-A antibody. We demonstrated that the centromere position varies among the clones, suggesting that centromere drift occurs during cell proliferation. However, when we analyzed this position in the subclones obtained from one isolated clone, the position was found to be relatively stable. Interestingly, the centromere drift was shown to occur frequently in CENP-U- and CENP-S-deficient cells. Based on these results, we suggest that the centromere position can change after many cell divisions, but this drift is suppressed in short-term cultures, and the complete centromere structure contributes to the suppression of the centromere drift.

| S-EPMC5223601 | biostudies-literature

A non-canonical function of Plk4 in centriolar satellite integrity and ciliogenesis through PCM1 phosphorylation.

Project description:Centrioles are the major constituents of the animal centrosome, in which Plk4 kinase serves as a master regulator of the duplication cycle. Many eukaryotes also contain numerous peripheral particles known as centriolar satellites. While centriolar satellites aid centriole assembly and primary cilium formation, it is unknown whether Plk4 plays any regulatory roles in centriolar satellite integrity. Here we show that Plk4 is a critical determinant of centriolar satellite organisation. Plk4 depletion leads to the dispersion of centriolar satellites and perturbed ciliogenesis. Plk4 interacts with the satellite component PCM1, and its kinase activity is required for phosphorylation of the conserved S372. The nonphosphorylatable PCM1 mutant recapitulates phenotypes of Plk4 depletion, while the phosphomimetic mutant partially rescues the dispersed centriolar satellite patterns and ciliogenesis in cells depleted of PCM1. We show that S372 phosphorylation occurs during the G1 phase of the cell cycle and is important for PCM1 dimerisation and interaction with other satellite components. Our findings reveal that Plk4 is required for centriolar satellite function, which may underlie the ciliogenesis defects caused by Plk4 dysfunction.

| S-EPMC4772974 | biostudies-literature

Centrosome-intrinsic mechanisms modulate centrosome integrity during fever.

Project description:The centrosome is critical for cell division, ciliogenesis, membrane trafficking, and immunological synapse function. The immunological synapse is part of the immune response, which is often accompanied by fever/heat stress (HS). Here we provide evidence that HS causes deconstruction of all centrosome substructures primarily through degradation by centrosome-associated proteasomes. This renders the centrosome nonfunctional. Heat-activated degradation is centrosome selective, as other nonmembranous organelles (midbody, kinetochore) and membrane-bounded organelles (mitochondria) remain largely intact. Heat-induced centrosome inactivation was rescued by targeting Hsp70 to the centrosome. In contrast, Hsp70 excluded from the centrosome via targeting to membranes failed to rescue, as did chaperone inactivation. This indicates that there is a balance between degradation and chaperone rescue at the centrosome after HS. This novel mechanism of centrosome regulation during fever contributes to immunological synapse formation. Heat-induced centrosome inactivation is a physiologically relevant event, as centrosomes in leukocytes of febrile patients are disrupted.

| S-EPMC4591690 | biostudies-literature

Cell cycle and centromere FISH studies in premature centromere division.

Project description:BACKGROUND: Mitotic configurations consistent in split centromeres and splayed chromatids in all or most of the chromosomes or premature centromere division (PCD) have been described in three categories. (1) Low frequency of PCD observed in colchicines-treated lymphocyte cultures from normal individuals. (2) High frequency of PCD with mosaic variegated aneuploidy. (3) High frequency of PCD as a sole chromosome abnormality observed in individuals with no recognizable clinical pattern. We report four members of a family with the third category of PCD. METHODS: Cell cycle duration assessed by average generation time using differential sister chromatid stain analysis and FISH studies of DNA centromere sequences in PCD individuals, are included and compared with previously reported PCD individuals from 9 families. RESULTS: We observed PCD in colchicine-treated cultures from the propositus, his father, and two paternal aunts but not in his mother and four other paternal and maternal family members, as well as in untreated cultures from the propositus and his father. We observed cytological evidence of active centromeres by Cd stain. Significative cell cycle time reduction in anaphases of PCD individuals (average generation time of 21.8 h;SD 0.4) with respect to individuals without PCD (average generation time of 31.8 h;SD 3.9) was observed (P < 0.005, Student t-test for independent samples). Increased cell proliferation kinetics was observed in anaphasic cells of individuals with PCD, by differential sister chromatid stain analysis. FISH studies revealed the presence of alpha satellite DNA from chromosomes 1, 13, 21/18, X, all centromeres, and CENP-B box sequences in metaphasic and anaphasic cells from PCD individuals. CONCLUSION: This report examines evidences of a functional relationship between PCD and cell cycle impairment. It seems that essential centromere integrity is present in these cases.

| S-EPMC1242348 | biostudies-literature

aPKC? controls epidermal homeostasis and stem cell fate through regulation of division orientation.

Project description:The atypical protein kinase C (aPKC) is a key regulator of polarity and cell fate in lower organisms. However, whether mammalian aPKCs control stem cells and fate in vivo is not known. Here we show that loss of aPKC? in a self-renewing epithelium, the epidermis, disturbed tissue homeostasis, differentiation, and stem cell dynamics, causing progressive changes in this tissue. This was accompanied by a gradual loss of quiescent hair follicle bulge stem cells and a temporary increase in proliferating progenitors. Lineage tracing analysis showed that loss of aPKC? altered the fate of lower bulge/hair germ stem cells. This ultimately led to loss of proliferative potential, stem cell exhaustion, alopecia, and premature aging. Inactivation of aPKC? produced more asymmetric divisions in different compartments, including the bulge. Thus, aPKC? is crucial for homeostasis of self-renewing stratifying epithelia, and for the regulation of cell fate, differentiation, and maintenance of epidermal bulge stem cells likely through its role in balancing symmetric and asymmetric division.

| S-EPMC3776350 | biostudies-literature

SRSF2 transcriptional function maintains genome integrity during cell division

Project description:To investigate the role of SRSF2 in skin we made use of mice where SRSF2 can be conditionally deleted or a point mutation can be introduced in an undifferentiated population marked by expression of Keratin 14.

2024-10-01 | GSE221444 | GEO

A novel role for CSA in the regulation of nuclear envelope integrity: uncovering a non-canonical function.

Project description:Cockayne syndrome (CS) is a premature ageing condition characterized by microcephaly, growth failure, and neurodegeneration. It is caused by mutations in ERCC6 or ERCC8 encoding for Cockayne syndrome B (CSB) and A (CSA) proteins, respectively. CSA and CSB have well-characterized roles in transcription-coupled nucleotide excision repair, responsible for removing bulky DNA lesions, including those caused by UV irradiation. Here, we report that CSA dysfunction causes defects in the nuclear envelope (NE) integrity. NE dysfunction is characteristic of progeroid disorders caused by a mutation in NE proteins, such as Hutchinson-Gilford progeria syndrome. However, it has never been reported in Cockayne syndrome. We observed CSA dysfunction affected LEMD2 incorporation at the NE and increased actin stress fibers that contributed to enhanced mechanical stress to the NE. Altogether, these led to NE abnormalities associated with the activation of the cGAS/STING pathway. Targeting the linker of the nucleoskeleton and cytoskeleton complex was sufficient to rescue these phenotypes. This work reveals NE dysfunction in a progeroid syndrome caused by mutations in a DNA damage repair protein, reinforcing the connection between NE deregulation and ageing.

| S-EPMC11361374 | biostudies-literature

Hook2, a microtubule-binding protein, interacts with Par6α and controls centrosome orientation during polarized cell migration.

Project description:Polarity protein complexes function during polarized cell migration and a subset of these proteins localizes to the reoriented centrosome during this process. Despite these observations, the mechanisms behind the recruitment of these polarity complexes such as the aPKC/PAR6α complex to the centrosome are not well understood. Here we identify Hook2 as an interactor for the aPKC/PAR6α complex that functions to localize this complex at the centrosome. We first demonstrate that Hook2 is essential for the polarized Golgi re-orientation towards the migration front. Depletion of Hook2 results in a decrease of PAR6α at the centrosome during cell migration, while overexpression of Hook2 in cells induced the formation of aggresomes with the recruitment of PAR6α, aPKC and PAR3. In addition, we demonstrate that the interaction between the C-terminal domain of Hook2 and the aPKC-binding domain of PAR6α localizes PAR6α to the centrosome during cell migration. Our data suggests that Hook2, a microtubule binding protein, plays an important role in the regulation of PAR6α recruitment to the centrosome to bridge microtubules and the aPKC/PAR complex. This data reveals how some of the polarity protein complexes are recruited to the centrosome and might regulate pericentriolar and microtubule organization and potentially impact on polarized migration.

| S-EPMC5021942 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data