Cyclin O is a cyclin-family regulatory protein that associates with and activates cyclin-dependent kinase complexes. Acting downstream of MCIDAS, it promotes the progression of multiciliated epithelial cells into a specialized differentiation program that amplifies centrioles and produces multiple motile cilia. Human CCNO deficiency impairs centriole production and causes autosomal recessive primary ciliary dyskinesia with reduced generation of motile cilia. CCNO is found in the apical cytoplasm of multiciliated cells and can also accumulate in nuclear compartments in other cellular contexts. Human-cell biochemical experiments establish CDK2 association and activation, while the physiological CDK partner in differentiating multiciliated cells remains unresolved. Lymphoid-cell studies also implicate cyclin O in intrinsic apoptosis, including induction in mouse thymus and spleen, although apoptosis after CCNO overexpression appears context dependent. Its historical uracil-DNA glycosylase assignment is erroneous; the DNA-repair protein now called UNG2 is a product of a different gene.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000082 G1/S transition of mitotic cell cycle | IBA GO_REF:0000033 | UNDECIDED | Summary: The inherited mitotic G1/S assertion is not resolved by the specialized multiciliated-cell cycle. Reason: GO:0000082 describes entry into the DNA-replication phase of a mitotic cycle. PMID:39740663 instead studies a differentiation-associated cycle variant in which centriole amplification is uncoupled from DNA replication and mitosis. That result does not disprove a mitotic function in another context. The PAINT IBD placement behind PTN000019791 has not been reconstructed, and the accessible historical human study does not establish a causal mitotic transition. Preserve the phylogenetic assertion as unresolved rather than challenging it by donor count or transferring the nonmitotic endpoint into this term. PMID:18927588 separates its lymphoid apoptotic effect from cell-cycle perturbation; this context-specific result does not resolve all possible mitotic functions. |
| GO:0000278 mitotic cell cycle | IDA PMID:8419333 Cell cycle regulation of a human cyclin-like gene encoding u... | UNDECIDED | Summary: The historical human study establishes cell-cycle-regulated expression, but its process-participation evidence remains unresolved. Reason: The complete available abstract of PMID:8419333 describes G1-associated CCNO transcript/protein abundance, promoter regulation and turnover in human HeLa S3 and WI38 cells. Expression controlled by the cell cycle does not by itself demonstrate that CCNO performs a mitotic step. The original full paper was not accessible, so its IDA assertion is not rejected from the abstract. The obsolete glycosylase interpretation is independently corrected in the reviewed UniProt record; that naming problem does not establish that this experimental process annotation is false. PMID:18927588 separates its lymphoid apoptotic effect from cell-cycle perturbation; this context-specific result does not resolve all possible mitotic functions. |
| GO:0000307 cyclin-dependent protein kinase holoenzyme complex | IBA GO_REF:0000033 | ACCEPT | Summary: CCNO functions as a cyclin regulatory subunit of a CDK-containing complex. Reason: The term explicitly includes the regulatory cyclin associated with the catalytic kinase. In PMID:25364462, expressed human CCNO and CDK2 co-immunoprecipitated reciprocally, and tagged CCNO also associated with endogenous CDK2; anti-CDK2 immunoprecipitates showed increased histone H1 phosphorylation when CCNO was expressed. These target-specific findings support the broad complex assignment independently of the conserved PAINT inference. They do not identify the native kinase partner in multiciliated cells. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: The CCNO–TLE5 isoform-2 interaction is retained without assigning a molecular mechanism. Reason: The original HuRI annotation preserves the exact partner Q08117-2. The reviewed CCNO UniProt record independently lists this same TLE5 isoform edge with three experiments and IntAct identifiers EBI-2556878/EBI-11741437. The cached HuRI Methods describe binary screening and pairwise verification, but the exact target supplement row and its assay configuration were not independently inspected. This corroborated curated association is retained under the project-specific binding policy; no transcription-regulator binding, adaptor activity or physiological complex is inferred merely from the partner identity. Supporting Evidence: |
| GO:0005634 nucleus | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Nuclear localization is supported, but is not used as a human multiciliation-specific core location. Reason: Human CCNO was detected in nucleoli in the target-specific immunohistochemistry of PMID:28860486, supporting the broader nuclear compartment. PMID:39740663 additionally reports nuclear enrichment during mouse brain multiciliated-cell differentiation, a distinct species and context. These observations support the localization without establishing that the human nuclear pool executes the principal multiciliation mechanism. The target accession in the PAINT descendant evidence is legitimate experimental grounding, not circular support. The IHC signal is from lung adenocarcinoma samples, with adjacent normal lung generally negative; it does not establish constitutive nucleolar localization across normal tissues. |
| GO:0005730 nucleolus | IDA GO_REF:0000052 | KEEP AS NON CORE | Summary: The nucleolar localization is retained with independent human CCNO corroboration. Reason: The original GO_REF:0000052 immunofluorescence mapping is preserved; its individual HPA image was not reanalyzed. Independently, PMID:28860486 assayed CCNO in human lung tissues and reported its nucleolar concentration, with antibody-validation and immunohistochemistry Methods available in the cache. This supports the compartment, while its functional significance in those cells is unresolved. The IHC signal is from lung adenocarcinoma samples, with adjacent normal lung generally negative; it does not establish constitutive nucleolar localization across normal tissues. |
| GO:0005730 nucleolus | IDA PMID:28860486 A systematic analysis of orphan cyclins reveals CNTD2 as a n... | KEEP AS NON CORE | Summary: Human lung adenocarcinoma immunohistochemistry supports CCNO nucleolar localization. Reason: Although the paper foregrounds CNTD2, its actual Results examine CCNO in six paired human lung tumor/adjacent-normal samples and place CCNO in nucleoli. The Methods specify the CCNO antibody and controls. This is target-level localization evidence, not a paralog attribution error. It does not establish a nucleolar molecular function or a statistically significant CCNO oncogenic phenotype. The IHC signal is from lung adenocarcinoma samples, with adjacent normal lung generally negative; it does not establish constitutive nucleolar localization across normal tissues. Supporting Evidence: PMID:28860486 CCNO appeared concentrated in nucleoli |
| GO:0005730 nucleolus | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: The UniProt nucleolus-to-GO mapping agrees with direct human localization evidence. Reason: SL-0188 denotes the nucleolar compartment and the preserved reviewed UniProt record explicitly assigns it to CCNO. The independent target-specific human immunohistochemistry in PMID:28860486 corroborates this localization. The electronic mapping is retained without treating localization as a distinct core biochemical activity. The IHC signal is from lung adenocarcinoma samples, with adjacent normal lung generally negative; it does not establish constitutive nucleolar localization across normal tissues. |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: Cytoplasmic localization is consistent with the compartment in which CCNO supports multiciliation. Reason: The target-specific human study PMID:24747639 places CCNO in the apical cytoplasm of multiciliated cells. That independent evidence supports the broad cytoplasmic location while the PAINT inference retains its own phylogenetic provenance. Inclusion of P22674 among the descendant evidence is expected and is not a reason to mark the source circular. |
| GO:0005737 cytoplasm | IDA PMID:24747639 Mutations in CCNO result in congenital mucociliary clearance... | ACCEPT | Summary: CCNO localizes to the apical cytoplasm of multiciliated cells. Reason: The complete cached abstract of the human CCNO disease and cell study explicitly states apical cytoplasmic localization. This supports the preserved IDA compartment and is consistent with the centriole-amplification phenotype. Localization does not identify a specific centrosomal substructure or establish that CCNO itself builds microtubules. Supporting Evidence: PMID:24747639 apical cytoplasm of multiciliated cells |
| GO:0005737 cytoplasm | IEA GO_REF:0000120 | ACCEPT | Summary: The combined electronic cytoplasm annotation is independently supported on the human target. Reason: The source preserves mouse P0C242/ENSMUSP00000040083 and the UniProt SL-0086 vocabulary as its combined IEA provenance. Human CCNO cytoplasmic localization is explicitly reported in PMID:24747639, so retention does not require inventing a particular donor experiment. GO_REF:0000120 is a combined electronic method, distinct from the PAINT rows. |
| GO:0005815 microtubule organizing center | IBA GO_REF:0000033 | UNDECIDED | Summary: A microtubule-organizing-center site of CCNO activity remains unresolved. Reason: CCNO controls centriole amplification, but that phenotype alone does not locate the protein at the microtubule-organizing center. Available human evidence identifies apical cytoplasm; the selected mouse differentiation study reports prominent nuclear enrichment and does not establish this particular site of action. The PAINT IBD/node history behind PTN007424001 was not inspected sufficiently to adjudicate the inherited localization. Neither broad cytoplasmic localization nor the donor list warrants rejecting it. |
| GO:0016538 cyclin-dependent protein serine/threonine kinase regulator activity | IBA GO_REF:0000033 | MODIFY | Summary: Human CCNO binding and kinase assays support the more specific CDK activator activity. Reason: The regulatory assignment is sound, and PMID:25364462 supplies a more precise activity: human CCNO associates with CDK2 and increases the histone H1 kinase activity recovered in anti-CDK2 immunoprecipitates. The S81A CCNO variant retains partial stimulation and must not be described as inactive. The result fits GO:0061575, which requires binding and increased CDK activity, without attributing catalytic kinase activity to CCNO. Mouse CCNO cyclin-fold-mutant controls in PMID:39740663 are separate corroboration; the native multiciliated-cell CDK partner remains unresolved. Proposed replacements: cyclin-dependent protein serine/threonine kinase activator activity |
| GO:0060271 cilium assembly | IEA GO_REF:0000117 | ACCEPT | Summary: The electronic ciliogenesis annotation agrees with target-specific centriole and cilia phenotypes. Reason: Human CCNO variants impair mother-centriole generation/placement and markedly reduce multiple motile cilia in PMID:24747639. The later human H9-derived airway and patient analysis in PMID:39740663 places the block near the onset of centriole biogenesis after acquisition of early multiciliated-cell markers. Together with CCNO cyclin-regulatory activity, this supports a role in the assembly program. The individual ARBA00027837 rule was not reconstructed, so the conclusion rests on independent biology rather than assumed rule predicates. Mouse Ccno-deletion experiments in PMID:25712475 independently corroborate defective deuterosome-mediated centriole amplification. |
| GO:0060271 cilium assembly | IMP PMID:24747639 Mutations in CCNO result in congenital mucociliary clearance... | ACCEPT | Summary: Human CCNO defects impair the centriole-amplification program needed to assemble multiple motile cilia. Reason: PMID:24747639 reports target variants in affected individuals, defective centriole generation/placement in patient-cell ciliogenesis assays and a marked decrease in multiple motile cilia. The few residual cilia retain motors and motility, distinguishing cilia production from an intrinsic beat-mechanism defect. Later human cellular evidence corroborates the assembly defect. CCNO contributes regulation rather than an axonemal structural component. Mouse Ccno-deletion experiments in PMID:25712475 independently corroborate defective deuterosome-mediated centriole amplification. Supporting Evidence: PMID:24747639 defective mother centriole generation and placement |
| GO:0160108 animal gross anatomical part developmental process | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Broad animal anatomical development is retained as a non-core ancestor of the epithelial differentiation role. Reason: The current ontology places multiciliated epithelial-cell differentiation under epithelial development and animal gross anatomical part developmental process. Human CCNO participates in the former process, so the broad developmental scope is not contradicted merely because the direct assays concern cells. It contributes little mechanistic precision compared with the existing epithelial differentiation annotation. The specific ARBA00098139 decision predicates were not inspected. |
| GO:1903251 multi-ciliated epithelial cell differentiation | IMP PMID:24747639 Mutations in CCNO result in congenital mucociliary clearance... | ACCEPT | Summary: CCNO enables progression of the multiciliated epithelial differentiation program. Reason: The human disease/ciliogenesis study links CCNO to the generation of multiciliated cells. PMID:39740663 refines the stage: human mutant H9-derived cells can acquire FOXJ1/RFX2/RFX3 positivity but fail to form normal SAS6-positive procentrioles and multiple cilia. Thus CCNO is required for progression and maturation of the program rather than initial fate specification. Mouse brain mechanistic and mutant-rescue experiments support a cyclin-regulatory contribution, with species and kinase-partner limits retained. Mouse Ccno-deletion experiments in PMID:25712475 independently corroborate defective deuterosome-mediated centriole amplification. |
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Download this section (compressed HTML)Q: Which CDK partner and immediate substrates mediate CCNO activity in human multiciliated epithelial cells?
Q: Does CCNO directly promote an ordinary mitotic G1/S transition in a defined human-cell context, separately from its role in the nonmitotic multiciliated-cell cycle variant?
Q: What functional roles, if any, distinguish the two reviewed CCNO splice products and the nuclear versus apical cytoplasmic pools?
Q: Do lymphoid intrinsic apoptosis and multiciliated-cell differentiation use the same CCNO-associated CDK and substrates, and what determines their different outcomes?
Experiment: Identify endogenous CCNO-associated CDKs in staged human airway differentiation and test whether interaction-defective, expression-matched CCNO variants rescue centriole amplification after CCNO depletion.
Experiment: Compare endogenous isoform-specific localization and activity during human airway differentiation, separating the onset of multiciliated-cell markers from procentriole assembly and mature cilia production.
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