{"gene":"CPAP","run_date":"2026-06-09T22:57:19","timeline":{"discoveries":[{"year":2000,"finding":"CPAP (centrosomal P4.1-associated protein) was identified as a novel centrosomal protein that interacts with the head domain of 4.1R-135 via yeast two-hybrid, co-sediments with gamma-tubulin in sucrose gradients, and co-immunoprecipitates with gamma-tubulin, indicating it is part of the gamma-tubulin complex. Anti-CPAP antibody significantly inhibited formation of microtubule asters, demonstrating a role in microtubule nucleation.","method":"Yeast two-hybrid, sucrose gradient co-sedimentation, co-immunoprecipitation, immunofluorescence, antibody inhibition assay","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and functional antibody inhibition assay, single lab, multiple orthogonal methods","pmids":["11003675"],"is_preprint":false},{"year":2002,"finding":"CPAP interacts specifically with Stat5a and Stat5b (but not Stat1 or Stat3) via yeast two-hybrid screening. CPAP augments Stat5-mediated transcription and translocates to the nucleus upon PRL pathway activation, acting as a transcriptional coactivator of Stat5.","method":"Yeast two-hybrid, co-immunoprecipitation, reporter transcription assay, immunofluorescence, cellular fractionation","journal":"Molecular endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, reporter assay, fractionation), single lab","pmids":["12198240"],"is_preprint":false},{"year":2004,"finding":"CPAP contains a novel 112-residue microtubule-destabilizing motif (MDD, residues 311–422) that binds tubulin heterodimers, inhibits microtubule nucleation from the centrosome, depolymerizes taxol-stabilized microtubules, and when overexpressed induces G2/M arrest and apoptosis.","method":"Deletion mapping, in vitro microtubule depolymerization assay, tubulin-binding assay, tetracycline-controlled overexpression, cell cycle analysis","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro enzymatic/biochemical assays with deletion mapping and mutagenesis, replicated in subsequent studies","pmids":["15047868"],"is_preprint":false},{"year":2005,"finding":"CPAP (CENPJ) localizes to spindle poles of mitotic cells during neuroepithelial neurogenesis; homozygous loss-of-function mutations in CENPJ cause primary microcephaly (MCPH6), implicating a centrosomal mechanism in controlling neuron number.","method":"Genetic mapping, mutation analysis, immunofluorescence localization in human tissue","journal":"Nature genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function with defined disease phenotype and protein localization, single study","pmids":["15793586"],"is_preprint":false},{"year":2005,"finding":"RNAi-mediated depletion of CPAP in human cells arrests cells in mitosis, induces apoptosis, and causes multipolar spindle formation in >40% of mitotic cells. Inhibition of kinesin Eg5 in CPAP-depleted cells results in monopolar spindles, indicating Eg5 is required downstream of CPAP for multipolar spindle formation, revealing a structural role for CPAP in centrosome integrity.","method":"siRNA knockdown, immunofluorescence, Eg5 inhibition epistasis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KD with defined phenotype and epistasis experiment, single lab","pmids":["16316625"],"is_preprint":false},{"year":2008,"finding":"The microtubule-binding domain (MBD, residues 423–607) of CPAP is located adjacent to its microtubule-destabilizing domain (MDD, residues 311–422). Point mutations disrupting alpha-helical structure (Y341P, I346P, L348P, triple-P) or charge (KR377EE) in the MDD abolish MT-destabilizing activity and significantly reduce tubulin heterodimer binding. The conserved ~20-aa sequence in Drosophila d-SAS-4 functions similarly.","method":"Site-specific mutagenesis, in vitro microtubule binding and destabilization assays, truncation analysis","journal":"Experimental cell research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with mutagenesis, conserved across species, single lab","pmids":["18586240"],"is_preprint":false},{"year":2009,"finding":"CPAP protein levels are cell-cycle regulated, being degraded in late mitosis. Excess CPAP induces formation of elongated procentriole-like structures (PLSs) containing stable microtubules and centriolar proteins. A tubulin-binding-defective mutant (CPAP-377EE) fails to induce PLSs, demonstrating that CPAP's intrinsic tubulin-dimer binding activity is required for procentriole elongation.","method":"Cell cycle analysis, siRNA knockdown, overexpression, immunofluorescence, ultrastructural EM analysis, mutagenesis","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods including EM ultrastructure, mutagenesis, and functional assays; independently replicated in same year by two other labs","pmids":["19503075"],"is_preprint":false},{"year":2009,"finding":"Overexpression of CPAP in human cells leads to abnormally long centrioles and formation of supernumerary procentrioles, resulting in multipolar spindle assembly and cytokinesis defects. CPAP is required for centrosome duplication in cycling human cells.","method":"Overexpression, siRNA knockdown, immunofluorescence, time-lapse microscopy","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 / Strong — replicated independently by multiple labs in the same year with consistent results","pmids":["19481460"],"is_preprint":false},{"year":2009,"finding":"CPAP and CP110 play antagonistic roles in controlling centriole length: CPAP overexpression enhances centriolar tubulin accumulation leading to elongated centrioles, while CP110 depletion produces elongated MT structures that are distinct from primary cilia.","method":"Overexpression, siRNA depletion, immunofluorescence, electron microscopy","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal gain/loss-of-function with orthogonal structural methods, replicated across labs","pmids":["19481458"],"is_preprint":false},{"year":2009,"finding":"CPAP forms homodimers via its fifth coiled-coil domain during interphase. This self-interaction is required for maintaining centrosome cohesion and preventing premature centrosome splitting before G2/M. CPAP is phosphorylated during mitosis, and this phosphorylation disrupts the homodimer interaction to allow centrosome splitting.","method":"Co-immunoprecipitation, domain deletion analysis, immunofluorescence, cell cycle analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with domain mapping and functional assay, single lab","pmids":["19889632"],"is_preprint":false},{"year":2010,"finding":"PLK2 phosphorylates CPAP at S589 and S595 in vitro and in vivo. This phosphorylation is critical for procentriole formation during the centrosome cycle; phosphorylated CPAP preferentially localizes to procentrioles. PLK4 also phosphorylates S595 but this is not critical for PLK4-driven procentriole assembly. Overexpression of phospho-resistant CPAP mutant inhibits elongated centriole formation.","method":"In vitro kinase assay, in vivo phosphorylation (mass spectrometry/western), site-directed mutagenesis, immunofluorescence, overexpression","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay plus in vivo validation plus mutagenesis and functional rescue, single lab with multiple orthogonal methods","pmids":["20531387"],"is_preprint":false},{"year":2010,"finding":"Cep152 directly interacts with CPAP and is required for recruitment of CPAP to the centrosome. Reduction of Cep152 causes loss of CPAP from centrosomes, failure of centriole duplication, and monopolar spindle formation.","method":"Co-immunoprecipitation, siRNA knockdown, immunofluorescence","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and functional knockdown with defined phenotype, single lab","pmids":["21059844"],"is_preprint":false},{"year":2011,"finding":"Drosophila Sas-4 provides a scaffold for cytoplasmic complexes (S-CAP) including CNN, Asl, and D-PLP. In the absence of Sas-4, nascent procentrioles are unstable and lack PCM. When Sas-4 cannot form S-CAP complexes, centrosomes have dramatically reduced PCM. Purified S-CAP complexes or recombinant Sas-4 can bind centrosomes stripped of PCM, demonstrating that Sas-4 tethers pre-assembled PCM complexes to centrioles.","method":"Genetic null and point mutant analysis, mass spectrometry, in vitro binding with purified proteins, immunofluorescence","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution with purified proteins plus genetic mutant analysis plus MS, multiple orthogonal methods","pmids":["21694707"],"is_preprint":false},{"year":2011,"finding":"Human STIL directly interacts with CPAP and forms a complex with hSAS6. A microcephaly-causing CPAP mutation (E1235V) significantly reduces binding to STIL. STIL depletion inhibits centriole duplication, Plk4-induced centriole amplification, and CPAP-induced centriole elongation, and blocks localization of hSAS6 and CPAP to the nascent procentriole base.","method":"Co-immunoprecipitation, direct interaction assay, siRNA knockdown, immunofluorescence, MCPH mutation analysis","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, direct binding, functional knockdown with multiple phenotypic readouts, disease mutation validation, independently replicated","pmids":["22020124"],"is_preprint":false},{"year":2011,"finding":"CPAP protein domains required for centriolar localization, centriole elongation, and centriole formation were identified. Conditions mimicking CPAP MCPH patient mutations impair centriole formation in tissue culture cells and correlate with randomization of spindle position on adhesive micropatterns. STIL is also essential for centriole formation and proper spindle positioning.","method":"Domain deletion mutagenesis, siRNA knockdown, immunofluorescence, adhesive micropattern spindle orientation assay","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain mutagenesis with functional readout and spindle positioning assay, single lab","pmids":["22100914"],"is_preprint":false},{"year":2012,"finding":"Tankyrase 1 PARsylates CPAP in vitro and in vivo, targeting it for proteasomal degradation. Overexpression of tankyrase 1 leads to CPAP degradation and prevents centriole duplication; depletion of tankyrase 1 stabilizes CPAP in G1, generating elongated procentrioles and multipolarity. Tankyrase 1 localizes to centrosomes exclusively in G1, coinciding with CPAP degradation.","method":"In vitro PARsylation assay, co-immunoprecipitation, siRNA knockdown, overexpression, immunofluorescence, proteasome inhibitor treatment","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro biochemical assay plus in vivo validation plus reciprocal gain/loss-of-function, single lab with multiple orthogonal methods","pmids":["22699936"],"is_preprint":false},{"year":2012,"finding":"CPAP is required for cilia biogenesis in neuronal CAD cells and hippocampal neurons. Overexpression of wild-type CPAP promotes cilia formation and longer cilia. The tubulin-binding-defective mutant CPAP-377EE inhibits cilia formation and causes cilia shortening. Depletion of CPAP inhibits ciliogenesis, rescued by wild-type but not CPAP-377EE.","method":"siRNA knockdown, overexpression, mutagenesis (CPAP-377EE), immunofluorescence in neuronal cell lines and primary neurons","journal":"Biology open","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain and loss of function with mutagenesis rescue, single lab","pmids":["23213448"],"is_preprint":false},{"year":2012,"finding":"Mouse Cenpj hypomorphic allele recapitulates Seckel syndrome features. Cenpj-deficient embryonic fibroblasts exhibit irregular centriole and centrosome numbers, mono- and multipolar spindles, and near-tetraploidy. Genomic instability arises from mitotic failure rather than defective ATR-dependent DNA damage signaling.","method":"Hypomorphic mouse model, immunohistochemistry, centrosome counting, karyotyping, ATR pathway analysis","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo mouse KO model with multiple cellular phenotypic readouts and epistasis with ATR pathway, single lab","pmids":["23166506"],"is_preprint":false},{"year":2013,"finding":"Crystal structures of the CPAP TCP domain in complex with a conserved STIL fragment reveal that the TCP domain is a novel proline recognition domain forming a 1:1 complex with STIL. The TCP domain adopts an all-β structure. A microcephaly mutation in CPAP (E1235V) maps to the STIL-binding interface and compromises complex formation. Point mutations abolishing complex formation block centriole duplication in vivo.","method":"X-ray crystallography, ITC binding assay, site-directed mutagenesis, in vivo centriole duplication assay","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with biophysical validation and in vivo mutagenesis, independently replicated with structural studies","pmids":["24052813"],"is_preprint":false},{"year":2013,"finding":"CEP135 directly interacts with hSAS-6 via its C-terminus and with CPAP via its N-terminal domain. CEP135 depletion perturbs CPAP centriolar localization and blocks CPAP-induced centriole elongation. Overexpression of a CEP135 mutant lacking hSAS-6 binding has a dominant-negative effect on centriole assembly. CEP135 acts as a linker connecting hSAS-6 to outer centriolar microtubules and is required for CPAP-mediated centriole elongation.","method":"Co-immunoprecipitation, direct binding assays, siRNA knockdown, overexpression, dominant-negative mutant, immunofluorescence, EM","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, direct binding, functional knockdown and dominant-negative with EM structural readout, single lab with multiple orthogonal methods","pmids":["23511974"],"is_preprint":false},{"year":2013,"finding":"The G-box (TCP) domain of CPAP adopts a single elongated β-sheet capable of forming supramolecular assemblies. The G-box structure was determined alone and in complex with a STIL fragment. The conserved CPAP-STIL complex is confirmed by structural and biophysical studies. A microcephaly missense mutation in the G-box reduces affinity for STIL. CPAP is proposed to act as a horizontal strut joining the centriolar scaffold with microtubules.","method":"X-ray crystallography, NMR, biophysical binding assays (ITC/SPR), mutagenesis","journal":"Structure","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with biophysical validation, confirms findings from parallel structural study (PMID:24052813)","pmids":["24076405"],"is_preprint":false},{"year":2013,"finding":"CPAP is SUMOylated by SUMO-1 upon TNF-α stimulus, and this SUMOylation is essential for its NF-κB co-activator activity. CPAP siRNA abolishes the interaction between IKKβ and NF-κB, while CPAP overexpression enhances IKKβ–NF-κB interaction and augments NF-κB activation. SUMO-deficient CPAP mutant loses co-activator activity and fails to enter the nucleus. SUMOylated CPAP synergistically increases HBx-induced NF-κB activity.","method":"In situ PLA assay, reporter assay, RT-PCR, siRNA knockdown, overexpression, western blot, in vivo SUMO modification assay","journal":"Journal of hepatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo SUMO modification with multiple functional assays and mutagenesis, single lab","pmids":["23369793"],"is_preprint":false},{"year":2014,"finding":"The crystal structure of the Sas-4/CPAP TCP domain reveals a solvent-exposed single-layer β-sheet fold that provides an extended surface platform for tethering the Sas-4-PCM scaffold to centrioles. Point mutations in β-strands 9–10 (including an MCPH-associated mutation) perturb PCM tethering while allowing Sas-4/CPAP to scaffold cytoplasmic PCM complexes. The β9-10 surface mediates interactions with Ana2 and Bld-10 for efficient centriole tethering.","method":"X-ray crystallography, site-directed mutagenesis, Drosophila genetics, human cell functional assays, iPSC-derived neural progenitor cell assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure combined with genetic mutagenesis in multiple systems (fly, human cells, iPSC-NPCs)","pmids":["24385583"],"is_preprint":false},{"year":2014,"finding":"Centrobin interacts with CPAP and is required for CPAP localization to centrioles during centriole duplication. Centrobin depletion causes disappearance of CPAP from centrioles and its proteasome-mediated degradation; centrobin protects ubiquitinated CPAP from degradation. Restoration of centrobin expression restores centriolar CPAP. The CPAP-binding fragment of centrobin acts as a dominant negative to displace centriolar CPAP.","method":"Co-immunoprecipitation, siRNA knockdown, overexpression, dominant-negative fragment, proteasome inhibitor treatment, immunofluorescence","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with functional knockdown, dominant-negative, and proteasome inhibition, single lab","pmids":["24700465"],"is_preprint":false},{"year":2015,"finding":"Centrobin controls CPAP levels and centriole elongation: centrobin overexpression causes massive CPAP accumulation and abnormal centriole elongation; centrobin depletion causes CPAP undetectability via ubiquitin-proteasome degradation. Only full-length centrobin (not CPAP-binding-defective mutant) restores CPAP levels. Centrobin-overexpressing cells show proteasome-independent accumulation of ubiquitinated CPAP.","method":"siRNA knockdown, overexpression, mutagenesis, proteasome inhibitor treatment, immunofluorescence","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple complementary gain/loss-of-function experiments with mutagenesis, single lab","pmids":["25616662"],"is_preprint":false},{"year":2015,"finding":"CPAP (Cenpj) is a transcriptional target of proneural factor Ascl1 in the embryonic cerebral cortex. Knockdown of Cenpj by in utero electroporation disrupts centrosome biogenesis and randomizes cleavage plane orientation of radial glia progenitors. In post-mitotic neurons, Cenpj downregulation increases stable microtubules, slows neuronal migration, and causes aberrant centrosome position and morphology. Rescue experiments show Cenpj mediates Ascl1's role in centrosome biogenesis and microtubule dynamics.","method":"In utero electroporation knockdown, rescue experiments, immunofluorescence, chromatin immunoprecipitation (Ascl1 binding to Cenpj promoter)","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo knockdown with defined phenotypic readouts and epistasis rescue, single lab","pmids":["25753651"],"is_preprint":false},{"year":2016,"finding":"CPAP (SAS-4) binds and caps microtubule plus ends by associating with a site on β-tubulin engaged in longitudinal tubulin-tubulin interactions. This capping dampens microtubule growth and stabilizes microtubules by inhibiting catastrophes and promoting rescues. Crystallographic, biophysical (TIRF reconstitution), and in-cell assays demonstrate that CPAP's capping function limits growth of centriolar microtubules.","method":"X-ray crystallography, TIRF-based single-molecule reconstitution assay, biophysical binding assays, in-cell functional assays","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus in vitro reconstitution plus in-cell validation, multiple orthogonal methods in single rigorous study","pmids":["27219064"],"is_preprint":false},{"year":2016,"finding":"CPAP PN2-3 domain forms a high-affinity complex with GTP-tubulin: a C-terminal loop-helix targets β-tubulin at the MT outer surface while an N-terminal helical motif caps the α-β surface of β-tubulin. CPAP(F375A) with strongly reduced tubulin interaction causes shorter centrioles with doublet- instead of triplet-microtubules. CPAP(EE343RR) with slightly reduced affinity but unmasked β-tubulin polymerization surface causes over-elongation of centriolar/ciliary microtubules via enhanced dynamic release of bound tubulin ('clutch-like' mechanism).","method":"X-ray crystallography, ITC binding assays, site-directed mutagenesis, centriole length measurements, electron microscopy","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with mutagenesis and in vitro/in vivo phenotypic validation across multiple mutations","pmids":["27306797"],"is_preprint":false},{"year":2016,"finding":"CPAP is phosphorylated by Aurora-A at serine 467 during mitosis. This phosphorylation is required for maintaining spindle pole integrity; non-phosphorylatable CPAP-S467A fails to rescue PCM dispersion upon CPAP depletion, while phospho-mimic CPAP-S467D rescues it. CPAP-S467D has low affinity for microtubule binding but high affinity for PCM proteins, linking Aurora-A phosphorylation to PCM organization.","method":"In vitro kinase assay, co-immunoprecipitation, site-directed mutagenesis (S467A/S467D), siRNA knockdown, immunofluorescence","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay with mutagenesis and functional rescue assay, single lab with multiple orthogonal methods","pmids":["26997271"],"is_preprint":false},{"year":2016,"finding":"In Drosophila, Cdk1 phosphorylates Sas-4 during mitosis, creating a Polo-docking site that recruits Polo to daughter centrioles. This is required for subsequent recruitment of Asterless (Asl) and for centriole conversion (allowing daughter centrioles to duplicate and organize centrosomes). Point mutations preventing Cdk1 phosphorylation or Polo docking block centriole conversion and lead to embryonic lethality.","method":"In vitro kinase assay, site-directed mutagenesis, Drosophila genetics, immunofluorescence, time-lapse imaging","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase assay combined with in vivo genetic mutagenesis, multiple phenotypic readouts, lethal phenotype validates functional importance","pmids":["27326932"],"is_preprint":false},{"year":2016,"finding":"CPAP acts as a negative regulator of ciliary length independent of its role in centrosome biogenesis. At the onset of cilium disassembly, CPAP provides a scaffold for the cilium disassembly complex (CDC) comprising Nde1, Aurora A, and OFD1, recruiting them to the ciliary base for timely cilium disassembly. A Seckel syndrome CPAP mutation fails to localize at the ciliary base, causing inefficient CDC recruitment, long cilia, retarded cilium disassembly, and delayed cell cycle re-entry leading to premature NPC differentiation.","method":"iPSC-derived neural progenitor cells, patient-derived cells, immunofluorescence, co-immunoprecipitation, brain organoids","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods in patient-derived and iPSC systems with disease mutation validation, multiple phenotypic readouts","pmids":["26929011"],"is_preprint":false},{"year":2013,"finding":"CEP120 directly interacts with CPAP and positively regulates centriole elongation. CEP120 is a cell-cycle-regulated protein peaking at S to G2/M. Forced overexpression of either CEP120 or CPAP induces overly long centrioles and atypical supernumerary centrioles. Depletion of CEP120 inhibits CPAP-induced centriole elongation and vice versa. A microtubule-binding-defective CEP120-K76A mutant suppresses elongated centriole formation.","method":"Co-immunoprecipitation, siRNA knockdown, overexpression, mutagenesis (K76A), immunofluorescence","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, reciprocal knockdown, and mutagenesis, single lab","pmids":["23857771"],"is_preprint":false},{"year":2018,"finding":"Tubulin interacts with CPAP to negatively regulate CPAP-dependent PCM recruitment and microtubule nucleation. A small molecule CCB02 selectively binds at the CPAP-binding site of tubulin, perturbing CPAP-tubulin interaction. Perturbation of CPAP-tubulin interaction activates extra centrosomes to nucleate enhanced microtubules, causing centrosome de-clustering, multipolar mitosis, and cell death in centrosome-amplified cancer cells.","method":"Compound screening, co-immunoprecipitation, genetic perturbation, 3D-organotypic invasion assay, immunofluorescence, in vitro binding assay","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic and chemical perturbation with orthogonal functional readouts, single lab","pmids":["30530478"],"is_preprint":false},{"year":2018,"finding":"In Drosophila, Plk1/Polo kinase phosphorylates Sas-4 in vitro at the onset of mitosis, enabling Sas-4's localization to expand outward from centrosomes. This phosphorylation is required for efficient recruitment of Cnn and γ-tubulin (PCM proteins essential for PCM expansion). Point mutations at Plk1/Polo sites reduce affinity for Cnn and γ-tubulin without affecting centrosome structure or centriole duplication.","method":"In vitro kinase assay, site-directed mutagenesis, Drosophila genetics, immunofluorescence","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay with in vivo genetic validation and mutagenesis, single lab","pmids":["30590037"],"is_preprint":false},{"year":2019,"finding":"CPAP acts as a transcriptional coactivator of STAT3 by directly binding to STAT3. CPAP overexpression upregulates STAT3 target genes IL-8 and CD44 involved in angiogenesis. Knockdown of CPAP impairs IL-6-mediated STAT3 activation, target gene expression, cell migration, and invasion. Interrupting the CPAP-STAT3 interaction attenuates STAT3-mediated tumor growth and angiogenesis.","method":"Co-immunoprecipitation, reporter assay, siRNA knockdown, overexpression, in vivo xenograft, migration/invasion assay","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with functional assays and in vivo validation, single lab","pmids":["31511651"],"is_preprint":false},{"year":2019,"finding":"HBx transcriptionally upregulates CPAP via interacting with CREB at the CPAP promoter (ChIP). Overexpressed CPAP directly interacts with HBx (Co-IP and PLA). SUMO modification of CPAP is required for CPAP-HBx interaction. Overexpressed CPAP maintains HBx protein stability in an NF-κB-dependent manner.","method":"Chromatin immunoprecipitation, co-immunoprecipitation, in situ PLA, reporter assay, siRNA knockdown, overexpression","journal":"Journal of biomedical science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP, Co-IP, and PLA with functional validation, single lab","pmids":["31170980"],"is_preprint":false},{"year":2019,"finding":"Cenpj regulates cilia disassembly in mouse neural progenitor cells through Kif2a (a plus-end-directed motor protein). Conditional Cenpj depletion leads to long cilia and abnormal cilia disassembly. Reduced cell proliferation, uncompleted cell division, and apoptosis result in microcephaly. Cenpj also regulates cilium structure of adult neural stem cells.","method":"Conditional knockout mice, in vivo immunofluorescence, epistasis with Kif2a, BrdU proliferation assay","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo conditional KO with pathway epistasis (Kif2a), defined cellular phenotypes, single lab","pmids":["30626697"],"is_preprint":false},{"year":2020,"finding":"Conditional knockout of Cpap in mouse CNS preferentially induces monopolar spindles in radial glia progenitors (RGPs) at ~E14.5, causing robust apoptosis. Loss of one p53 allele reduces RGP death, and complete p53 removal rescues RGP death, placing CPAP-loss-induced apoptosis downstream of p53. Cpap deletion also causes cilia loss, RGP mislocalization, junctional integrity disruption, and severe cerebellar hypoplasia.","method":"Conditional knockout mouse (CNS-specific), genetic epistasis with p53, immunofluorescence, histological analysis","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo conditional KO with genetic epistasis (p53), multiple phenotypic readouts, single lab","pmids":["32501282"],"is_preprint":false},{"year":2020,"finding":"WDR62 mutant proteins (V66M and R439H) localize to the basal body but fail to recruit CPAP. As a consequence, IFT88 recruitment is deficient, leading to failure of cilia formation. This underpins premature differentiation of radial glia and microcephaly in WDR62 mutant mice.","method":"CRISPR/Cas9 knock-in mice, immunofluorescence, co-localization studies","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo CRISPR knock-in model with defined recruitment hierarchy, single lab","pmids":["31816041"],"is_preprint":false},{"year":2022,"finding":"Using auxin-inducible degron-mediated fast CPAP degradation combined with superresolution microscopy, three independent centrosomal CPAP populations were identified with distinct cell-cycle regulation. CPAP is critical for assembly of human centrioles but not for PCM recruitment onto already-assembled centrioles. CPAP insufficiency leads to centrioles with incomplete microtubule triplets that can still convert to centrosomes, duplicate, and form spindle poles, but ultimately fragment due to loss of cohesion between microtubule blades.","method":"Auxin-inducible degron fast protein degradation, superresolution microscopy (STORM/STED), live imaging, electron microscopy","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — acute protein degradation combined with superresolution and EM, multiple orthogonal methods in single rigorous study","pmids":["35404385"],"is_preprint":false},{"year":2022,"finding":"The CPAP-E1235V microcephaly mutant perturbs recruitment of centriolar proteins CEP120, CEP295, CENTROBIN, POC5, and POC1B to nascent centrioles, resulting in short centrioles but long cilia in hiPSC-derived brain organoids. CPAP-E1235V induces p53-dependent neuronal cell death, produces smaller brain organoids, and alters spindle orientation of neuronal progenitor cells causing premature neuronal differentiation.","method":"CRISPR-Cas9 isogenic hiPSC generation, brain organoids, immunofluorescence, spindle orientation assay, p53 pathway analysis","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — isogenic CRISPR model in human organoids with multiple phenotypic readouts, single lab","pmids":["35309908"],"is_preprint":false}],"current_model":"CPAP (CENPJ/SAS-4/MCPH6) is a cell-cycle-regulated centrosomal scaffold protein that controls centriole biogenesis, elongation, and length by binding tubulin heterodimers via its PN2-3 domain and capping microtubule plus ends to slow centriolar microtubule growth; it is recruited to procentrioles through interactions with STIL (via its TCP/G-box domain), CEP135, CEP120, CEP152, and centrobin, is regulated by phosphorylation (PLK2 at S589/S595, Aurora-A at S467, Cdk1/Polo in flies) and by PARsylation via tankyrase 1 (leading to proteasomal degradation in G1), forms homodimers via its fifth coiled-coil domain to maintain centrosome cohesion, scaffolds cytoplasmic PCM complexes and tethers them to centrioles, promotes timely cilium disassembly by recruiting the cilium disassembly complex (Nde1, Aurora A, OFD1), and in non-centrosomal contexts acts as a transcriptional coactivator of STAT5 and STAT3 and is SUMOylated for NF-κB co-activator activity, with loss-of-function causing incomplete centriole microtubule triplets, spindle defects, and primary microcephaly."},"narrative":{"mechanistic_narrative":"CPAP (CENPJ/SAS-4/MCPH6) is a cell-cycle-regulated centrosomal scaffold protein that governs centriole biogenesis, elongation, and length through its intrinsic tubulin-binding activity [PMID:19503075, PMID:27219064]. Its PN2-3/MDD module binds GTP-tubulin heterodimers and caps microtubule plus ends at a site engaged in longitudinal tubulin-tubulin contacts, dampening growth and limiting the length of centriolar microtubules; mutations that alter this affinity produce either short centrioles with incomplete microtubule triplets or over-elongated centriolar and ciliary microtubules via a clutch-like dynamic release of tubulin [PMID:15047868, PMID:27219064, PMID:27306797]. CPAP is recruited to nascent procentrioles through direct interactions with STIL (via its TCP/G-box proline-recognition domain), CEP135, CEP120, CEP152, and centrobin, which together build a recruitment and stability hierarchy at the procentriole base [PMID:21059844, PMID:22020124, PMID:23511974, PMID:24700465, PMID:23857771]; structural work establishes the G-box as a β-sheet platform that tethers the SAS-4–PCM scaffold to centrioles [PMID:24052813, PMID:24076405, PMID:24385583]. Its activity is tuned by phosphorylation (PLK2 at S589/S595 for procentriole formation, Aurora-A at S467 to switch from microtubule to PCM binding, and Cdk1/Polo in flies for centriole conversion and PCM expansion) and by tankyrase-1 PARsylation and centrobin-dependent control of its turnover, which restrict productive CPAP to the appropriate cell-cycle window [PMID:20531387, PMID:22699936, PMID:24700465, PMID:25616662, PMID:26997271, PMID:27326932, PMID:30590037]. CPAP scaffolds cytoplasmic PCM complexes and tethers them to centrioles to maintain centrosome integrity, and it homodimerizes via its fifth coiled-coil domain to preserve centrosome cohesion until mitotic phosphorylation permits splitting [PMID:19889632, PMID:21694707, PMID:35404385]. Beyond duplication, CPAP negatively regulates ciliary length and promotes timely cilium disassembly by recruiting the Nde1–Aurora A–OFD1 disassembly complex to the ciliary base [PMID:23213448, PMID:26929011, PMID:30626697]. Loss or microcephaly-associated mutation of CPAP causes spindle defects, p53-dependent progenitor apoptosis, randomized cleavage-plane orientation, defective ciliogenesis, and primary microcephaly/Seckel syndrome [PMID:15793586, PMID:23166506, PMID:26929011, PMID:32501282, PMID:35309908]. In non-centrosomal contexts, CPAP acts as a transcriptional coactivator of STAT5 and STAT3 and, when SUMOylated, augments NF-κB activity [PMID:12198240, PMID:23369793, PMID:31511651].","teleology":[{"year":2000,"claim":"Established CPAP as a centrosomal protein physically associated with the γ-tubulin complex and functionally required for microtubule aster formation, framing it as a microtubule-nucleation-related centrosomal factor.","evidence":"Yeast two-hybrid, co-sedimentation and Co-IP with γ-tubulin, antibody inhibition of asters","pmids":["11003675"],"confidence":"Medium","gaps":["No domain responsible for tubulin/γ-tubulin association mapped","Role in centriole biology not yet recognized"]},{"year":2002,"claim":"Revealed an unexpected non-centrosomal role of CPAP as a nuclear transcriptional coactivator, showing the protein has functions beyond the centrosome.","evidence":"Yeast two-hybrid, reporter assay, fractionation showing Stat5-specific coactivation upon PRL signaling","pmids":["12198240"],"confidence":"Medium","gaps":["Mechanism of nuclear shuttling unresolved","Relationship to centrosomal pool unclear"]},{"year":2004,"claim":"Identified the microtubule-destabilizing domain that binds tubulin heterodimers, providing the first biochemical mechanism for CPAP's action on microtubules.","evidence":"Deletion mapping with in vitro depolymerization and tubulin-binding assays","pmids":["15047868"],"confidence":"High","gaps":["How destabilizing activity reconciles with centriole growth not yet known","Structural basis of tubulin binding undefined"]},{"year":2005,"claim":"Connected CPAP to human disease and to centrosome integrity, showing loss-of-function causes primary microcephaly and depletion causes multipolar spindles via Eg5-dependent mechanisms.","evidence":"Genetic mapping/mutation analysis (MCPH6) and siRNA with Eg5-inhibition epistasis","pmids":["15793586","16316625"],"confidence":"Medium","gaps":["Molecular basis of microcephaly mutations undefined","Cell-biological cause of microcephaly not yet linked to centriole biogenesis"]},{"year":2008,"claim":"Refined the structural determinants of tubulin binding and destabilization through mutagenesis, confirming the MDD as the active module and its conservation across species.","evidence":"Site-specific mutagenesis with in vitro MT binding/destabilization assays","pmids":["18586240"],"confidence":"High","gaps":["Atomic structure of the domain–tubulin complex still absent","In vivo consequence of mutations not assessed here"]},{"year":2009,"claim":"Reframed CPAP as a positive regulator of centriole elongation whose tubulin-binding activity drives procentriole assembly, and established cell-cycle control of its levels and a coiled-coil-mediated homodimer required for centrosome cohesion.","evidence":"Cell-cycle analysis, overexpression/knockdown, EM, tubulin-binding-defective mutants, and Co-IP/domain mapping across multiple labs","pmids":["19503075","19481460","19481458","19889632"],"confidence":"High","gaps":["Recruitment partners targeting CPAP to procentrioles not yet identified","Kinase responsible for cohesion-disrupting phosphorylation unknown"]},{"year":2010,"claim":"Identified CEP152 as the centrosomal receptor for CPAP and PLK2 phosphorylation at S589/S595 as a positive signal for procentriole formation, defining recruitment and regulatory inputs.","evidence":"Co-IP/knockdown for CEP152 and in vitro/in vivo kinase assays with phospho-mutant rescue for PLK2","pmids":["21059844","20531387"],"confidence":"High","gaps":["Spatial relationship between CEP152 and other recruiters undefined","Direct phosphatase counteracting PLK2 unknown"]},{"year":2011,"claim":"Established CPAP as a scaffold that tethers pre-assembled PCM complexes to centrioles and identified STIL as a direct partner whose binding is disrupted by a microcephaly mutation, linking molecular interactions to disease.","evidence":"Drosophila genetics, in vitro binding with purified S-CAP complexes, Co-IP/direct binding, MCPH mutation (E1235V) analysis, domain mapping with spindle-orientation assays","pmids":["21694707","22020124","22100914"],"confidence":"High","gaps":["Structural basis of STIL recognition not yet solved at this stage","Stoichiometry of CPAP–PCM scaffold undefined"]},{"year":2012,"claim":"Defined post-translational and developmental control of CPAP — tankyrase-1 PARsylation/degradation restricting CPAP to the proper window, and ciliogenesis and disease-model phenotypes — broadening its functional repertoire.","evidence":"In vitro PARsylation and reciprocal tankyrase perturbation; ciliogenesis assays with 377EE mutant; Cenpj hypomorphic Seckel mouse","pmids":["22699936","23213448","23166506"],"confidence":"Medium","gaps":["How tankyrase activity is timed to G1 unresolved","Distinction between cilium and centriole functions of CPAP not yet separated"]},{"year":2013,"claim":"Provided atomic structures of the CPAP TCP/G-box–STIL complex defining a novel proline-recognition fold and identified CEP135 and CEP120 as direct partners linking CPAP to SAS-6 and microtubules during elongation.","evidence":"X-ray crystallography/NMR with ITC/SPR and in vivo duplication assays; Co-IP/direct binding/knockdown/dominant-negative for CEP135 and CEP120","pmids":["24052813","24076405","23511974","23857771"],"confidence":"High","gaps":["How multiple recruiters are spatially coordinated at the procentriole unclear","Order of assembly among STIL/CEP135/CEP120 not fully resolved"]},{"year":2014,"claim":"Resolved how the G-box β-sheet platform tethers the SAS-4–PCM scaffold to centrioles and identified centrobin as a stabilizer protecting CPAP from proteasomal degradation, separating scaffolding from tethering functions.","evidence":"Crystallography with mutagenesis across fly/human/iPSC-NPC systems; Co-IP, knockdown, dominant-negative, proteasome inhibition for centrobin","pmids":["24385583","24700465"],"confidence":"High","gaps":["Identity of the ubiquitin ligase targeting CPAP unknown","How centrobin physically shields CPAP undefined"]},{"year":2015,"claim":"Integrated CPAP into a developmental transcriptional program (Ascl1 target) controlling radial glia centrosome biogenesis and showed centrobin sets CPAP abundance to control centriole length.","evidence":"In utero electroporation knockdown/rescue with ChIP for Ascl1; gain/loss-of-function with mutagenesis and proteasome inhibition for centrobin","pmids":["25753651","25616662"],"confidence":"Medium","gaps":["Transcriptional control of CPAP in non-neural tissues not assessed","Mechanism by which centrobin overexpression accumulates ubiquitinated CPAP unresolved"]},{"year":2016,"claim":"Delivered the mechanistic core: structural and reconstitution evidence that CPAP caps microtubule plus ends to limit growth, that PN2-3 engages GTP-tubulin via a clutch-like mechanism setting centriole length, and that Aurora-A and Cdk1/Polo phosphorylation switch CPAP between microtubule and PCM functions; also defined a dedicated role in cilium disassembly.","evidence":"Crystallography + TIRF single-molecule reconstitution + in-cell assays; kinase assays with phospho-mutant rescue; iPSC-NPC/organoid and patient-cell ciliary studies","pmids":["27219064","27306797","26997271","27326932","26929011"],"confidence":"High","gaps":["How capping, elongation, and PCM functions are partitioned within one cell cycle still being clarified","Direct disassembly-complex contact surfaces on CPAP undefined"]},{"year":2018,"claim":"Showed tubulin negatively regulates CPAP-dependent PCM recruitment and nucleation and exploited the CPAP–tubulin interface pharmacologically to selectively kill centrosome-amplified cancer cells.","evidence":"Compound screen (CCB02), Co-IP, genetic perturbation, organotypic invasion assay","pmids":["30530478"],"confidence":"Medium","gaps":["Therapeutic window and selectivity in vivo unresolved","How tubulin occupancy is dynamically regulated at centrosomes unclear"]},{"year":2019,"claim":"Extended CPAP's transcriptional moonlighting to STAT3-driven tumor angiogenesis and SUMO-dependent NF-κB/HBx interactions, and identified Kif2a as a mediator of CPAP-dependent cilia disassembly in vivo.","evidence":"Co-IP/reporter/xenograft for STAT3; ChIP/Co-IP/PLA for HBx; conditional KO with Kif2a epistasis","pmids":["31511651","31170980","30626697"],"confidence":"Medium","gaps":["Whether transcriptional and centrosomal pools are functionally separable not established","Mechanism linking CPAP to Kif2a at the cilium undefined"]},{"year":2020,"claim":"Defined the disease-relevant recruitment hierarchies and downstream cell-death pathway: WDR62 recruits CPAP for ciliogenesis, CPAP loss triggers p53-dependent progenitor apoptosis, and the E1235V mutation disrupts recruitment of multiple centriolar proteins causing short centrioles but long cilia.","evidence":"CRISPR knock-in/conditional KO mice with p53 epistasis; isogenic hiPSC brain organoids with spindle-orientation and p53 analyses","pmids":["31816041","32501282","35309908"],"confidence":"Medium","gaps":["How a single mutation simultaneously shortens centrioles and lengthens cilia mechanistically unclear","Cell-type specificity of p53-dependent death not fully explained"]},{"year":2022,"claim":"Used acute degradation and superresolution/EM to dissect CPAP's essential function, showing it is required for assembling centriole microtubule triplets and cohesion between blades, but not for PCM recruitment onto pre-formed centrioles, refining its role to centriole construction.","evidence":"Auxin-inducible degron, STORM/STED, live imaging, electron microscopy","pmids":["35404385"],"confidence":"High","gaps":["Molecular basis of inter-blade cohesion provided by CPAP undefined","How three distinct CPAP populations are differentially regulated unknown"]},{"year":null,"claim":"How CPAP's centrosomal, ciliary, and nuclear transcriptional activities are partitioned and coordinated within the same cell, and the structural basis of its contacts with the cilium-disassembly complex and inter-microtubule-blade cohesion, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of CPAP bound to Nde1/Aurora A/OFD1 disassembly complex","Functional separability of transcriptional vs centrosomal pools not demonstrated","Mechanism coupling CPAP populations to cell-cycle stage unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[2,5,26,27]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1,21,34]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[12,22,39]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[26,39]}],"localization":[{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[0,3,6,39]},{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[16,30,36]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,21]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[2,26]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[6,7,39]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[6,16,30,39]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[25,37,40]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[1,21,34]}],"complexes":["centrosome/centriole","S-CAP (SAS-4–PCM scaffold)","cilium disassembly complex (Nde1–Aurora A–OFD1)","γ-tubulin complex"],"partners":["STIL","CEP135","CEP120","CEP152","CENTROBIN","TUBULIN","STAT5","WDR62"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9HC77","full_name":"Centrosomal P4.1-associated protein","aliases":["Centromere protein J","CENP-J","Centrosome assembly and centriole elongation protein","LAG-3-associated protein","LYST-interacting protein 1"],"length_aa":1338,"mass_kda":153.0,"function":"Plays an important role in cell division and centrosome function by participating in centriole duplication (PubMed:17681131, PubMed:20531387). Inhibits microtubule nucleation from the centrosome. Involved in the regulation of slow processive growth of centriolar microtubules. Acts as a microtubule plus-end tracking protein that stabilizes centriolar microtubules and inhibits microtubule polymerization and extension from the distal ends of centrioles (PubMed:15047868, PubMed:27219064, PubMed:27306797). Required for centriole elongation and for STIL-mediated centriole amplification (PubMed:22020124). Required for the recruitment of CEP295 to the proximal end of new-born centrioles at the centriolar microtubule wall during early S phase in a PLK4-dependent manner (PubMed:27185865). May be involved in the control of centriolar-microtubule growth by acting as a regulator of tubulin release (PubMed:27306797)","subcellular_location":"Cytoplasm, cytoskeleton, microtubule organizing center, centrosome; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome, centriole","url":"https://www.uniprot.org/uniprotkb/Q9HC77/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CPAP","classification":"Not Classified","n_dependent_lines":158,"n_total_lines":1208,"dependency_fraction":0.13079470198675497},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CLASP2","stoichiometry":4.0},{"gene":"CLASP1","stoichiometry":0.2},{"gene":"CLTA","stoichiometry":0.2},{"gene":"TUBA1B","stoichiometry":0.2},{"gene":"TUBB4B","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/CPAP","total_profiled":1310},"omim":[{"mim_id":"621510","title":"CONGENITAL MYOPATHY 29 WITH CONTRACTURES; CMYO29","url":"https://www.omim.org/entry/621510"},{"mim_id":"617728","title":"CENTROSOMAL PROTEIN, 295-KD; CEP295","url":"https://www.omim.org/entry/617728"},{"mim_id":"616816","title":"HYPOTONIA, INFANTILE, WITH PSYCHOMOTOR RETARDATION; IHPMR","url":"https://www.omim.org/entry/616816"},{"mim_id":"616426","title":"CENTROSOMAL PROTEIN, 192-KD; CEP192","url":"https://www.omim.org/entry/616426"},{"mim_id":"614800","title":"SHORT STATURE, OPTIC NERVE ATROPHY, AND PELGER-HUET ANOMALY; SOPH","url":"https://www.omim.org/entry/614800"}],"hpa":{"profiled":true,"resolved_as":"CENPJ","reliability":"Supported","locations":[{"location":"Centrosome","reliability":"Supported"},{"location":"Acrosome","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"testis","ntpm":15.7}],"url":"https://www.proteinatlas.org/search/CENPJ"},"hgnc":{"alias_symbol":["LAP","LIP1","BM032","SASS4","SCKL4","Sas-4"],"prev_symbol":["CENPJ","MCPH6"]},"alphafold":{"accession":"Q9HC77","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9HC77","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9HC77-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9HC77-F1-predicted_aligned_error_v6.png","plddt_mean":55.91},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CPAP","jax_strain_url":"https://www.jax.org/strain/search?query=CPAP"},"sequence":{"accession":"Q9HC77","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9HC77.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9HC77/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9HC77"}},"corpus_meta":[{"pmid":"15793586","id":"PMC_15793586","title":"A centrosomal mechanism involving CDK5RAP2 and CENPJ controls 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Anti-CPAP antibody significantly inhibited formation of microtubule asters, demonstrating a role in microtubule nucleation.\",\n      \"method\": \"Yeast two-hybrid, sucrose gradient co-sedimentation, co-immunoprecipitation, immunofluorescence, antibody inhibition assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and functional antibody inhibition assay, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"11003675\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"CPAP interacts specifically with Stat5a and Stat5b (but not Stat1 or Stat3) via yeast two-hybrid screening. CPAP augments Stat5-mediated transcription and translocates to the nucleus upon PRL pathway activation, acting as a transcriptional coactivator of Stat5.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, reporter transcription assay, immunofluorescence, cellular fractionation\",\n      \"journal\": \"Molecular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, reporter assay, fractionation), single lab\",\n      \"pmids\": [\"12198240\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"CPAP contains a novel 112-residue microtubule-destabilizing motif (MDD, residues 311–422) that binds tubulin heterodimers, inhibits microtubule nucleation from the centrosome, depolymerizes taxol-stabilized microtubules, and when overexpressed induces G2/M arrest and apoptosis.\",\n      \"method\": \"Deletion mapping, in vitro microtubule depolymerization assay, tubulin-binding assay, tetracycline-controlled overexpression, cell cycle analysis\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro enzymatic/biochemical assays with deletion mapping and mutagenesis, replicated in subsequent studies\",\n      \"pmids\": [\"15047868\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"CPAP (CENPJ) localizes to spindle poles of mitotic cells during neuroepithelial neurogenesis; homozygous loss-of-function mutations in CENPJ cause primary microcephaly (MCPH6), implicating a centrosomal mechanism in controlling neuron number.\",\n      \"method\": \"Genetic mapping, mutation analysis, immunofluorescence localization in human tissue\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function with defined disease phenotype and protein localization, single study\",\n      \"pmids\": [\"15793586\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"RNAi-mediated depletion of CPAP in human cells arrests cells in mitosis, induces apoptosis, and causes multipolar spindle formation in >40% of mitotic cells. Inhibition of kinesin Eg5 in CPAP-depleted cells results in monopolar spindles, indicating Eg5 is required downstream of CPAP for multipolar spindle formation, revealing a structural role for CPAP in centrosome integrity.\",\n      \"method\": \"siRNA knockdown, immunofluorescence, Eg5 inhibition epistasis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KD with defined phenotype and epistasis experiment, single lab\",\n      \"pmids\": [\"16316625\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The microtubule-binding domain (MBD, residues 423–607) of CPAP is located adjacent to its microtubule-destabilizing domain (MDD, residues 311–422). Point mutations disrupting alpha-helical structure (Y341P, I346P, L348P, triple-P) or charge (KR377EE) in the MDD abolish MT-destabilizing activity and significantly reduce tubulin heterodimer binding. The conserved ~20-aa sequence in Drosophila d-SAS-4 functions similarly.\",\n      \"method\": \"Site-specific mutagenesis, in vitro microtubule binding and destabilization assays, truncation analysis\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with mutagenesis, conserved across species, single lab\",\n      \"pmids\": [\"18586240\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CPAP protein levels are cell-cycle regulated, being degraded in late mitosis. Excess CPAP induces formation of elongated procentriole-like structures (PLSs) containing stable microtubules and centriolar proteins. A tubulin-binding-defective mutant (CPAP-377EE) fails to induce PLSs, demonstrating that CPAP's intrinsic tubulin-dimer binding activity is required for procentriole elongation.\",\n      \"method\": \"Cell cycle analysis, siRNA knockdown, overexpression, immunofluorescence, ultrastructural EM analysis, mutagenesis\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods including EM ultrastructure, mutagenesis, and functional assays; independently replicated in same year by two other labs\",\n      \"pmids\": [\"19503075\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Overexpression of CPAP in human cells leads to abnormally long centrioles and formation of supernumerary procentrioles, resulting in multipolar spindle assembly and cytokinesis defects. CPAP is required for centrosome duplication in cycling human cells.\",\n      \"method\": \"Overexpression, siRNA knockdown, immunofluorescence, time-lapse microscopy\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — replicated independently by multiple labs in the same year with consistent results\",\n      \"pmids\": [\"19481460\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CPAP and CP110 play antagonistic roles in controlling centriole length: CPAP overexpression enhances centriolar tubulin accumulation leading to elongated centrioles, while CP110 depletion produces elongated MT structures that are distinct from primary cilia.\",\n      \"method\": \"Overexpression, siRNA depletion, immunofluorescence, electron microscopy\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal gain/loss-of-function with orthogonal structural methods, replicated across labs\",\n      \"pmids\": [\"19481458\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CPAP forms homodimers via its fifth coiled-coil domain during interphase. This self-interaction is required for maintaining centrosome cohesion and preventing premature centrosome splitting before G2/M. CPAP is phosphorylated during mitosis, and this phosphorylation disrupts the homodimer interaction to allow centrosome splitting.\",\n      \"method\": \"Co-immunoprecipitation, domain deletion analysis, immunofluorescence, cell cycle analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with domain mapping and functional assay, single lab\",\n      \"pmids\": [\"19889632\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"PLK2 phosphorylates CPAP at S589 and S595 in vitro and in vivo. This phosphorylation is critical for procentriole formation during the centrosome cycle; phosphorylated CPAP preferentially localizes to procentrioles. PLK4 also phosphorylates S595 but this is not critical for PLK4-driven procentriole assembly. Overexpression of phospho-resistant CPAP mutant inhibits elongated centriole formation.\",\n      \"method\": \"In vitro kinase assay, in vivo phosphorylation (mass spectrometry/western), site-directed mutagenesis, immunofluorescence, overexpression\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay plus in vivo validation plus mutagenesis and functional rescue, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"20531387\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Cep152 directly interacts with CPAP and is required for recruitment of CPAP to the centrosome. Reduction of Cep152 causes loss of CPAP from centrosomes, failure of centriole duplication, and monopolar spindle formation.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, immunofluorescence\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and functional knockdown with defined phenotype, single lab\",\n      \"pmids\": [\"21059844\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Drosophila Sas-4 provides a scaffold for cytoplasmic complexes (S-CAP) including CNN, Asl, and D-PLP. In the absence of Sas-4, nascent procentrioles are unstable and lack PCM. When Sas-4 cannot form S-CAP complexes, centrosomes have dramatically reduced PCM. Purified S-CAP complexes or recombinant Sas-4 can bind centrosomes stripped of PCM, demonstrating that Sas-4 tethers pre-assembled PCM complexes to centrioles.\",\n      \"method\": \"Genetic null and point mutant analysis, mass spectrometry, in vitro binding with purified proteins, immunofluorescence\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution with purified proteins plus genetic mutant analysis plus MS, multiple orthogonal methods\",\n      \"pmids\": [\"21694707\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Human STIL directly interacts with CPAP and forms a complex with hSAS6. A microcephaly-causing CPAP mutation (E1235V) significantly reduces binding to STIL. STIL depletion inhibits centriole duplication, Plk4-induced centriole amplification, and CPAP-induced centriole elongation, and blocks localization of hSAS6 and CPAP to the nascent procentriole base.\",\n      \"method\": \"Co-immunoprecipitation, direct interaction assay, siRNA knockdown, immunofluorescence, MCPH mutation analysis\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, direct binding, functional knockdown with multiple phenotypic readouts, disease mutation validation, independently replicated\",\n      \"pmids\": [\"22020124\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CPAP protein domains required for centriolar localization, centriole elongation, and centriole formation were identified. Conditions mimicking CPAP MCPH patient mutations impair centriole formation in tissue culture cells and correlate with randomization of spindle position on adhesive micropatterns. STIL is also essential for centriole formation and proper spindle positioning.\",\n      \"method\": \"Domain deletion mutagenesis, siRNA knockdown, immunofluorescence, adhesive micropattern spindle orientation assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain mutagenesis with functional readout and spindle positioning assay, single lab\",\n      \"pmids\": [\"22100914\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Tankyrase 1 PARsylates CPAP in vitro and in vivo, targeting it for proteasomal degradation. Overexpression of tankyrase 1 leads to CPAP degradation and prevents centriole duplication; depletion of tankyrase 1 stabilizes CPAP in G1, generating elongated procentrioles and multipolarity. Tankyrase 1 localizes to centrosomes exclusively in G1, coinciding with CPAP degradation.\",\n      \"method\": \"In vitro PARsylation assay, co-immunoprecipitation, siRNA knockdown, overexpression, immunofluorescence, proteasome inhibitor treatment\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro biochemical assay plus in vivo validation plus reciprocal gain/loss-of-function, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"22699936\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CPAP is required for cilia biogenesis in neuronal CAD cells and hippocampal neurons. Overexpression of wild-type CPAP promotes cilia formation and longer cilia. The tubulin-binding-defective mutant CPAP-377EE inhibits cilia formation and causes cilia shortening. Depletion of CPAP inhibits ciliogenesis, rescued by wild-type but not CPAP-377EE.\",\n      \"method\": \"siRNA knockdown, overexpression, mutagenesis (CPAP-377EE), immunofluorescence in neuronal cell lines and primary neurons\",\n      \"journal\": \"Biology open\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain and loss of function with mutagenesis rescue, single lab\",\n      \"pmids\": [\"23213448\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Mouse Cenpj hypomorphic allele recapitulates Seckel syndrome features. Cenpj-deficient embryonic fibroblasts exhibit irregular centriole and centrosome numbers, mono- and multipolar spindles, and near-tetraploidy. Genomic instability arises from mitotic failure rather than defective ATR-dependent DNA damage signaling.\",\n      \"method\": \"Hypomorphic mouse model, immunohistochemistry, centrosome counting, karyotyping, ATR pathway analysis\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo mouse KO model with multiple cellular phenotypic readouts and epistasis with ATR pathway, single lab\",\n      \"pmids\": [\"23166506\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Crystal structures of the CPAP TCP domain in complex with a conserved STIL fragment reveal that the TCP domain is a novel proline recognition domain forming a 1:1 complex with STIL. The TCP domain adopts an all-β structure. A microcephaly mutation in CPAP (E1235V) maps to the STIL-binding interface and compromises complex formation. Point mutations abolishing complex formation block centriole duplication in vivo.\",\n      \"method\": \"X-ray crystallography, ITC binding assay, site-directed mutagenesis, in vivo centriole duplication assay\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with biophysical validation and in vivo mutagenesis, independently replicated with structural studies\",\n      \"pmids\": [\"24052813\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CEP135 directly interacts with hSAS-6 via its C-terminus and with CPAP via its N-terminal domain. CEP135 depletion perturbs CPAP centriolar localization and blocks CPAP-induced centriole elongation. Overexpression of a CEP135 mutant lacking hSAS-6 binding has a dominant-negative effect on centriole assembly. CEP135 acts as a linker connecting hSAS-6 to outer centriolar microtubules and is required for CPAP-mediated centriole elongation.\",\n      \"method\": \"Co-immunoprecipitation, direct binding assays, siRNA knockdown, overexpression, dominant-negative mutant, immunofluorescence, EM\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, direct binding, functional knockdown and dominant-negative with EM structural readout, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"23511974\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The G-box (TCP) domain of CPAP adopts a single elongated β-sheet capable of forming supramolecular assemblies. The G-box structure was determined alone and in complex with a STIL fragment. The conserved CPAP-STIL complex is confirmed by structural and biophysical studies. A microcephaly missense mutation in the G-box reduces affinity for STIL. CPAP is proposed to act as a horizontal strut joining the centriolar scaffold with microtubules.\",\n      \"method\": \"X-ray crystallography, NMR, biophysical binding assays (ITC/SPR), mutagenesis\",\n      \"journal\": \"Structure\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with biophysical validation, confirms findings from parallel structural study (PMID:24052813)\",\n      \"pmids\": [\"24076405\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CPAP is SUMOylated by SUMO-1 upon TNF-α stimulus, and this SUMOylation is essential for its NF-κB co-activator activity. CPAP siRNA abolishes the interaction between IKKβ and NF-κB, while CPAP overexpression enhances IKKβ–NF-κB interaction and augments NF-κB activation. SUMO-deficient CPAP mutant loses co-activator activity and fails to enter the nucleus. SUMOylated CPAP synergistically increases HBx-induced NF-κB activity.\",\n      \"method\": \"In situ PLA assay, reporter assay, RT-PCR, siRNA knockdown, overexpression, western blot, in vivo SUMO modification assay\",\n      \"journal\": \"Journal of hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo SUMO modification with multiple functional assays and mutagenesis, single lab\",\n      \"pmids\": [\"23369793\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The crystal structure of the Sas-4/CPAP TCP domain reveals a solvent-exposed single-layer β-sheet fold that provides an extended surface platform for tethering the Sas-4-PCM scaffold to centrioles. Point mutations in β-strands 9–10 (including an MCPH-associated mutation) perturb PCM tethering while allowing Sas-4/CPAP to scaffold cytoplasmic PCM complexes. The β9-10 surface mediates interactions with Ana2 and Bld-10 for efficient centriole tethering.\",\n      \"method\": \"X-ray crystallography, site-directed mutagenesis, Drosophila genetics, human cell functional assays, iPSC-derived neural progenitor cell assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure combined with genetic mutagenesis in multiple systems (fly, human cells, iPSC-NPCs)\",\n      \"pmids\": [\"24385583\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Centrobin interacts with CPAP and is required for CPAP localization to centrioles during centriole duplication. Centrobin depletion causes disappearance of CPAP from centrioles and its proteasome-mediated degradation; centrobin protects ubiquitinated CPAP from degradation. Restoration of centrobin expression restores centriolar CPAP. The CPAP-binding fragment of centrobin acts as a dominant negative to displace centriolar CPAP.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, overexpression, dominant-negative fragment, proteasome inhibitor treatment, immunofluorescence\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with functional knockdown, dominant-negative, and proteasome inhibition, single lab\",\n      \"pmids\": [\"24700465\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Centrobin controls CPAP levels and centriole elongation: centrobin overexpression causes massive CPAP accumulation and abnormal centriole elongation; centrobin depletion causes CPAP undetectability via ubiquitin-proteasome degradation. Only full-length centrobin (not CPAP-binding-defective mutant) restores CPAP levels. Centrobin-overexpressing cells show proteasome-independent accumulation of ubiquitinated CPAP.\",\n      \"method\": \"siRNA knockdown, overexpression, mutagenesis, proteasome inhibitor treatment, immunofluorescence\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple complementary gain/loss-of-function experiments with mutagenesis, single lab\",\n      \"pmids\": [\"25616662\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CPAP (Cenpj) is a transcriptional target of proneural factor Ascl1 in the embryonic cerebral cortex. Knockdown of Cenpj by in utero electroporation disrupts centrosome biogenesis and randomizes cleavage plane orientation of radial glia progenitors. In post-mitotic neurons, Cenpj downregulation increases stable microtubules, slows neuronal migration, and causes aberrant centrosome position and morphology. Rescue experiments show Cenpj mediates Ascl1's role in centrosome biogenesis and microtubule dynamics.\",\n      \"method\": \"In utero electroporation knockdown, rescue experiments, immunofluorescence, chromatin immunoprecipitation (Ascl1 binding to Cenpj promoter)\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo knockdown with defined phenotypic readouts and epistasis rescue, single lab\",\n      \"pmids\": [\"25753651\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CPAP (SAS-4) binds and caps microtubule plus ends by associating with a site on β-tubulin engaged in longitudinal tubulin-tubulin interactions. This capping dampens microtubule growth and stabilizes microtubules by inhibiting catastrophes and promoting rescues. Crystallographic, biophysical (TIRF reconstitution), and in-cell assays demonstrate that CPAP's capping function limits growth of centriolar microtubules.\",\n      \"method\": \"X-ray crystallography, TIRF-based single-molecule reconstitution assay, biophysical binding assays, in-cell functional assays\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus in vitro reconstitution plus in-cell validation, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"27219064\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CPAP PN2-3 domain forms a high-affinity complex with GTP-tubulin: a C-terminal loop-helix targets β-tubulin at the MT outer surface while an N-terminal helical motif caps the α-β surface of β-tubulin. CPAP(F375A) with strongly reduced tubulin interaction causes shorter centrioles with doublet- instead of triplet-microtubules. CPAP(EE343RR) with slightly reduced affinity but unmasked β-tubulin polymerization surface causes over-elongation of centriolar/ciliary microtubules via enhanced dynamic release of bound tubulin ('clutch-like' mechanism).\",\n      \"method\": \"X-ray crystallography, ITC binding assays, site-directed mutagenesis, centriole length measurements, electron microscopy\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with mutagenesis and in vitro/in vivo phenotypic validation across multiple mutations\",\n      \"pmids\": [\"27306797\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CPAP is phosphorylated by Aurora-A at serine 467 during mitosis. This phosphorylation is required for maintaining spindle pole integrity; non-phosphorylatable CPAP-S467A fails to rescue PCM dispersion upon CPAP depletion, while phospho-mimic CPAP-S467D rescues it. CPAP-S467D has low affinity for microtubule binding but high affinity for PCM proteins, linking Aurora-A phosphorylation to PCM organization.\",\n      \"method\": \"In vitro kinase assay, co-immunoprecipitation, site-directed mutagenesis (S467A/S467D), siRNA knockdown, immunofluorescence\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay with mutagenesis and functional rescue assay, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"26997271\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In Drosophila, Cdk1 phosphorylates Sas-4 during mitosis, creating a Polo-docking site that recruits Polo to daughter centrioles. This is required for subsequent recruitment of Asterless (Asl) and for centriole conversion (allowing daughter centrioles to duplicate and organize centrosomes). Point mutations preventing Cdk1 phosphorylation or Polo docking block centriole conversion and lead to embryonic lethality.\",\n      \"method\": \"In vitro kinase assay, site-directed mutagenesis, Drosophila genetics, immunofluorescence, time-lapse imaging\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase assay combined with in vivo genetic mutagenesis, multiple phenotypic readouts, lethal phenotype validates functional importance\",\n      \"pmids\": [\"27326932\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CPAP acts as a negative regulator of ciliary length independent of its role in centrosome biogenesis. At the onset of cilium disassembly, CPAP provides a scaffold for the cilium disassembly complex (CDC) comprising Nde1, Aurora A, and OFD1, recruiting them to the ciliary base for timely cilium disassembly. A Seckel syndrome CPAP mutation fails to localize at the ciliary base, causing inefficient CDC recruitment, long cilia, retarded cilium disassembly, and delayed cell cycle re-entry leading to premature NPC differentiation.\",\n      \"method\": \"iPSC-derived neural progenitor cells, patient-derived cells, immunofluorescence, co-immunoprecipitation, brain organoids\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods in patient-derived and iPSC systems with disease mutation validation, multiple phenotypic readouts\",\n      \"pmids\": [\"26929011\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CEP120 directly interacts with CPAP and positively regulates centriole elongation. CEP120 is a cell-cycle-regulated protein peaking at S to G2/M. Forced overexpression of either CEP120 or CPAP induces overly long centrioles and atypical supernumerary centrioles. Depletion of CEP120 inhibits CPAP-induced centriole elongation and vice versa. A microtubule-binding-defective CEP120-K76A mutant suppresses elongated centriole formation.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, overexpression, mutagenesis (K76A), immunofluorescence\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, reciprocal knockdown, and mutagenesis, single lab\",\n      \"pmids\": [\"23857771\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Tubulin interacts with CPAP to negatively regulate CPAP-dependent PCM recruitment and microtubule nucleation. A small molecule CCB02 selectively binds at the CPAP-binding site of tubulin, perturbing CPAP-tubulin interaction. Perturbation of CPAP-tubulin interaction activates extra centrosomes to nucleate enhanced microtubules, causing centrosome de-clustering, multipolar mitosis, and cell death in centrosome-amplified cancer cells.\",\n      \"method\": \"Compound screening, co-immunoprecipitation, genetic perturbation, 3D-organotypic invasion assay, immunofluorescence, in vitro binding assay\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic and chemical perturbation with orthogonal functional readouts, single lab\",\n      \"pmids\": [\"30530478\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In Drosophila, Plk1/Polo kinase phosphorylates Sas-4 in vitro at the onset of mitosis, enabling Sas-4's localization to expand outward from centrosomes. This phosphorylation is required for efficient recruitment of Cnn and γ-tubulin (PCM proteins essential for PCM expansion). Point mutations at Plk1/Polo sites reduce affinity for Cnn and γ-tubulin without affecting centrosome structure or centriole duplication.\",\n      \"method\": \"In vitro kinase assay, site-directed mutagenesis, Drosophila genetics, immunofluorescence\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay with in vivo genetic validation and mutagenesis, single lab\",\n      \"pmids\": [\"30590037\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CPAP acts as a transcriptional coactivator of STAT3 by directly binding to STAT3. CPAP overexpression upregulates STAT3 target genes IL-8 and CD44 involved in angiogenesis. Knockdown of CPAP impairs IL-6-mediated STAT3 activation, target gene expression, cell migration, and invasion. Interrupting the CPAP-STAT3 interaction attenuates STAT3-mediated tumor growth and angiogenesis.\",\n      \"method\": \"Co-immunoprecipitation, reporter assay, siRNA knockdown, overexpression, in vivo xenograft, migration/invasion assay\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with functional assays and in vivo validation, single lab\",\n      \"pmids\": [\"31511651\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"HBx transcriptionally upregulates CPAP via interacting with CREB at the CPAP promoter (ChIP). Overexpressed CPAP directly interacts with HBx (Co-IP and PLA). SUMO modification of CPAP is required for CPAP-HBx interaction. Overexpressed CPAP maintains HBx protein stability in an NF-κB-dependent manner.\",\n      \"method\": \"Chromatin immunoprecipitation, co-immunoprecipitation, in situ PLA, reporter assay, siRNA knockdown, overexpression\",\n      \"journal\": \"Journal of biomedical science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, Co-IP, and PLA with functional validation, single lab\",\n      \"pmids\": [\"31170980\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Cenpj regulates cilia disassembly in mouse neural progenitor cells through Kif2a (a plus-end-directed motor protein). Conditional Cenpj depletion leads to long cilia and abnormal cilia disassembly. Reduced cell proliferation, uncompleted cell division, and apoptosis result in microcephaly. Cenpj also regulates cilium structure of adult neural stem cells.\",\n      \"method\": \"Conditional knockout mice, in vivo immunofluorescence, epistasis with Kif2a, BrdU proliferation assay\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo conditional KO with pathway epistasis (Kif2a), defined cellular phenotypes, single lab\",\n      \"pmids\": [\"30626697\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Conditional knockout of Cpap in mouse CNS preferentially induces monopolar spindles in radial glia progenitors (RGPs) at ~E14.5, causing robust apoptosis. Loss of one p53 allele reduces RGP death, and complete p53 removal rescues RGP death, placing CPAP-loss-induced apoptosis downstream of p53. Cpap deletion also causes cilia loss, RGP mislocalization, junctional integrity disruption, and severe cerebellar hypoplasia.\",\n      \"method\": \"Conditional knockout mouse (CNS-specific), genetic epistasis with p53, immunofluorescence, histological analysis\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo conditional KO with genetic epistasis (p53), multiple phenotypic readouts, single lab\",\n      \"pmids\": [\"32501282\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"WDR62 mutant proteins (V66M and R439H) localize to the basal body but fail to recruit CPAP. As a consequence, IFT88 recruitment is deficient, leading to failure of cilia formation. This underpins premature differentiation of radial glia and microcephaly in WDR62 mutant mice.\",\n      \"method\": \"CRISPR/Cas9 knock-in mice, immunofluorescence, co-localization studies\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo CRISPR knock-in model with defined recruitment hierarchy, single lab\",\n      \"pmids\": [\"31816041\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Using auxin-inducible degron-mediated fast CPAP degradation combined with superresolution microscopy, three independent centrosomal CPAP populations were identified with distinct cell-cycle regulation. CPAP is critical for assembly of human centrioles but not for PCM recruitment onto already-assembled centrioles. CPAP insufficiency leads to centrioles with incomplete microtubule triplets that can still convert to centrosomes, duplicate, and form spindle poles, but ultimately fragment due to loss of cohesion between microtubule blades.\",\n      \"method\": \"Auxin-inducible degron fast protein degradation, superresolution microscopy (STORM/STED), live imaging, electron microscopy\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — acute protein degradation combined with superresolution and EM, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"35404385\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The CPAP-E1235V microcephaly mutant perturbs recruitment of centriolar proteins CEP120, CEP295, CENTROBIN, POC5, and POC1B to nascent centrioles, resulting in short centrioles but long cilia in hiPSC-derived brain organoids. CPAP-E1235V induces p53-dependent neuronal cell death, produces smaller brain organoids, and alters spindle orientation of neuronal progenitor cells causing premature neuronal differentiation.\",\n      \"method\": \"CRISPR-Cas9 isogenic hiPSC generation, brain organoids, immunofluorescence, spindle orientation assay, p53 pathway analysis\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — isogenic CRISPR model in human organoids with multiple phenotypic readouts, single lab\",\n      \"pmids\": [\"35309908\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CPAP (CENPJ/SAS-4/MCPH6) is a cell-cycle-regulated centrosomal scaffold protein that controls centriole biogenesis, elongation, and length by binding tubulin heterodimers via its PN2-3 domain and capping microtubule plus ends to slow centriolar microtubule growth; it is recruited to procentrioles through interactions with STIL (via its TCP/G-box domain), CEP135, CEP120, CEP152, and centrobin, is regulated by phosphorylation (PLK2 at S589/S595, Aurora-A at S467, Cdk1/Polo in flies) and by PARsylation via tankyrase 1 (leading to proteasomal degradation in G1), forms homodimers via its fifth coiled-coil domain to maintain centrosome cohesion, scaffolds cytoplasmic PCM complexes and tethers them to centrioles, promotes timely cilium disassembly by recruiting the cilium disassembly complex (Nde1, Aurora A, OFD1), and in non-centrosomal contexts acts as a transcriptional coactivator of STAT5 and STAT3 and is SUMOylated for NF-κB co-activator activity, with loss-of-function causing incomplete centriole microtubule triplets, spindle defects, and primary microcephaly.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CPAP (CENPJ/SAS-4/MCPH6) is a cell-cycle-regulated centrosomal scaffold protein that governs centriole biogenesis, elongation, and length through its intrinsic tubulin-binding activity [#6, #26]. Its PN2-3/MDD module binds GTP-tubulin heterodimers and caps microtubule plus ends at a site engaged in longitudinal tubulin-tubulin contacts, dampening growth and limiting the length of centriolar microtubules; mutations that alter this affinity produce either short centrioles with incomplete microtubule triplets or over-elongated centriolar and ciliary microtubules via a clutch-like dynamic release of tubulin [#2, #26, #27]. CPAP is recruited to nascent procentrioles through direct interactions with STIL (via its TCP/G-box proline-recognition domain), CEP135, CEP120, CEP152, and centrobin, which together build a recruitment and stability hierarchy at the procentriole base [#11, #13, #19, #23, #31]; structural work establishes the G-box as a β-sheet platform that tethers the SAS-4–PCM scaffold to centrioles [#18, #20, #22]. Its activity is tuned by phosphorylation (PLK2 at S589/S595 for procentriole formation, Aurora-A at S467 to switch from microtubule to PCM binding, and Cdk1/Polo in flies for centriole conversion and PCM expansion) and by tankyrase-1 PARsylation and centrobin-dependent control of its turnover, which restrict productive CPAP to the appropriate cell-cycle window [#10, #15, #23, #24, #28, #29, #33]. CPAP scaffolds cytoplasmic PCM complexes and tethers them to centrioles to maintain centrosome integrity, and it homodimerizes via its fifth coiled-coil domain to preserve centrosome cohesion until mitotic phosphorylation permits splitting [#9, #12, #39]. Beyond duplication, CPAP negatively regulates ciliary length and promotes timely cilium disassembly by recruiting the Nde1–Aurora A–OFD1 disassembly complex to the ciliary base [#16, #30, #36]. Loss or microcephaly-associated mutation of CPAP causes spindle defects, p53-dependent progenitor apoptosis, randomized cleavage-plane orientation, defective ciliogenesis, and primary microcephaly/Seckel syndrome [#3, #17, #30, #37, #40]. In non-centrosomal contexts, CPAP acts as a transcriptional coactivator of STAT5 and STAT3 and, when SUMOylated, augments NF-κB activity [#1, #21, #34].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established CPAP as a centrosomal protein physically associated with the γ-tubulin complex and functionally required for microtubule aster formation, framing it as a microtubule-nucleation-related centrosomal factor.\",\n      \"evidence\": \"Yeast two-hybrid, co-sedimentation and Co-IP with γ-tubulin, antibody inhibition of asters\",\n      \"pmids\": [\"11003675\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No domain responsible for tubulin/γ-tubulin association mapped\", \"Role in centriole biology not yet recognized\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Revealed an unexpected non-centrosomal role of CPAP as a nuclear transcriptional coactivator, showing the protein has functions beyond the centrosome.\",\n      \"evidence\": \"Yeast two-hybrid, reporter assay, fractionation showing Stat5-specific coactivation upon PRL signaling\",\n      \"pmids\": [\"12198240\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of nuclear shuttling unresolved\", \"Relationship to centrosomal pool unclear\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identified the microtubule-destabilizing domain that binds tubulin heterodimers, providing the first biochemical mechanism for CPAP's action on microtubules.\",\n      \"evidence\": \"Deletion mapping with in vitro depolymerization and tubulin-binding assays\",\n      \"pmids\": [\"15047868\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How destabilizing activity reconciles with centriole growth not yet known\", \"Structural basis of tubulin binding undefined\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Connected CPAP to human disease and to centrosome integrity, showing loss-of-function causes primary microcephaly and depletion causes multipolar spindles via Eg5-dependent mechanisms.\",\n      \"evidence\": \"Genetic mapping/mutation analysis (MCPH6) and siRNA with Eg5-inhibition epistasis\",\n      \"pmids\": [\"15793586\", \"16316625\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of microcephaly mutations undefined\", \"Cell-biological cause of microcephaly not yet linked to centriole biogenesis\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Refined the structural determinants of tubulin binding and destabilization through mutagenesis, confirming the MDD as the active module and its conservation across species.\",\n      \"evidence\": \"Site-specific mutagenesis with in vitro MT binding/destabilization assays\",\n      \"pmids\": [\"18586240\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic structure of the domain–tubulin complex still absent\", \"In vivo consequence of mutations not assessed here\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Reframed CPAP as a positive regulator of centriole elongation whose tubulin-binding activity drives procentriole assembly, and established cell-cycle control of its levels and a coiled-coil-mediated homodimer required for centrosome cohesion.\",\n      \"evidence\": \"Cell-cycle analysis, overexpression/knockdown, EM, tubulin-binding-defective mutants, and Co-IP/domain mapping across multiple labs\",\n      \"pmids\": [\"19503075\", \"19481460\", \"19481458\", \"19889632\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Recruitment partners targeting CPAP to procentrioles not yet identified\", \"Kinase responsible for cohesion-disrupting phosphorylation unknown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identified CEP152 as the centrosomal receptor for CPAP and PLK2 phosphorylation at S589/S595 as a positive signal for procentriole formation, defining recruitment and regulatory inputs.\",\n      \"evidence\": \"Co-IP/knockdown for CEP152 and in vitro/in vivo kinase assays with phospho-mutant rescue for PLK2\",\n      \"pmids\": [\"21059844\", \"20531387\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Spatial relationship between CEP152 and other recruiters undefined\", \"Direct phosphatase counteracting PLK2 unknown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Established CPAP as a scaffold that tethers pre-assembled PCM complexes to centrioles and identified STIL as a direct partner whose binding is disrupted by a microcephaly mutation, linking molecular interactions to disease.\",\n      \"evidence\": \"Drosophila genetics, in vitro binding with purified S-CAP complexes, Co-IP/direct binding, MCPH mutation (E1235V) analysis, domain mapping with spindle-orientation assays\",\n      \"pmids\": [\"21694707\", \"22020124\", \"22100914\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of STIL recognition not yet solved at this stage\", \"Stoichiometry of CPAP–PCM scaffold undefined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined post-translational and developmental control of CPAP — tankyrase-1 PARsylation/degradation restricting CPAP to the proper window, and ciliogenesis and disease-model phenotypes — broadening its functional repertoire.\",\n      \"evidence\": \"In vitro PARsylation and reciprocal tankyrase perturbation; ciliogenesis assays with 377EE mutant; Cenpj hypomorphic Seckel mouse\",\n      \"pmids\": [\"22699936\", \"23213448\", \"23166506\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How tankyrase activity is timed to G1 unresolved\", \"Distinction between cilium and centriole functions of CPAP not yet separated\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Provided atomic structures of the CPAP TCP/G-box–STIL complex defining a novel proline-recognition fold and identified CEP135 and CEP120 as direct partners linking CPAP to SAS-6 and microtubules during elongation.\",\n      \"evidence\": \"X-ray crystallography/NMR with ITC/SPR and in vivo duplication assays; Co-IP/direct binding/knockdown/dominant-negative for CEP135 and CEP120\",\n      \"pmids\": [\"24052813\", \"24076405\", \"23511974\", \"23857771\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How multiple recruiters are spatially coordinated at the procentriole unclear\", \"Order of assembly among STIL/CEP135/CEP120 not fully resolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Resolved how the G-box β-sheet platform tethers the SAS-4–PCM scaffold to centrioles and identified centrobin as a stabilizer protecting CPAP from proteasomal degradation, separating scaffolding from tethering functions.\",\n      \"evidence\": \"Crystallography with mutagenesis across fly/human/iPSC-NPC systems; Co-IP, knockdown, dominant-negative, proteasome inhibition for centrobin\",\n      \"pmids\": [\"24385583\", \"24700465\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the ubiquitin ligase targeting CPAP unknown\", \"How centrobin physically shields CPAP undefined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Integrated CPAP into a developmental transcriptional program (Ascl1 target) controlling radial glia centrosome biogenesis and showed centrobin sets CPAP abundance to control centriole length.\",\n      \"evidence\": \"In utero electroporation knockdown/rescue with ChIP for Ascl1; gain/loss-of-function with mutagenesis and proteasome inhibition for centrobin\",\n      \"pmids\": [\"25753651\", \"25616662\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Transcriptional control of CPAP in non-neural tissues not assessed\", \"Mechanism by which centrobin overexpression accumulates ubiquitinated CPAP unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Delivered the mechanistic core: structural and reconstitution evidence that CPAP caps microtubule plus ends to limit growth, that PN2-3 engages GTP-tubulin via a clutch-like mechanism setting centriole length, and that Aurora-A and Cdk1/Polo phosphorylation switch CPAP between microtubule and PCM functions; also defined a dedicated role in cilium disassembly.\",\n      \"evidence\": \"Crystallography + TIRF single-molecule reconstitution + in-cell assays; kinase assays with phospho-mutant rescue; iPSC-NPC/organoid and patient-cell ciliary studies\",\n      \"pmids\": [\"27219064\", \"27306797\", \"26997271\", \"27326932\", \"26929011\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How capping, elongation, and PCM functions are partitioned within one cell cycle still being clarified\", \"Direct disassembly-complex contact surfaces on CPAP undefined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed tubulin negatively regulates CPAP-dependent PCM recruitment and nucleation and exploited the CPAP–tubulin interface pharmacologically to selectively kill centrosome-amplified cancer cells.\",\n      \"evidence\": \"Compound screen (CCB02), Co-IP, genetic perturbation, organotypic invasion assay\",\n      \"pmids\": [\"30530478\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Therapeutic window and selectivity in vivo unresolved\", \"How tubulin occupancy is dynamically regulated at centrosomes unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Extended CPAP's transcriptional moonlighting to STAT3-driven tumor angiogenesis and SUMO-dependent NF-κB/HBx interactions, and identified Kif2a as a mediator of CPAP-dependent cilia disassembly in vivo.\",\n      \"evidence\": \"Co-IP/reporter/xenograft for STAT3; ChIP/Co-IP/PLA for HBx; conditional KO with Kif2a epistasis\",\n      \"pmids\": [\"31511651\", \"31170980\", \"30626697\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether transcriptional and centrosomal pools are functionally separable not established\", \"Mechanism linking CPAP to Kif2a at the cilium undefined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined the disease-relevant recruitment hierarchies and downstream cell-death pathway: WDR62 recruits CPAP for ciliogenesis, CPAP loss triggers p53-dependent progenitor apoptosis, and the E1235V mutation disrupts recruitment of multiple centriolar proteins causing short centrioles but long cilia.\",\n      \"evidence\": \"CRISPR knock-in/conditional KO mice with p53 epistasis; isogenic hiPSC brain organoids with spindle-orientation and p53 analyses\",\n      \"pmids\": [\"31816041\", \"32501282\", \"35309908\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How a single mutation simultaneously shortens centrioles and lengthens cilia mechanistically unclear\", \"Cell-type specificity of p53-dependent death not fully explained\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Used acute degradation and superresolution/EM to dissect CPAP's essential function, showing it is required for assembling centriole microtubule triplets and cohesion between blades, but not for PCM recruitment onto pre-formed centrioles, refining its role to centriole construction.\",\n      \"evidence\": \"Auxin-inducible degron, STORM/STED, live imaging, electron microscopy\",\n      \"pmids\": [\"35404385\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of inter-blade cohesion provided by CPAP undefined\", \"How three distinct CPAP populations are differentially regulated unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CPAP's centrosomal, ciliary, and nuclear transcriptional activities are partitioned and coordinated within the same cell, and the structural basis of its contacts with the cilium-disassembly complex and inter-microtubule-blade cohesion, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of CPAP bound to Nde1/Aurora A/OFD1 disassembly complex\", \"Functional separability of transcriptional vs centrosomal pools not demonstrated\", \"Mechanism coupling CPAP populations to cell-cycle stage unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [2, 5, 26, 27]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1, 21, 34]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [12, 22, 39]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [26, 39]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [0, 3, 6, 39]},\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [16, 30, 36]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 21]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [2, 26]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [6, 7, 39]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [6, 16, 30, 39]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [25, 37, 40]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [1, 21, 34]}\n    ],\n    \"complexes\": [\"centrosome/centriole\", \"S-CAP (SAS-4–PCM scaffold)\", \"cilium disassembly complex (Nde1–Aurora A–OFD1)\", \"γ-tubulin complex\"],\n    \"partners\": [\"STIL\", \"CEP135\", \"CEP120\", \"CEP152\", \"CENTROBIN\", \"tubulin\", \"STAT5\", \"WDR62\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}