{"gene":"CETN3","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2015,"finding":"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.","method":"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","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro kinase assay (Tier 1) combined with cellular gain- and loss-of-function experiments and phosphomimetic rescue (multiple orthogonal methods), single lab","pmids":["26354417"],"is_preprint":false},{"year":2011,"finding":"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.","method":"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","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean KO with defined cellular phenotype, multiple orthogonal methods (survival, repair kinetics, ultrastructure), single lab","pmids":["21482720"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Gene targeting (single and double knockout mice), electroretinography (ERG), immunofluorescence, ultrastructural analysis by electron microscopy, immunoblotting","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean in vivo KO with defined cellular and structural phenotypes, multiple orthogonal methods (ERG, IF, EM), single lab","pmids":["30647131"],"is_preprint":false},{"year":2025,"finding":"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.","method":"Whole-exome sequencing of patient, CETN3 knockout in cerebral organoids, transcriptomic analysis, histological and protein analyses, centrosome assembly assays, apoptosis assays","journal":"EMBO molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO organoid model with multiple readouts (transcriptomics, histology, centrosome assembly, apoptosis), single lab; splicing interaction inferred but not fully reconstituted","pmids":["40926052"],"is_preprint":false},{"year":2023,"finding":"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.","method":"In vivo crosslinking immunoprecipitation (CLIP) of SRSF2, RNA-seq, isoform-specific knockdown, cell proliferation assays, cell cycle analysis by flow cytometry, rescue experiments","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CLIP establishes direct RNA binding, isoform-specific KD with rescue, multiple functional readouts; single lab","pmids":["36623729"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Fluorescence microscopy (centrin localization to LDs), domain deletion analysis, CETN3 knockout in chicken cone cells, simulation analysis of LD positioning and light sensitivity","journal":"Developmental cell","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — direct localization by microscopy with functional consequence (LD mislocalization on KO), domain analysis, single lab","pmids":["37699389"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Immunofluorescence microscopy for CETN3 and CEP164 in mouse spermatocytes, identification of cilia by marker co-localization","journal":"Cells","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single localization study, single lab, no functional perturbation of CETN3 specifically","pmids":["36611937"],"is_preprint":false}],"current_model":"CETN3 (centrin 3) is a calcium-binding centriolar protein that inhibits the kinase Mps1 to suppress centrosome duplication, cooperates with CETN2 to stabilize the photoreceptor connecting cilium/axoneme, contributes to nucleotide excision repair in a centrosome-independent manner, supports neural stem/progenitor cell cycle progression and neuronal differentiation via centrosome assembly, and undergoes SRSF2-dependent alternative splicing to generate a short isoform that promotes cell cycle progression in colorectal cancer cells."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":2011,"claim":"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","pmids":["21482720"],"confidence":"High","gaps":["No molecular partner or biochemical step in NER assigned to CETN3","Whether the human protein performs the same NER role is untested"]},{"year":2015,"claim":"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","pmids":["26354417"],"confidence":"High","gaps":["Structural basis of the CETN3-Mps1 interaction not resolved","Whether calcium binding modulates the inhibitory activity is untested"]},{"year":2019,"claim":"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","pmids":["30647131"],"confidence":"High","gaps":["Molecular mechanism by which CETN3 stabilizes the axoneme not defined","Direct interaction with SPATA7 not demonstrated"]},{"year":2023,"claim":"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","pmids":["36623729"],"confidence":"Medium","gaps":["Distinct molecular function of CETN3-S versus the full-length protein not defined","Whether CETN3-S acts at centrosomes or elsewhere is unknown"]},{"year":2023,"claim":"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","pmids":["37699389"],"confidence":"Medium","gaps":["Mechanism by which CETN3 tethers the droplet via SPDL1-L not detailed","Relevance to mammalian photoreceptors untested"]},{"year":2025,"claim":"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","pmids":["40926052"],"confidence":"Medium","gaps":["The splicing-machinery interaction is inferred but not reconstituted","Causality of the patient variant not demonstrated by rescue","Single lab, single organoid model"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unifying biochemical model linking the centrosomal and non-centrosomal functions","Role of calcium binding across these activities not systematically tested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[0,6]},{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[2]},{"term_id":"GO:0005811","term_label":"lipid droplet","supporting_discovery_ids":[5]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0,3]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[1]}],"complexes":[],"partners":["CETN2","MPS1","SRSF2","SPDL1-L","CEP164"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O15182","full_name":"Centrin-3","aliases":[],"length_aa":167,"mass_kda":19.6,"function":"Plays a fundamental role in microtubule-organizing center structure and function As a component of the TREX-2 complex, involved in the export of mRNAs to the cytoplasm through the nuclear pores","subcellular_location":"Cytoplasm, cytoskeleton, microtubule organizing center, centrosome; Nucleus, nucleolus; Nucleus envelope; Nucleus, nuclear pore complex; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome, centriole","url":"https://www.uniprot.org/uniprotkb/O15182/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CETN3","classification":"Not Classified","n_dependent_lines":15,"n_total_lines":1208,"dependency_fraction":0.012417218543046357},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000153140","cell_line_id":"CID000206","localizations":[{"compartment":"centrosome","grade":3},{"compartment":"cytoskeleton","grade":2},{"compartment":"cytoplasmic","grade":1},{"compartment":"nucleoplasm","grade":1}],"interactors":[{"gene":"CETN2","stoichiometry":10.0},{"gene":"CALM1","stoichiometry":0.2},{"gene":"CALM2","stoichiometry":0.2},{"gene":"CALM3","stoichiometry":0.2},{"gene":"ANKS6","stoichiometry":0.2},{"gene":"SMG8","stoichiometry":0.2},{"gene":"POC5","stoichiometry":0.2},{"gene":"SFI1","stoichiometry":0.2},{"gene":"PCM1","stoichiometry":0.2},{"gene":"STT3A","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000206","total_profiled":1310},"omim":[{"mim_id":"618934","title":"COILED-COIL SERINE-RICH PROTEIN 1; CCSER1","url":"https://www.omim.org/entry/618934"},{"mim_id":"617880","title":"POC5 CENTRIOLAR PROTEIN; POC5","url":"https://www.omim.org/entry/617880"},{"mim_id":"613443","title":"NEURODEVELOPMENTAL DISORDER WITH HYPOTONIA, STEREOTYPIC HAND MOVEMENTS, AND IMPAIRED LANGUAGE; NEDHSIL","url":"https://www.omim.org/entry/613443"},{"mim_id":"612765","title":"SFI1 CENTRIN-BINDING PROTEIN; SFI1","url":"https://www.omim.org/entry/612765"},{"mim_id":"603191","title":"CILIA- AND FLAGELLA-ASSOCIATED PROTEIN 410; CFAP410","url":"https://www.omim.org/entry/603191"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Centrosome","reliability":"Supported"},{"location":"Basal body","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"testis","ntpm":121.8}],"url":"https://www.proteinatlas.org/search/CETN3"},"hgnc":{"alias_symbol":["CEN3"],"prev_symbol":[]},"alphafold":{"accession":"O15182","domains":[{"cath_id":"1.10.238.10","chopping":"22-95","consensus_level":"high","plddt":95.0705,"start":22,"end":95},{"cath_id":"1.10.238.10","chopping":"98-163","consensus_level":"high","plddt":95.3871,"start":98,"end":163}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O15182","model_url":"https://alphafold.ebi.ac.uk/files/AF-O15182-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O15182-F1-predicted_aligned_error_v6.png","plddt_mean":89.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CETN3","jax_strain_url":"https://www.jax.org/strain/search?query=CETN3"},"sequence":{"accession":"O15182","fasta_url":"https://rest.uniprot.org/uniprotkb/O15182.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O15182/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O15182"}},"corpus_meta":[{"pmid":"27251275","id":"PMC_27251275","title":"Proteogenomics connects somatic mutations to signalling in breast cancer.","date":"2016","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/27251275","citation_count":1290,"is_preprint":false},{"pmid":"6999364","id":"PMC_6999364","title":"Isolation of a yeast centromere and construction of functional small circular chromosomes.","date":"1980","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/6999364","citation_count":639,"is_preprint":false},{"pmid":"7049398","id":"PMC_7049398","title":"Nucleotide sequence comparisons and functional analysis of yeast centromere DNAs.","date":"1982","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/7049398","citation_count":334,"is_preprint":false},{"pmid":"8287474","id":"PMC_8287474","title":"Position effect variegation at fission yeast centromeres.","date":"1994","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/8287474","citation_count":293,"is_preprint":false},{"pmid":"3881185","id":"PMC_3881185","title":"Genetic analysis of the mitotic transmission of minichromosomes.","date":"1985","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/3881185","citation_count":267,"is_preprint":false},{"pmid":"6288253","id":"PMC_6288253","title":"Yeast centromere DNA is in a unique and highly ordered structure in chromosomes and small circular minichromosomes.","date":"1982","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/6288253","citation_count":266,"is_preprint":false},{"pmid":"10761928","id":"PMC_10761928","title":"Establishing biorientation occurs with precocious separation of the sister kinetochores, but not the arms, in the early spindle of budding yeast.","date":"2000","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/10761928","citation_count":253,"is_preprint":false},{"pmid":"22968715","id":"PMC_22968715","title":"Repeatless and repeat-based centromeres in potato: implications for centromere evolution.","date":"2012","source":"The Plant cell","url":"https://pubmed.ncbi.nlm.nih.gov/22968715","citation_count":205,"is_preprint":false},{"pmid":"2541922","id":"PMC_2541922","title":"Composite motifs and repeat symmetry in S. pombe centromeres: direct analysis by integration of NotI restriction sites.","date":"1989","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/2541922","citation_count":195,"is_preprint":false},{"pmid":"23527013","id":"PMC_23527013","title":"Influence of vitamin D status and vitamin D3 supplementation on genome wide expression of white blood cells: a randomized double-blind clinical trial.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23527013","citation_count":183,"is_preprint":false},{"pmid":"18007593","id":"PMC_18007593","title":"Trf4 targets ncRNAs from telomeric and rDNA spacer regions and functions in rDNA copy number control.","date":"2007","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/18007593","citation_count":158,"is_preprint":false},{"pmid":"2583093","id":"PMC_2583093","title":"Characterization of Schizosaccharomyces pombe minichromosome deletion derivatives and a functional allocation of their centromere.","date":"1989","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/2583093","citation_count":131,"is_preprint":false},{"pmid":"1508202","id":"PMC_1508202","title":"Replication forks pause at yeast centromeres.","date":"1992","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/1508202","citation_count":127,"is_preprint":false},{"pmid":"3537689","id":"PMC_3537689","title":"Single base-pair mutations in centromere element III cause aberrant chromosome segregation in Saccharomyces cerevisiae.","date":"1986","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/3537689","citation_count":102,"is_preprint":false},{"pmid":"1629244","id":"PMC_1629244","title":"Visualization of centromeric and nucleolar DNA in fission yeast by fluorescence in situ hybridization.","date":"1992","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/1629244","citation_count":95,"is_preprint":false},{"pmid":"3539697","id":"PMC_3539697","title":"Repression of meiotic crossing over by a centromere (CEN3) in Saccharomyces cerevisiae.","date":"1986","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/3539697","citation_count":94,"is_preprint":false},{"pmid":"6327282","id":"PMC_6327282","title":"Centromeric DNA from chromosome VI in Saccharomyces cerevisiae strains.","date":"1982","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/6327282","citation_count":94,"is_preprint":false},{"pmid":"6352414","id":"PMC_6352414","title":"Copy number control by a yeast centromere.","date":"1983","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/6352414","citation_count":92,"is_preprint":false},{"pmid":"2543684","id":"PMC_2543684","title":"Purification of the yeast centromere binding protein CP1 and a mutational analysis of its binding site.","date":"1989","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/2543684","citation_count":92,"is_preprint":false},{"pmid":"3537715","id":"PMC_3537715","title":"Toxic effects of excess cloned centromeres.","date":"1986","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/3537715","citation_count":89,"is_preprint":false},{"pmid":"2830498","id":"PMC_2830498","title":"Mutational and in vitro protein-binding studies on centromere DNA from Saccharomyces cerevisiae.","date":"1987","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/2830498","citation_count":87,"is_preprint":false},{"pmid":"3550426","id":"PMC_3550426","title":"Alterations in the adenine-plus-thymine-rich region of CEN3 affect centromere function in Saccharomyces cerevisiae.","date":"1987","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/3550426","citation_count":86,"is_preprint":false},{"pmid":"19471318","id":"PMC_19471318","title":"A novel microdeletion syndrome involving 5q14.3-q15: clinical and molecular cytogenetic characterization of three patients.","date":"2009","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/19471318","citation_count":84,"is_preprint":false},{"pmid":"3311877","id":"PMC_3311877","title":"Mutational analysis of meiotic and mitotic centromere function in Saccharomyces cerevisiae.","date":"1987","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/3311877","citation_count":84,"is_preprint":false},{"pmid":"8336703","id":"PMC_8336703","title":"Centromeres of the fission yeast Schizosaccharomyces pombe are highly variable genetic loci.","date":"1993","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/8336703","citation_count":83,"is_preprint":false},{"pmid":"6092387","id":"PMC_6092387","title":"Chromatin conformation of yeast centromeres.","date":"1984","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/6092387","citation_count":78,"is_preprint":false},{"pmid":"2829168","id":"PMC_2829168","title":"Chromatin structure of altered yeast centromeres.","date":"1988","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/2829168","citation_count":76,"is_preprint":false},{"pmid":"2554310","id":"PMC_2554310","title":"Transcription terminates near the poly(A) site in the CYC1 gene of the yeast Saccharomyces cerevisiae.","date":"1989","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/2554310","citation_count":70,"is_preprint":false},{"pmid":"16877494","id":"PMC_16877494","title":"Genomic and genetic characterization of rice Cen3 reveals extensive transcription and evolutionary implications of a complex centromere.","date":"2006","source":"The Plant cell","url":"https://pubmed.ncbi.nlm.nih.gov/16877494","citation_count":69,"is_preprint":false},{"pmid":"9396745","id":"PMC_9396745","title":"Probing the architecture of a simple kinetochore using DNA-protein crosslinking.","date":"1997","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/9396745","citation_count":67,"is_preprint":false},{"pmid":"3280137","id":"PMC_3280137","title":"A yeast centromere acts in cis to inhibit meiotic gene conversion of adjacent sequences.","date":"1988","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/3280137","citation_count":67,"is_preprint":false},{"pmid":"2233714","id":"PMC_2233714","title":"Nucleosome depletion alters the chromatin structure of Saccharomyces cerevisiae centromeres.","date":"1990","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/2233714","citation_count":60,"is_preprint":false},{"pmid":"1572649","id":"PMC_1572649","title":"Long-range chromosomal mapping of the carcinoembryonic antigen (CEA) gene family cluster.","date":"1992","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/1572649","citation_count":59,"is_preprint":false},{"pmid":"7022454","id":"PMC_7022454","title":"Direct selection procedure for the isolation of functional centromeric DNA.","date":"1981","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/7022454","citation_count":59,"is_preprint":false},{"pmid":"8164697","id":"PMC_8164697","title":"Chromosomal DNA replication initiates at the same origins in meiosis and mitosis.","date":"1994","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/8164697","citation_count":53,"is_preprint":false},{"pmid":"21482720","id":"PMC_21482720","title":"Defective nucleotide excision repair with normal centrosome structures and functions in the absence of all vertebrate centrins.","date":"2011","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/21482720","citation_count":50,"is_preprint":false},{"pmid":"6397474","id":"PMC_6397474","title":"Structural and functional analysis of a yeast centromere (CEN3).","date":"1984","source":"Journal of cell science. Supplement","url":"https://pubmed.ncbi.nlm.nih.gov/6397474","citation_count":46,"is_preprint":false},{"pmid":"2934294","id":"PMC_2934294","title":"Construction of multicopy yeast plasmids with regulated centromere function.","date":"1985","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/2934294","citation_count":43,"is_preprint":false},{"pmid":"29266188","id":"PMC_29266188","title":"ADGRV1 is implicated in myoclonic epilepsy.","date":"2017","source":"Epilepsia","url":"https://pubmed.ncbi.nlm.nih.gov/29266188","citation_count":42,"is_preprint":false},{"pmid":"3940061","id":"PMC_3940061","title":"A mutant of Saccharomyces cerevisiae with impaired maintenance of centromeric plasmids.","date":"1985","source":"Current genetics","url":"https://pubmed.ncbi.nlm.nih.gov/3940061","citation_count":42,"is_preprint":false},{"pmid":"23028372","id":"PMC_23028372","title":"SWI/SNF-like chromatin remodeling factor Fun30 supports point centromere function in S. cerevisiae.","date":"2012","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/23028372","citation_count":41,"is_preprint":false},{"pmid":"7028571","id":"PMC_7028571","title":"Characterization of a yeast replication origin (ars2) and construction of stable minichromosomes containing cloned yeast centromere DNA (CEN3).","date":"1981","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/7028571","citation_count":40,"is_preprint":false},{"pmid":"8516310","id":"PMC_8516310","title":"Yeast calmodulin and a conserved nuclear protein participate in the in vivo binding of a matrix association region.","date":"1993","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/8516310","citation_count":40,"is_preprint":false},{"pmid":"11063678","id":"PMC_11063678","title":"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.","date":"2000","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/11063678","citation_count":39,"is_preprint":false},{"pmid":"2991081","id":"PMC_2991081","title":"Resolution of dicentric chromosomes by Ty-mediated recombination in yeast.","date":"1985","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/2991081","citation_count":37,"is_preprint":false},{"pmid":"2653962","id":"PMC_2653962","title":"Mutations in CEN3 cause aberrant chromosome segregation during meiosis in Saccharomyces cerevisiae.","date":"1989","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/2653962","citation_count":35,"is_preprint":false},{"pmid":"11124900","id":"PMC_11124900","title":"Only centromeres can supply the partition system required for ARS function in the yeast Yarrowia lipolytica.","date":"2001","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/11124900","citation_count":34,"is_preprint":false},{"pmid":"3064490","id":"PMC_3064490","title":"Genetic control of chromosome stability in the yeast Saccharomyces cerevisiae.","date":"1988","source":"Yeast (Chichester, England)","url":"https://pubmed.ncbi.nlm.nih.gov/3064490","citation_count":33,"is_preprint":false},{"pmid":"1459444","id":"PMC_1459444","title":"Donor locus selection during Saccharomyces cerevisiae mating type interconversion responds to distant regulatory signals.","date":"1992","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/1459444","citation_count":31,"is_preprint":false},{"pmid":"1840557","id":"PMC_1840557","title":"Genetic analysis of a meiotic recombination hotspot on chromosome III of Saccharomyces cerevisiae.","date":"1991","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/1840557","citation_count":30,"is_preprint":false},{"pmid":"33741944","id":"PMC_33741944","title":"Structural and dynamic mechanisms of CBF3-guided centromeric nucleosome formation.","date":"2021","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/33741944","citation_count":28,"is_preprint":false},{"pmid":"9192840","id":"PMC_9192840","title":"A YAC contig joining the desmocollin and desmoglein loci on human chromosome 18 and ordering of the desmocollin genes.","date":"1997","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/9192840","citation_count":28,"is_preprint":false},{"pmid":"30086210","id":"PMC_30086210","title":"Role of microRNA-410 in molecular oncology: A double edged sword.","date":"2018","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/30086210","citation_count":25,"is_preprint":false},{"pmid":"6376287","id":"PMC_6376287","title":"Stability of recombinant plasmids containing the ars sequence of yeast extrachromosomal rDNA in several strains of Saccharomyces cerevisiae.","date":"1984","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/6376287","citation_count":25,"is_preprint":false},{"pmid":"30647131","id":"PMC_30647131","title":"Deletion of both centrin 2 (CETN2) and CETN3 destabilizes the distal connecting cilium of mouse photoreceptors.","date":"2019","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/30647131","citation_count":22,"is_preprint":false},{"pmid":"23143648","id":"PMC_23143648","title":"High-resolution mapping and transcriptional activity analysis of chicken centromere sequences on giant lampbrush chromosomes.","date":"2012","source":"Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology","url":"https://pubmed.ncbi.nlm.nih.gov/23143648","citation_count":22,"is_preprint":false},{"pmid":"7898434","id":"PMC_7898434","title":"A large circular minichromosome of Schizosaccharomyces pombe requires a high dose of type II DNA topoisomerase for its stabilization.","date":"1995","source":"Molecular & general genetics : MGG","url":"https://pubmed.ncbi.nlm.nih.gov/7898434","citation_count":22,"is_preprint":false},{"pmid":"30675230","id":"PMC_30675230","title":"ACTG1 and TLR3 are biomarkers for alcohol-associated hepatocellular carcinoma.","date":"2018","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/30675230","citation_count":21,"is_preprint":false},{"pmid":"3915768","id":"PMC_3915768","title":"Identification and characterization of the centromere from chromosome XIV in Saccharomyces cerevisiae.","date":"1985","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/3915768","citation_count":21,"is_preprint":false},{"pmid":"2675488","id":"PMC_2675488","title":"Saccharomyces cerevisiae mutants defective in chromosome segregation.","date":"1989","source":"Yeast (Chichester, England)","url":"https://pubmed.ncbi.nlm.nih.gov/2675488","citation_count":20,"is_preprint":false},{"pmid":"8514126","id":"PMC_8514126","title":"Stimulation of meiotic recombination in yeast by an ARS element.","date":"1993","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/8514126","citation_count":20,"is_preprint":false},{"pmid":"11250075","id":"PMC_11250075","title":"Characterization of the X-linked murine centrin Cetn2 gene.","date":"2001","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/11250075","citation_count":19,"is_preprint":false},{"pmid":"28831743","id":"PMC_28831743","title":"Recurrent establishment of de novo centromeres in the pericentromeric region of maize chromosome 3.","date":"2017","source":"Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology","url":"https://pubmed.ncbi.nlm.nih.gov/28831743","citation_count":19,"is_preprint":false},{"pmid":"2542894","id":"PMC_2542894","title":"Sequences that promote formation of catenated intertwines during termination of DNA replication.","date":"1989","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/2542894","citation_count":17,"is_preprint":false},{"pmid":"26354417","id":"PMC_26354417","title":"Centrin 3 is an inhibitor of centrosomal Mps1 and antagonizes centrin 2 function.","date":"2015","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/26354417","citation_count":16,"is_preprint":false},{"pmid":"3032143","id":"PMC_3032143","title":"Structural studies on centromeres in the yeast Saccharomyces cerevisiae.","date":"1986","source":"Basic life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/3032143","citation_count":16,"is_preprint":false},{"pmid":"1874411","id":"PMC_1874411","title":"Isolation and characterization of Schizosaccharomyces pombe mutants affected in mitotic recombination.","date":"1991","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/1874411","citation_count":16,"is_preprint":false},{"pmid":"24252580","id":"PMC_24252580","title":"CETN1 is a cancer testis antigen with expression in prostate and pancreatic cancers.","date":"2013","source":"Biomarker research","url":"https://pubmed.ncbi.nlm.nih.gov/24252580","citation_count":15,"is_preprint":false},{"pmid":"32805644","id":"PMC_32805644","title":"Transcriptional profile of ovine oocytes matured under lipopolysaccharide treatment in vitro.","date":"2020","source":"Theriogenology","url":"https://pubmed.ncbi.nlm.nih.gov/32805644","citation_count":15,"is_preprint":false},{"pmid":"16940283","id":"PMC_16940283","title":"Centrosomal protein centrin is not detectable during early pre-implantation development but reappears during late blastocyst stage in porcine embryos.","date":"2006","source":"Reproduction (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/16940283","citation_count":15,"is_preprint":false},{"pmid":"29773426","id":"PMC_29773426","title":"Stem cell transcription factor SOX2 in synovial sarcoma and other soft tissue tumors.","date":"2018","source":"Pathology, research and practice","url":"https://pubmed.ncbi.nlm.nih.gov/29773426","citation_count":14,"is_preprint":false},{"pmid":"36611937","id":"PMC_36611937","title":"The Male Mouse Meiotic Cilium Emanates from the Mother Centriole at Zygotene Prior to Centrosome Duplication.","date":"2022","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/36611937","citation_count":12,"is_preprint":false},{"pmid":"33134164","id":"PMC_33134164","title":"Integrative Analysis of DNA Methylation Identified 12 Signature Genes Specific to Metastatic ccRCC.","date":"2020","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/33134164","citation_count":12,"is_preprint":false},{"pmid":"2839524","id":"PMC_2839524","title":"Selective excision of the centromere chromatin complex from Saccharomyces cerevisiae.","date":"1988","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/2839524","citation_count":12,"is_preprint":false},{"pmid":"26339383","id":"PMC_26339383","title":"Comparison of structural genetics of non-schistosoma-associated squamous cell carcinoma of the urinary bladder.","date":"2015","source":"International journal of clinical and experimental pathology","url":"https://pubmed.ncbi.nlm.nih.gov/26339383","citation_count":12,"is_preprint":false},{"pmid":"8198056","id":"PMC_8198056","title":"Plasma and tissue lipids of piglets fed formula containing saturated fatty acids from medium-chain triglycerides with or without fish oil.","date":"1994","source":"The American journal of clinical nutrition","url":"https://pubmed.ncbi.nlm.nih.gov/8198056","citation_count":12,"is_preprint":false},{"pmid":"36623729","id":"PMC_36623729","title":"Comprehensive analysis of RNA-binding protein SRSF2-dependent alternative splicing signature in malignant proliferation of colorectal carcinoma.","date":"2023","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/36623729","citation_count":11,"is_preprint":false},{"pmid":"29642177","id":"PMC_29642177","title":"Companied P16 genetic and protein status together providing useful information on the clinical outcome of urinary bladder cancer.","date":"2018","source":"Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/29642177","citation_count":7,"is_preprint":false},{"pmid":"36543086","id":"PMC_36543086","title":"Changes in mechanical and bacterial properties of denture base resin following nanoceria incorporation with and without SBA-15 carriers.","date":"2022","source":"Journal of the mechanical behavior of biomedical materials","url":"https://pubmed.ncbi.nlm.nih.gov/36543086","citation_count":7,"is_preprint":false},{"pmid":"24177529","id":"PMC_24177529","title":"Regulation of transcription of the Saccharomyces cerevisiae CYC1 gene: Identification of a DNA region involved in heme control.","date":"1984","source":"Current genetics","url":"https://pubmed.ncbi.nlm.nih.gov/24177529","citation_count":7,"is_preprint":false},{"pmid":"7721103","id":"PMC_7721103","title":"Construction of a human DNA library in a circular centromere-based yeast plasmid.","date":"1995","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/7721103","citation_count":6,"is_preprint":false},{"pmid":"37699389","id":"PMC_37699389","title":"Centrins control chicken cone cell lipid droplet dynamics through lipid-droplet-localized SPDL1.","date":"2023","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/37699389","citation_count":5,"is_preprint":false},{"pmid":"17341606","id":"PMC_17341606","title":"Oxidative stress response in telomerase-immortalized fibroblasts from a centenarian.","date":"2006","source":"Annals of the New York Academy of Sciences","url":"https://pubmed.ncbi.nlm.nih.gov/17341606","citation_count":5,"is_preprint":false},{"pmid":"40926052","id":"PMC_40926052","title":"CETN3 deficiency induces microcephaly by disrupting neural stem/progenitor cell fate through impaired centrosome assembly and RNA splicing.","date":"2025","source":"EMBO molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/40926052","citation_count":4,"is_preprint":false},{"pmid":"39694081","id":"PMC_39694081","title":"Single-cell RNA sequencing unveils dynamic transcriptional profiles during the process of donkey spermatogenesis and maturation.","date":"2024","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/39694081","citation_count":3,"is_preprint":false},{"pmid":"3326785","id":"PMC_3326785","title":"[Chromosome stability in saccharomycete yeasts].","date":"1987","source":"Genetika","url":"https://pubmed.ncbi.nlm.nih.gov/3326785","citation_count":2,"is_preprint":false},{"pmid":"40696606","id":"PMC_40696606","title":"Associations of 2923 plasma proteins with incident atopic dermatitis in a prospective cohort study and genetic analysis.","date":"2025","source":"Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/40696606","citation_count":1,"is_preprint":false},{"pmid":"6355825","id":"PMC_6355825","title":"[Extrachromosomal DNA in yeast-Saccharomyces].","date":"1983","source":"Molekuliarnaia biologiia","url":"https://pubmed.ncbi.nlm.nih.gov/6355825","citation_count":1,"is_preprint":false},{"pmid":"39220737","id":"PMC_39220737","title":"Identification and Mendelian randomization validation of pathogenic gene biomarkers in obstructive sleep apnea.","date":"2024","source":"Frontiers in neurology","url":"https://pubmed.ncbi.nlm.nih.gov/39220737","citation_count":0,"is_preprint":false},{"pmid":"27354270","id":"PMC_27354270","title":"Tumor Profiling: Adding Proteomics to Genomics.","date":"2016","source":"Cancer discovery","url":"https://pubmed.ncbi.nlm.nih.gov/27354270","citation_count":0,"is_preprint":false},{"pmid":"10563386","id":"PMC_10563386","title":"[C-terminal domain of saccharomyces cerevisiae protein ChI4 binds to centromere DNA fragment of yeast chromosome III].","date":"1999","source":"Tsitologiia","url":"https://pubmed.ncbi.nlm.nih.gov/10563386","citation_count":0,"is_preprint":false},{"pmid":"3405230","id":"PMC_3405230","title":"[Behavior in a cell of artificial mini-chromosomes during induced transcription of centromeric DNA].","date":"1988","source":"Molekuliarnaia genetika, mikrobiologiia i virusologiia","url":"https://pubmed.ncbi.nlm.nih.gov/3405230","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":40645,"output_tokens":2183,"usd":0.07734,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9207,"output_tokens":2524,"usd":0.054567,"stage2_stop_reason":"end_turn"},"total_usd":0.131907,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro kinase assay (Tier 1) combined with cellular gain- and loss-of-function experiments and phosphomimetic rescue (multiple orthogonal methods), single lab\",\n      \"pmids\": [\"26354417\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with defined cellular phenotype, multiple orthogonal methods (survival, repair kinetics, ultrastructure), single lab\",\n      \"pmids\": [\"21482720\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Gene targeting (single and double knockout mice), electroretinography (ERG), immunofluorescence, ultrastructural analysis by electron microscopy, immunoblotting\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean in vivo KO with defined cellular and structural phenotypes, multiple orthogonal methods (ERG, IF, EM), single lab\",\n      \"pmids\": [\"30647131\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"Whole-exome sequencing of patient, CETN3 knockout in cerebral organoids, transcriptomic analysis, histological and protein analyses, centrosome assembly assays, apoptosis assays\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO organoid model with multiple readouts (transcriptomics, histology, centrosome assembly, apoptosis), single lab; splicing interaction inferred but not fully reconstituted\",\n      \"pmids\": [\"40926052\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"In vivo crosslinking immunoprecipitation (CLIP) of SRSF2, RNA-seq, isoform-specific knockdown, cell proliferation assays, cell cycle analysis by flow cytometry, rescue experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CLIP establishes direct RNA binding, isoform-specific KD with rescue, multiple functional readouts; single lab\",\n      \"pmids\": [\"36623729\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Fluorescence microscopy (centrin localization to LDs), domain deletion analysis, CETN3 knockout in chicken cone cells, simulation analysis of LD positioning and light sensitivity\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — direct localization by microscopy with functional consequence (LD mislocalization on KO), domain analysis, single lab\",\n      \"pmids\": [\"37699389\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Immunofluorescence microscopy for CETN3 and CEP164 in mouse spermatocytes, identification of cilia by marker co-localization\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single localization study, single lab, no functional perturbation of CETN3 specifically\",\n      \"pmids\": [\"36611937\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CETN3 (centrin 3) is a calcium-binding centriolar protein that inhibits the kinase Mps1 to suppress centrosome duplication, cooperates with CETN2 to stabilize the photoreceptor connecting cilium/axoneme, contributes to nucleotide excision repair in a centrosome-independent manner, supports neural stem/progenitor cell cycle progression and neuronal differentiation via centrosome assembly, and undergoes SRSF2-dependent alternative splicing to generate a short isoform that promotes cell cycle progression in colorectal cancer cells.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#0, #1, #3]. 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 [#0]. Independently of centrosome architecture, CETN3 contributes to nucleotide excision repair of UV damage, a function genetically separable from intact centrosome ultrastructure [#1]. 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 [#2, #5]. 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 [#3]. 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 [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 2011,\n      \"claim\": \"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.\",\n      \"evidence\": \"Single and multiple centrin knockouts in chicken DT40 cells with UV survival, repair kinetics, and centrosome ultrastructure analysis\",\n      \"pmids\": [\"21482720\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No molecular partner or biochemical step in NER assigned to CETN3\", \"Whether the human protein performs the same NER role is untested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"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.\",\n      \"evidence\": \"In vitro Mps1 kinase assays, cellular overexpression/depletion, phospho-Thr-676 detection, and phosphomimetic CETN2 rescue\",\n      \"pmids\": [\"26354417\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the CETN3-Mps1 interaction not resolved\", \"Whether calcium binding modulates the inhibitory activity is untested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"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.\",\n      \"evidence\": \"Single and double knockout mice with ERG, immunofluorescence, electron microscopy, and immunoblotting\",\n      \"pmids\": [\"30647131\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism by which CETN3 stabilizes the axoneme not defined\", \"Direct interaction with SPATA7 not demonstrated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Linked CETN3 to alternative splicing regulation in cancer, revealing a non-centriolar pathway in which an SRSF2-generated short isoform promotes proliferation.\",\n      \"evidence\": \"SRSF2 CLIP, RNA-seq, isoform-specific knockdown, flow cytometry cell cycle analysis, and rescue in colon cancer cells\",\n      \"pmids\": [\"36623729\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Distinct molecular function of CETN3-S versus the full-length protein not defined\", \"Whether CETN3-S acts at centrosomes or elsewhere is unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified a lipid-droplet localization for CETN3 mediated by its C-terminal calcium-binding domain, extending centrin function to organelle positioning for vision.\",\n      \"evidence\": \"Fluorescence microscopy, domain deletion, CETN3 knockout in chicken cone cells, and light-sensitivity simulation\",\n      \"pmids\": [\"37699389\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which CETN3 tethers the droplet via SPDL1-L not detailed\", \"Relevance to mammalian photoreceptors untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Connected CETN3 loss-of-function to human primary microcephaly, establishing disease relevance and integrating its centrosome-assembly and splicing roles in neural development.\",\n      \"evidence\": \"Whole-exome sequencing of patient plus CETN3 knockout cerebral organoids with transcriptomics, centrosome assembly, and apoptosis assays\",\n      \"pmids\": [\"40926052\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The splicing-machinery interaction is inferred but not reconstituted\", \"Causality of the patient variant not demonstrated by rescue\", \"Single lab, single organoid model\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unifying biochemical model linking the centrosomal and non-centrosomal functions\", \"Role of calcium binding across these activities not systematically tested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [0, 6]},\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0005811\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CETN2\", \"MPS1\", \"SRSF2\", \"SPDL1-L\", \"CEP164\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}