Affinage

CETN3

Centrin-3 · UniProt O15182

Length
167 aa
Mass
19.6 kDa
Annotated
2026-06-09
92 papers in source corpus 7 papers cited in narrative 7 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CETN3 (centrin 3) is a calcium-binding centrin that constrains centriole number and supports centrosome-dependent cell cycle progression while also acting through centrosome-independent routes (PMID:26354417, PMID:21482720, PMID:40926052). At centrosomes, CETN3 functions as a biochemical inhibitor of the kinase Mps1: it blocks Mps1 autophosphorylation at the T-loop site Thr-676 and prevents Mps1-dependent phosphorylation of CETN2, thereby limiting CETN2 incorporation into centrioles and suppressing centrosome reduplication; phosphomimetic CETN2 bypasses this inhibition, placing CETN3's control of centriole copy number downstream of Mps1 suppression (PMID:26354417). Independently of centrosome architecture, CETN3 contributes to nucleotide excision repair of UV damage, a function genetically separable from intact centrosome ultrastructure (PMID:21482720). In differentiated cells, CETN3 cooperates with CETN2 to stabilize the photoreceptor connecting cilium and axoneme, maintaining SPATA7 and proper CETN1 distribution, and localizes via its C-terminal calcium-binding domain to cone-cell lipid droplets in a SPDL1-L-dependent manner to position the droplet for optimal light sensitivity (PMID:30647131, PMID:37699389). Loss-of-function mutations in CETN3 cause primary microcephaly: CETN3 deficiency impairs centrosome assembly required for neural stem/progenitor cell cycle progression and differentiation, and CETN3 additionally interacts with RNA splicing machinery, an indirect pathway to brain development (PMID:40926052). Consistent with a link to splicing, SRSF2 binds CETN3 pre-mRNA to generate a short isoform (CETN3-S) that drives colon cancer cell cycle progression (PMID:36623729).

Mechanistic history

Synthesis pass · year-by-year structured walk · 6 steps
  1. 2011 High

    Established that CETN3 has a centrosome-independent role, resolving whether centrin function is confined to the centrosome by showing it contributes to nucleotide excision repair.

    Evidence Single and multiple centrin knockouts in chicken DT40 cells with UV survival, repair kinetics, and centrosome ultrastructure analysis

    PMID:21482720

    Open questions at the time
    • No molecular partner or biochemical step in NER assigned to CETN3
    • Whether the human protein performs the same NER role is untested
  2. 2015 High

    Defined the molecular mechanism by which CETN3 limits centriole number, answering how centrosome copy control is enforced by identifying CETN3 as a direct inhibitor of Mps1.

    Evidence In vitro Mps1 kinase assays, cellular overexpression/depletion, phospho-Thr-676 detection, and phosphomimetic CETN2 rescue

    PMID:26354417

    Open questions at the time
    • Structural basis of the CETN3-Mps1 interaction not resolved
    • Whether calcium binding modulates the inhibitory activity is untested
  3. 2019 High

    Showed CETN3 and CETN2 are functionally redundant at the photoreceptor connecting cilium, explaining why single CETN3 loss is silent and establishing a cooperative ciliary stabilization role.

    Evidence Single and double knockout mice with ERG, immunofluorescence, electron microscopy, and immunoblotting

    PMID:30647131

    Open questions at the time
    • Molecular mechanism by which CETN3 stabilizes the axoneme not defined
    • Direct interaction with SPATA7 not demonstrated
  4. 2023 Medium

    Linked CETN3 to alternative splicing regulation in cancer, revealing a non-centriolar pathway in which an SRSF2-generated short isoform promotes proliferation.

    Evidence SRSF2 CLIP, RNA-seq, isoform-specific knockdown, flow cytometry cell cycle analysis, and rescue in colon cancer cells

    PMID:36623729

    Open questions at the time
    • Distinct molecular function of CETN3-S versus the full-length protein not defined
    • Whether CETN3-S acts at centrosomes or elsewhere is unknown
  5. 2023 Medium

    Identified a lipid-droplet localization for CETN3 mediated by its C-terminal calcium-binding domain, extending centrin function to organelle positioning for vision.

    Evidence Fluorescence microscopy, domain deletion, CETN3 knockout in chicken cone cells, and light-sensitivity simulation

    PMID:37699389

    Open questions at the time
    • Mechanism by which CETN3 tethers the droplet via SPDL1-L not detailed
    • Relevance to mammalian photoreceptors untested
  6. 2025 Medium

    Connected CETN3 loss-of-function to human primary microcephaly, establishing disease relevance and integrating its centrosome-assembly and splicing roles in neural development.

    Evidence Whole-exome sequencing of patient plus CETN3 knockout cerebral organoids with transcriptomics, centrosome assembly, and apoptosis assays

    PMID:40926052

    Open questions at the time
    • The splicing-machinery interaction is inferred but not reconstituted
    • Causality of the patient variant not demonstrated by rescue
    • Single lab, single organoid model

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CETN3's distinct activities — Mps1 inhibition, NER, ciliary/axonemal stabilization, lipid-droplet positioning, and splicing regulation — are integrated or differentially deployed across cell types remains unresolved.
  • No unifying biochemical model linking the centrosomal and non-centrosomal functions
  • Role of calcium binding across these activities not systematically tested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 1
Localization
GO:0005815 microtubule organizing center 2 GO:0005811 lipid droplet 1 GO:0005929 cilium 1
Pathway
R-HSA-1640170 Cell Cycle 2 R-HSA-73894 DNA Repair 1
Partners
CEP164CETN2MPS1SPDL1-LSRSF2

Evidence

Reading pass · 7 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2015 CETN3 (centrin 3) acts as a biochemical inhibitor of the protein kinase Mps1 and a biological inhibitor of centrosome duplication. In vitro, CETN3 inhibits Mps1 autophosphorylation at Thr-676 (a T-loop autoactivation site) and interferes with Mps1-dependent phosphorylation of CETN2. Cellular overexpression of CETN3 attenuates CETN2 incorporation into centrioles and suppresses centrosome reduplication, while depletion of CETN3 generates extra centrioles. Mimicking Mps1-dependent phosphorylation of CETN2 bypasses the inhibitory effect of CETN3, indicating that CETN3's biological effects are mediated through inhibition of Mps1 at centrosomes. In vitro kinase assays with Mps1, cellular overexpression and depletion experiments, immunofluorescence for CETN2 incorporation and centrosome number, phospho-specific antibody detection of Mps1 Thr-676 Molecular biology of the cell High 26354417
2011 Vertebrate CETN3 contributes to nucleotide excision repair (NER). In chicken DT40 cells lacking all centrin genes, NER of UV-induced DNA damage was delayed. Cetn3 deficiency specifically exacerbated the UV sensitivity of Cetn4/Cetn2 double-mutant cells. DNA damage checkpoints were intact, indicating the defect is repair-specific. Centrosome composition and ultrastructure were normal in centrin-null cells, demonstrating the NER role is separable from centrosome function. Gene targeting in DT40 cells (single and multiple centrin knockouts), UV irradiation survival assays, DNA damage repair kinetics, light and electron microscopy of centrosome ultrastructure, DNA damage checkpoint assays The Journal of cell biology High 21482720
2019 CETN2 and CETN3 cooperate to stabilize the photoreceptor connecting cilium (CC) and axoneme. Cetn3 single knockout mice had no photoreceptor defect, but Cetn2/Cetn3 double knockout caused progressive retinal degeneration with destabilization of the CC axoneme, reduction of CC length by P22, depletion of SPATA7 (a distal CC organizer), condensation of CETN1 to the mid-CC segment, and radial expansion of the axoneme with misaligned outer-segment discs. Gene targeting (single and double knockout mice), electroretinography (ERG), immunofluorescence, ultrastructural analysis by electron microscopy, immunoblotting The Journal of biological chemistry High 30647131
2025 Loss-of-function mutations in CETN3 cause primary microcephaly. In human pluripotent stem cell-derived cerebral organoids, CETN3 KO recapitulated microcephaly with reduced organoid size. CETN3 deficiency impaired centrosome assembly required for cell cycle progression in neural stem/progenitor cells, reduced proliferative capacity, activated apoptosis, and disrupted neuronal differentiation. Additionally, CETN3 interacts with RNA splicing machinery involved in brain development, revealing an indirect pathway through splicing regulation. Whole-exome sequencing of patient, CETN3 knockout in cerebral organoids, transcriptomic analysis, histological and protein analyses, centrosome assembly assays, apoptosis assays EMBO molecular medicine Medium 40926052
2023 SRSF2 directly binds CETN3 pre-mRNA (via its RNA recognition motif binding to exon 6) and facilitates exclusion of CETN3 alternative exon 5, generating a short isoform (CETN3-S). Knockdown of the CETN3-S splice isoform suppresses colon cancer cell growth and causes G1 cell cycle arrest. Rescue of CETN3-S in SRSF2 knockdown cells reverses inhibition of proliferation and restores cell cycle progression. In vivo crosslinking immunoprecipitation (CLIP) of SRSF2, RNA-seq, isoform-specific knockdown, cell proliferation assays, cell cycle analysis by flow cytometry, rescue experiments The Journal of biological chemistry Medium 36623729
2023 CETN3, along with other centrins, localizes to lipid droplets in chicken cone cells via its C-terminal calcium-binding domain. Localization to cone cell lipid droplets requires the lipid-droplet-associated protein SPDL1-L. Loss of CETN3 abrogates the apical localization of the single cone cell lipid droplet, which is required for optimal light sensitivity. Fluorescence microscopy (centrin localization to LDs), domain deletion analysis, CETN3 knockout in chicken cone cells, simulation analysis of LD positioning and light sensitivity Developmental cell Medium 37699389
2022 In male mouse meiosis, CETN3 localizes to the mother centriole, and CEP164/CETN3 localization studies demonstrate that transient cilia observed in ~20% of zygotene spermatocytes emanate from the mother centriole prior to centrosome duplication. Immunofluorescence microscopy for CETN3 and CEP164 in mouse spermatocytes, identification of cilia by marker co-localization Cells Low 36611937

Source papers

Stage 0 corpus · 92 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2016 Proteogenomics connects somatic mutations to signalling in breast cancer. Nature 1290 27251275
1980 Isolation of a yeast centromere and construction of functional small circular chromosomes. Nature 639 6999364
1982 Nucleotide sequence comparisons and functional analysis of yeast centromere DNAs. Cell 334 7049398
1994 Position effect variegation at fission yeast centromeres. Cell 293 8287474
1985 Genetic analysis of the mitotic transmission of minichromosomes. Cell 267 3881185
1982 Yeast centromere DNA is in a unique and highly ordered structure in chromosomes and small circular minichromosomes. Cell 266 6288253
2000 Establishing biorientation occurs with precocious separation of the sister kinetochores, but not the arms, in the early spindle of budding yeast. Cell 253 10761928
2012 Repeatless and repeat-based centromeres in potato: implications for centromere evolution. The Plant cell 205 22968715
1989 Composite motifs and repeat symmetry in S. pombe centromeres: direct analysis by integration of NotI restriction sites. Cell 195 2541922
2013 Influence of vitamin D status and vitamin D3 supplementation on genome wide expression of white blood cells: a randomized double-blind clinical trial. PloS one 183 23527013
2007 Trf4 targets ncRNAs from telomeric and rDNA spacer regions and functions in rDNA copy number control. The EMBO journal 158 18007593
1989 Characterization of Schizosaccharomyces pombe minichromosome deletion derivatives and a functional allocation of their centromere. The EMBO journal 131 2583093
1992 Replication forks pause at yeast centromeres. Molecular and cellular biology 127 1508202
1986 Single base-pair mutations in centromere element III cause aberrant chromosome segregation in Saccharomyces cerevisiae. Molecular and cellular biology 102 3537689
1992 Visualization of centromeric and nucleolar DNA in fission yeast by fluorescence in situ hybridization. Journal of cell science 95 1629244
1986 Repression of meiotic crossing over by a centromere (CEN3) in Saccharomyces cerevisiae. Genetics 94 3539697
1982 Centromeric DNA from chromosome VI in Saccharomyces cerevisiae strains. The EMBO journal 94 6327282
1989 Purification of the yeast centromere binding protein CP1 and a mutational analysis of its binding site. The Journal of biological chemistry 92 2543684
1983 Copy number control by a yeast centromere. Gene 92 6352414
1986 Toxic effects of excess cloned centromeres. Molecular and cellular biology 89 3537715
1987 Mutational and in vitro protein-binding studies on centromere DNA from Saccharomyces cerevisiae. Molecular and cellular biology 87 2830498
1987 Alterations in the adenine-plus-thymine-rich region of CEN3 affect centromere function in Saccharomyces cerevisiae. Molecular and cellular biology 86 3550426
2009 A novel microdeletion syndrome involving 5q14.3-q15: clinical and molecular cytogenetic characterization of three patients. European journal of human genetics : EJHG 84 19471318
1987 Mutational analysis of meiotic and mitotic centromere function in Saccharomyces cerevisiae. Genetics 84 3311877
1993 Centromeres of the fission yeast Schizosaccharomyces pombe are highly variable genetic loci. Molecular and cellular biology 83 8336703
1984 Chromatin conformation of yeast centromeres. The Journal of cell biology 78 6092387
1988 Chromatin structure of altered yeast centromeres. Proceedings of the National Academy of Sciences of the United States of America 76 2829168
1989 Transcription terminates near the poly(A) site in the CYC1 gene of the yeast Saccharomyces cerevisiae. Proceedings of the National Academy of Sciences of the United States of America 70 2554310
2006 Genomic and genetic characterization of rice Cen3 reveals extensive transcription and evolutionary implications of a complex centromere. The Plant cell 69 16877494
1997 Probing the architecture of a simple kinetochore using DNA-protein crosslinking. The Journal of cell biology 67 9396745
1988 A yeast centromere acts in cis to inhibit meiotic gene conversion of adjacent sequences. Cell 67 3280137
1990 Nucleosome depletion alters the chromatin structure of Saccharomyces cerevisiae centromeres. Molecular and cellular biology 60 2233714
1992 Long-range chromosomal mapping of the carcinoembryonic antigen (CEA) gene family cluster. Genomics 59 1572649
1981 Direct selection procedure for the isolation of functional centromeric DNA. Proceedings of the National Academy of Sciences of the United States of America 59 7022454
1994 Chromosomal DNA replication initiates at the same origins in meiosis and mitosis. Molecular and cellular biology 53 8164697
2011 Defective nucleotide excision repair with normal centrosome structures and functions in the absence of all vertebrate centrins. The Journal of cell biology 50 21482720
1984 Structural and functional analysis of a yeast centromere (CEN3). Journal of cell science. Supplement 46 6397474
1985 Construction of multicopy yeast plasmids with regulated centromere function. Gene 43 2934294
2017 ADGRV1 is implicated in myoclonic epilepsy. Epilepsia 42 29266188
1985 A mutant of Saccharomyces cerevisiae with impaired maintenance of centromeric plasmids. Current genetics 42 3940061
2012 SWI/SNF-like chromatin remodeling factor Fun30 supports point centromere function in S. cerevisiae. PLoS genetics 41 23028372
1993 Yeast calmodulin and a conserved nuclear protein participate in the in vivo binding of a matrix association region. Proceedings of the National Academy of Sciences of the United States of America 40 8516310
1981 Characterization of a yeast replication origin (ars2) and construction of stable minichromosomes containing cloned yeast centromere DNA (CEN3). Gene 40 7028571
2000 CSE4 genetically interacts with the Saccharomyces cerevisiae centromere DNA elements CDE I and CDE II but not CDE III. Implications for the path of the centromere dna around a cse4p variant nucleosome. Genetics 39 11063678
1985 Resolution of dicentric chromosomes by Ty-mediated recombination in yeast. Genetics 37 2991081
1989 Mutations in CEN3 cause aberrant chromosome segregation during meiosis in Saccharomyces cerevisiae. Genetics 35 2653962
2001 Only centromeres can supply the partition system required for ARS function in the yeast Yarrowia lipolytica. Journal of molecular biology 34 11124900
1988 Genetic control of chromosome stability in the yeast Saccharomyces cerevisiae. Yeast (Chichester, England) 33 3064490
1992 Donor locus selection during Saccharomyces cerevisiae mating type interconversion responds to distant regulatory signals. Genetics 31 1459444
1991 Genetic analysis of a meiotic recombination hotspot on chromosome III of Saccharomyces cerevisiae. Genetics 30 1840557
2021 Structural and dynamic mechanisms of CBF3-guided centromeric nucleosome formation. Nature communications 28 33741944
1997 A YAC contig joining the desmocollin and desmoglein loci on human chromosome 18 and ordering of the desmocollin genes. Genomics 28 9192840
2018 Role of microRNA-410 in molecular oncology: A double edged sword. Journal of cellular biochemistry 25 30086210
1984 Stability of recombinant plasmids containing the ars sequence of yeast extrachromosomal rDNA in several strains of Saccharomyces cerevisiae. Gene 25 6376287
2019 Deletion of both centrin 2 (CETN2) and CETN3 destabilizes the distal connecting cilium of mouse photoreceptors. The Journal of biological chemistry 22 30647131
2012 High-resolution mapping and transcriptional activity analysis of chicken centromere sequences on giant lampbrush chromosomes. Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology 22 23143648
1995 A large circular minichromosome of Schizosaccharomyces pombe requires a high dose of type II DNA topoisomerase for its stabilization. Molecular & general genetics : MGG 22 7898434
2018 ACTG1 and TLR3 are biomarkers for alcohol-associated hepatocellular carcinoma. Oncology letters 21 30675230
1985 Identification and characterization of the centromere from chromosome XIV in Saccharomyces cerevisiae. Molecular and cellular biology 21 3915768
1993 Stimulation of meiotic recombination in yeast by an ARS element. Genetics 20 8514126
1989 Saccharomyces cerevisiae mutants defective in chromosome segregation. Yeast (Chichester, England) 20 2675488
2017 Recurrent establishment of de novo centromeres in the pericentromeric region of maize chromosome 3. Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology 19 28831743
2001 Characterization of the X-linked murine centrin Cetn2 gene. Gene 19 11250075
1989 Sequences that promote formation of catenated intertwines during termination of DNA replication. Nucleic acids research 17 2542894
2015 Centrin 3 is an inhibitor of centrosomal Mps1 and antagonizes centrin 2 function. Molecular biology of the cell 16 26354417
1991 Isolation and characterization of Schizosaccharomyces pombe mutants affected in mitotic recombination. Genetics 16 1874411
1986 Structural studies on centromeres in the yeast Saccharomyces cerevisiae. Basic life sciences 16 3032143
2020 Transcriptional profile of ovine oocytes matured under lipopolysaccharide treatment in vitro. Theriogenology 15 32805644
2013 CETN1 is a cancer testis antigen with expression in prostate and pancreatic cancers. Biomarker research 15 24252580
2006 Centrosomal protein centrin is not detectable during early pre-implantation development but reappears during late blastocyst stage in porcine embryos. Reproduction (Cambridge, England) 15 16940283
2018 Stem cell transcription factor SOX2 in synovial sarcoma and other soft tissue tumors. Pathology, research and practice 14 29773426
2022 The Male Mouse Meiotic Cilium Emanates from the Mother Centriole at Zygotene Prior to Centrosome Duplication. Cells 12 36611937
2020 Integrative Analysis of DNA Methylation Identified 12 Signature Genes Specific to Metastatic ccRCC. Frontiers in oncology 12 33134164
2015 Comparison of structural genetics of non-schistosoma-associated squamous cell carcinoma of the urinary bladder. International journal of clinical and experimental pathology 12 26339383
1994 Plasma and tissue lipids of piglets fed formula containing saturated fatty acids from medium-chain triglycerides with or without fish oil. The American journal of clinical nutrition 12 8198056
1988 Selective excision of the centromere chromatin complex from Saccharomyces cerevisiae. The Journal of cell biology 12 2839524
2023 Comprehensive analysis of RNA-binding protein SRSF2-dependent alternative splicing signature in malignant proliferation of colorectal carcinoma. The Journal of biological chemistry 11 36623729
2022 Changes in mechanical and bacterial properties of denture base resin following nanoceria incorporation with and without SBA-15 carriers. Journal of the mechanical behavior of biomedical materials 7 36543086
2018 Companied P16 genetic and protein status together providing useful information on the clinical outcome of urinary bladder cancer. Medicine 7 29642177
1984 Regulation of transcription of the Saccharomyces cerevisiae CYC1 gene: Identification of a DNA region involved in heme control. Current genetics 7 24177529
1995 Construction of a human DNA library in a circular centromere-based yeast plasmid. Gene 6 7721103
2023 Centrins control chicken cone cell lipid droplet dynamics through lipid-droplet-localized SPDL1. Developmental cell 5 37699389
2006 Oxidative stress response in telomerase-immortalized fibroblasts from a centenarian. Annals of the New York Academy of Sciences 5 17341606
2025 CETN3 deficiency induces microcephaly by disrupting neural stem/progenitor cell fate through impaired centrosome assembly and RNA splicing. EMBO molecular medicine 4 40926052
2024 Single-cell RNA sequencing unveils dynamic transcriptional profiles during the process of donkey spermatogenesis and maturation. Genomics 3 39694081
1987 [Chromosome stability in saccharomycete yeasts]. Genetika 2 3326785
2025 Associations of 2923 plasma proteins with incident atopic dermatitis in a prospective cohort study and genetic analysis. Medicine 1 40696606
1983 [Extrachromosomal DNA in yeast-Saccharomyces]. Molekuliarnaia biologiia 1 6355825
2024 Identification and Mendelian randomization validation of pathogenic gene biomarkers in obstructive sleep apnea. Frontiers in neurology 0 39220737
2016 Tumor Profiling: Adding Proteomics to Genomics. Cancer discovery 0 27354270
1999 [C-terminal domain of saccharomyces cerevisiae protein ChI4 binds to centromere DNA fragment of yeast chromosome III]. Tsitologiia 0 10563386
1988 [Behavior in a cell of artificial mini-chromosomes during induced transcription of centromeric DNA]. Molekuliarnaia genetika, mikrobiologiia i virusologiia 0 3405230

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