Affinage

CEP63

Centrosomal protein of 63 kDa · UniProt Q96MT8

Length
703 aa
Mass
81.3 kDa
Annotated
2026-06-09
18 papers in source corpus 11 papers cited in narrative 11 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CEP63 is a centrosomal scaffold protein that controls centriole duplication and mitotic fidelity by organizing the proximal end of centrioles within a CEP57–CEP63–CEP152 ring complex (PMID:23333316). Through direct binding to CEP152 it recruits PLK4 to drive mother-centriole-dependent centriole biogenesis; its paralogue DEUP1 uses the same CEP152-binding mechanism to assemble deuterosomes for de novo centriole production during multiciliogenesis (PMID:24240477). CEP63 also binds and recruits CDK1 to centrosomes to regulate mitotic entry, with its loss causing polyploidy and its overexpression driving centrosome amplification (PMID:21406398). Localization of CEP63 and CEP152 to the centrosome is sustained by liquid–liquid phase separation of the CEP63·CEP152 complex, driven by hydrophobic motifs in each protein (PMID:33208041), and CEP63 centrosomal recruitment depends on the upstream proximal-end protein CCDC57 (PMID:32402286). The DNA-damage kinases ATM and ATR phosphorylate CEP63 on Ser560, delocalizing it from the centrosome to inhibit spindle assembly (PMID:19182792), while selective autophagy degrades CEP63 via the receptor p62 to limit centrosome number (PMID:27869116). Consistent with these roles, loss of CEP63 in mice produces microcephaly through p53-dependent apoptosis of neural progenitors driven by mitotic errors, as well as meiotic defects and male infertility (PMID:26158450). Outside the centrosome, CEP63 stabilizes the RNA-binding protein FXR1 by blocking its K63-ubiquitylation-dependent degradation, promoting YAP1 expression and cancer stem-like properties (PMID:35989368).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2009 High

    Established CEP63 as a node linking DNA-damage signaling to centrosome-driven spindle control, answering how DSBs restrain mitotic spindle assembly.

    Evidence cDNA library screen for ATM/ATR substrates, Xenopus egg extract spindle assembly with S560A mutagenesis, and CEP63 knockout in DT40 cells

    PMID:19182792

    Open questions at the time
    • Does not define the structural basis of Ser560-dependent delocalization
    • Does not identify which centrosomal partners are lost upon phosphorylation
  2. 2011 Medium

    Showed CEP63 recruits CDK1 to centrosomes to govern mitotic entry, connecting the scaffold to cell-cycle progression and ploidy control.

    Evidence Reciprocal Co-IP, RNAi depletion with polyploidy/mitotic-skipping readout, and overexpression with roscovitine rescue in U2OS cells

    PMID:21406398

    Open questions at the time
    • Direct vs. indirect CDK1 binding not resolved
    • Single lab without orthogonal interaction validation
  3. 2013 High

    Defined the core mechanism of centriole duplication: CEP63 binds CEP152 to recruit PLK4, with the same module repurposed for deuterosome-based biogenesis.

    Evidence Reciprocal Co-IP, RNAi in multiciliated cell differentiation, phylogenetic analysis, and functional rescue

    PMID:24240477

    Open questions at the time
    • Stoichiometry of the CEP63-CEP152-PLK4 assembly not defined
    • Does not establish how PLK4 activity is spatially restricted
  4. 2013 Medium

    Placed CEP63 architecturally within a CEP57-CEP63-CEP152 ring at the proximal centriole end, providing the spatial framework for its scaffolding role.

    Evidence Selective chemical crosslinking and superresolution microscopy across 31 centrosomal proteins

    PMID:23333316

    Open questions at the time
    • Ring geometry inferred from crosslinking distances, not atomic structure
    • Single lab
  5. 2015 High

    Demonstrated the organismal consequence of CEP63 loss—microcephaly via p53-dependent neural progenitor apoptosis—and distinguished mitotic-error causation from a DNA-damage-response mechanism.

    Evidence Cep63 knockout mouse with p53 double-knockout epistasis, centrosome/chromosome immunofluorescence, and meiotic spread analysis

    PMID:26158450

    Open questions at the time
    • Does not pinpoint the molecular trigger of mitotic errors in progenitors
    • Mechanism of telomere clustering failure in meiosis unresolved
  6. 2016 High

    Identified selective autophagy as a degradative route controlling CEP63 abundance and thereby centrosome number, adding a turnover axis to its regulation.

    Evidence Autophagy-deficient and p62-/- cells, CEP63-p62 Co-IP, autophagosome co-localization, and overexpression phenotype

    PMID:27869116

    Open questions at the time
    • E3 ligase ubiquitylating CEP63 for p62 recognition not identified
    • Trigger that signals CEP63 for autophagic turnover unknown
  7. 2020 Medium

    Identified CCDC57 as an upstream proximal-end factor required to localize CEP63 and CEP152 to centrosomes, defining a recruitment hierarchy.

    Evidence BioID proximity mapping, superresolution imaging, CCDC57 siRNA with CEP63/CEP152 localization readout, and domain truncation

    PMID:32402286

    Open questions at the time
    • Whether CCDC57-CEP63 binding is direct vs. mediated not fully resolved
    • Single lab
  8. 2020 High

    Revealed that CEP63·CEP152 form phase-separated condensates, explaining how the scaffold concentrates at and maintains centrosomal localization.

    Evidence FRAP, in vitro reconstitution of purified complex, 1,6-hexanediol treatment, hydrophobic-motif mutagenesis, and 3D-SIM

    PMID:33208041

    Open questions at the time
    • Physiological regulation of condensate formation in cells not established
    • Relationship between in vitro cylindrical/hollow structures and centriole architecture unclear
  9. 2022 Medium

    Showed APC/C-mediated ubiquitylation of CEP152 dismantles the inhibitory CEP152-CEP63-CEP57 complex to liberate CEP57 for spindle assembly, integrating CEP63 into mitotic ubiquitin signaling.

    Evidence Co-IP of APC/C with centrosomal proteins, ubiquitylation assays, and epistasis of CEP57-pericentrin interaction

    PMID:34878135

    Open questions at the time
    • Direct role of CEP63 in this release step not isolated
    • Single lab
  10. 2022 Medium

    Uncovered a non-centrosomal function: CEP63 stabilizes FXR1 by blocking its K63-ubiquitylation-dependent degradation, linking CEP63 to YAP1-driven cancer stem-like properties.

    Evidence Co-IP, ubiquitylation assays, FXR1 KH-domain mapping, USP36-CEP63 stabilization, and tumor growth assays

    PMID:35989368

    Open questions at the time
    • Whether this function requires centrosomal CEP63 or a separate pool is unknown
    • Single lab
  11. 2025 Medium

    Proposed that CEP152-CEP63-PCNT aggregates act as ALMS1-dependent cartwheel seeds enabling de novo centriole assembly independent of pre-existing centrioles.

    Evidence ALMS1 Co-IP with CEP152/CEP63/PCNT, depletion/re-expression with centriole readout, and superresolution imaging (preprint)

    PMID:40667363

    Open questions at the time
    • Preprint, not yet peer-reviewed
    • How seeds template cartwheel symmetry mechanistically unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CEP63's distinct activities—centriole duplication scaffold, mitotic-entry regulator, DNA-damage-responsive sensor, autophagy substrate, and FXR1 stabilizer—are coordinated within a cell remains unresolved.
  • No structural model integrating CEP63's binding interfaces
  • Direct E3 ligase for CEP63 turnover unidentified
  • Spatial separation of centrosomal vs. FXR1-stabilizing pools undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 1
Localization
GO:0005815 microtubule organizing center 3
Pathway
R-HSA-1640170 Cell Cycle 3 R-HSA-1852241 Organelle biogenesis and maintenance 2 R-HSA-9612973 Autophagy 1
Partners
CCDC57CDK1CEP152CEP57FXR1PCNTPLK4SQSTM1
Complex memberships
CEP57-CEP63-CEP152 ring complex

Evidence

Reading pass · 11 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2009 ATM and ATR phosphorylate Xenopus CEP63 (XCEP63) on Ser 560 following DNA double-strand breaks, promoting its delocalization from the centrosome and thereby inhibiting centrosome-driven spindle assembly. Mutation of XCEP63 Ser 560 to Ala prevented spindle assembly defects, and CEP63 gene inactivation in DT40 cells impaired spindle assembly and prevented ATM/ATR-dependent mitotic effects. In vitro Xenopus egg extract spindle assembly assay, site-directed mutagenesis (S560A), cDNA expression library screen for ATM/ATR substrates, CEP63 gene knockout in avian DT40 cells Nature cell biology High 19182792
2011 Human CEP63 binds to and recruits CDK1 to centrosomes, regulating mitotic entry. RNAi-mediated CEP63 depletion in U2OS cells caused polyploidization through mitotic skipping associated with loss of centrosomal CDK1. CEP63 overexpression induced de novo centrosome amplification during interphase, suppressible by the CDK inhibitor roscovitine. Co-immunoprecipitation, RNAi knockdown with cell cycle phenotype readout (polyploidy, mitotic skipping), overexpression with CDK inhibitor rescue Cancer research Medium 21406398
2013 CEP63 regulates mother-centriole-dependent centriole duplication by binding to CEP152 and recruiting PLK4 to activate centriole biogenesis. Its paralogue DEUP1 (Cep63-derived) uses the same CEP152-binding mechanism to assemble deuterosomes for large-scale de novo centriole biogenesis in multiciliogenesis. Co-immunoprecipitation, RNAi knockdown in multiciliated cell differentiation assay, phylogenetic analysis, functional rescue experiments Nature cell biology High 24240477
2013 CEP57, CEP63, and CEP152 form a ring-like complex localizing around the proximal end of centrioles, as revealed by selective chemical crosslinking combined with superresolution microscopy. Selective chemical crosslinking, superresolution microscopy (STORM/PALM), proximity-based interaction mapping of 31 centrosomal proteins Current biology : CB Medium 23333316
2015 CEP63-deficient mice develop microcephaly through p53-dependent apoptosis of neural progenitor cells triggered by centrosome-based mitotic errors (not aberrant DNA damage response). Brain size was rescued by p53 deletion. Additionally, CEP63 loss caused centrosome aberrations in spermatocytes, chromosome entanglements, and defective telomere clustering, leading to failed meiotic recombination and male infertility. Cep63 knockout mouse model, p53 double knockout epistasis, immunofluorescence of centrosome/chromosome defects, meiotic spread analysis Nature communications High 26158450
2016 Autophagy controls centrosome number by degrading CEP63. Autophagy-deficient cells accumulate extra centrosomes with multiple CEP63 dots. CEP63 is recruited to autophagosomes via interaction with p62 (a selective autophagy receptor). Upregulation of CEP63 increases centrosome number. Autophagy-deficient cell lines and p62-/- mouse hematopoietic cells, co-immunoprecipitation of CEP63 with p62, immunofluorescence of autophagosome-CEP63 co-localization, CEP63 overexpression phenotype Nature communications High 27869116
2020 CCDC57 localizes to the proximal end of centrioles and directly interacts with CEP63. Loss of CCDC57 causes failure to localize CEP63 and CEP152 to the centrosome and results in centriole duplication defects. The centrosome-targeting region of CCDC57 is required for its interaction with CEP63 and for centriole duplication and cilium assembly functions. Proximity mapping (BioID), superresolution imaging, CCDC57 siRNA knockdown with CEP63/CEP152 localization readout, domain truncation analysis Cell reports Medium 32402286
2020 The CEP63•CEP152 complex undergoes liquid-liquid phase separation to form dynamic condensates at centrosomes. Two hydrophobic motifs, one from CEP63 and one from CEP152, are required for generating phase-separating condensates and high-molecular-weight assemblies. Treatment with 1,6-hexanediol (a phase separation disruptor) diminished endogenous CEP63 and CEP152 localization to centrosomes. In vitro, purified CEP63•CEP152 complex forms cylindrical structures or vesicle-like hollow spheres depending on spatial context. FRAP, in vitro reconstitution of purified complex, 1,6-hexanediol treatment, hydrophobic motif mutagenesis, 3D-SIM superresolution microscopy, macromolecular crowding assay Cell cycle (Georgetown, Tex.) High 33208041
2022 The APC/C localizes to centrosomes during mitosis in a CEP152-dependent manner and ubiquitylates CEP152, which releases CEP57 from the inhibitory CEP152-CEP63-CEP57 complex. Freed CEP57 then interacts with pericentrin to promote microtubule nucleation and spindle assembly. Co-immunoprecipitation of APC/C with centrosomal proteins, ubiquitylation assays, epistasis analysis of CEP57-pericentrin interaction after CEP152 degradation Journal of cell science Medium 34878135
2022 CEP63 stabilizes the RNA-binding protein FXR1 by binding it and inhibiting its K63-ubiquitylation-dependent degradation. This stabilization promotes YAP1 expression and cancer stem-like properties in colorectal cancer cells. The KH domain of FXR1 is required for the CEP63-FXR1 interaction. USP36 was identified as a deubiquitinase that stabilizes CEP63 by reducing its K48-linked ubiquitination. Co-immunoprecipitation, ubiquitylation assays, domain mapping (FXR1 KH domain), in vitro and in vivo tumor growth assays, CEP63 overexpression/knockdown Oncogene Medium 35989368
2025 CEP152, CEP63, and PCNT form aggregates that function as cartwheel seeds (CS) for centriole assembly, operating independently of pre-existing centrioles. These seeds form in interphase as nanoscale concentric rings comprising CEP152 and CEP63 from which the cartwheel grows. ALMS1 interacts with CEP152, CEP63, and PCNT and is required for CS assembly and disassembly; depleting ALMS1 abolishes CS assembly and eliminates centrioles, while reintroducing ALMS1 generates de novo centrioles. ALMS1 co-immunoprecipitation with CEP152/CEP63/PCNT, ALMS1 depletion/re-expression with centriole biogenesis readout, disease-linked ALMS1 mutations, superresolution imaging of cartwheel seeds bioRxivpreprint Medium 40667363

Source papers

Stage 0 corpus · 18 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 The Cep63 paralogue Deup1 enables massive de novo centriole biogenesis for vertebrate multiciliogenesis. Nature cell biology 168 24240477
2013 Selective chemical crosslinking reveals a Cep57-Cep63-Cep152 centrosomal complex. Current biology : CB 100 23333316
2015 CEP63 deficiency promotes p53-dependent microcephaly and reveals a role for the centrosome in meiotic recombination. Nature communications 87 26158450
2009 An ATM- and ATR-dependent checkpoint inactivates spindle assembly by targeting CEP63. Nature cell biology 58 19182792
2011 Cep63 recruits Cdk1 to the centrosome: implications for regulation of mitotic entry, centrosome amplification, and genome maintenance. Cancer research 51 21406398
2012 Computational investigation of pathogenic nsSNPs in CEP63 protein. Gene 47 22555018
2016 Autophagy controls centrosome number by degrading Cep63. Nature communications 28 27869116
2020 CCDC57 Cooperates with Microtubules and Microcephaly Protein CEP63 and Regulates Centriole Duplication and Mitotic Progression. Cell reports 21 32402286
2015 Mutation in CEP63 co-segregating with developmental dyslexia in a Swedish family. Human genetics 21 26400686
2006 The transcripts of SFRP1,CEP63 and EIF4G2 genes are frequently downregulated in transitional cell carcinomas of the bladder. Oncology 21 16410684
2020 Phase separation of the Cep63•Cep152 complex underlies the formation of dynamic supramolecular self-assemblies at human centrosomes. Cell cycle (Georgetown, Tex.) 19 33208041
2022 The APC/C targets the Cep152-Cep63 complex at the centrosome to regulate mitotic spindle assembly. Journal of cell science 13 34878135
2022 CEP63 upregulates YAP1 to promote colorectal cancer progression through stabilizing RNA binding protein FXR1. Oncogene 9 35989368
2021 Modifier Genes in Microcephaly: A Report on WDR62, CEP63, RAD50 and PCNT Variants Exacerbating Disease Caused by Biallelic Mutations of ASPM and CENPJ. Genes 9 34068194
2021 Cep63 knockout inhibits the malignant phenotypes of papillary thyroid cancer cell line TPC‑1. Oncology reports 3 34296302
2021 Polymorphism in miRNA target sites of CEP-63 and CEP-152 ring complex influences expression of CEP genes and favors tumorigenesis in glioma. Future oncology (London, England) 2 34156311
2025 Centriole biogenesis is seeded by CEP152-CEP63-PCNT aggregates propagating outside the centriole through the Alström syndrome protein ALMS1. bioRxiv : the preprint server for biology 0 40667363
2021 [Study on Cep63 expression and apoptosis of thyroid papillary carcinoma cell lines TPC-1]. Zhonghua er bi yan hou tou jing wai ke za zhi = Chinese journal of otorhinolaryngology head and neck surgery 0 33472304

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