CIC encodes capicua, a nuclear sequence-specific transcriptional repressor that links RTK/Ras–MAPK signaling to gene expression. Its HMG-box and C1 domains jointly recognize TGAATGAA-like octamers in regulatory DNA, including ETV-family promoters. RTK activation can downregulate CIC and release its target genes from repression. CIC associates with ATXN1 and ATXN1L in repressive complexes and controls developmental gene-expression programs. CIC also functions as a tumor suppressor; somatic mutations, including missense changes in its DNA-recognition domains, recur in oligodendroglioma. In contrast, oncogenic CIC–DUX4 fusions activate CIC target genes in a subset of sarcomas. Loss of CIC disrupts neural maturation and behavior, and human heterozygous loss-of-function variants cause neurodevelopmental disease. Short and long CIC products share the DNA-recognition domains but differ in their N-terminal regions.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000785 chromatin | ISA GO_REF:0000113 | ACCEPT | Summary: CIC associates with regulatory chromatin. Reason: Human GFP-CIC is enriched at endogenous ETV1, ETV4 and ETV5 promoters in anti-GFP ChIP with empty-vector and non-CIC-site controls. This directly corroborates the TFClass-derived chromatin location; it does not imply that CIC is a histone or permanent chromatin structural constituent. Supporting Evidence: |
| GO:0000977 RNA polymerase II transcription regulatory region sequence-specific DNA binding | IBA GO_REF:0000033 | ACCEPT | Summary: CIC directly recognizes sequence-specific regulatory DNA sites. Reason: Human HMG-C1 fragments bind isolated ETV regulatory octamers in sequence-dependent EMSA assays, and GFP-tagged human CIC occupies endogenous ETV1/4/5 promoter regions. The 2025 engineered-module structure and specificity controls corroborate direct target-sequence recognition. This positively supports regulatory-region sequence-specific binding; it is not inferred solely from ChIP or from a donor count. The historical PAINT node has not been reconstructed. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000990637 SUPPORTS TRANSFER Current fly Cic/Q9U1H0 records include direct regulatory-DNA binding from PMID:28278156, which also tests human CIC. These support transfer; historical IBD placement and alignment were not reconstructed. |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IBA GO_REF:0000033 | MODIFY | Summary: Refine the broad transcription factor activity to sequence-specific repression. Reason: Human GFP-CIC represses a CIC-site reporter while occupying endogenous ETV promoters; HMG/C1 mutations impair repression and promoter association in the 2017 assays. Together with direct fragment binding this supports the repressor-specific molecular function. Refinement describes normal CIC, not the transcriptional activation conferred by a DUX4 fusion. Preserve the original IBA and PTN source fields; target evidence does not reconstruct ancestral placement. Propagation Review Root cause: TERM SCOPING PROBLEM Sources checked: PANTHER:PTN000990637 SUPPORTS TRANSFER Direct human motif binding and repression support the broad inherited function and its repressor-specific refinement. Current fly experimental sources are authenticated; the historical node was not reconstructed. Proposed replacements: DNA-binding transcription repressor activity, RNA polymerase II-specific |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | ISA GO_REF:0000113 | MODIFY | Summary: Human CIC is a sequence-specific transcriptional repressor. Reason: The TFClass-sourced broad DNA-binding transcription factor assertion can be refined to repressor activity using the direct human reporter, ChIP and sequence-dependent binding evidence. The 2025 structural module confirms recognition geometry but does not itself assay full-length repression. Proposed replacements: DNA-binding transcription repressor activity, RNA polymerase II-specific |
| GO:0003682 chromatin binding | IEA GO_REF:0000107 | ACCEPT | Summary: CIC binds promoter chromatin. Reason: Independent human anti-GFP ChIP detects CIC at endogenous ETV1/4/5 promoter chromatin, with empty-vector and non-CBS-region controls. This supports the existing chromatin-binding claim while the isolated fragment assays separately establish DNA specificity. The human corroboration is distinct from the original mouse Ensembl transfer and does not change that machine source. |
| GO:0005515 protein binding | IPI PMID:16713569 A protein-protein interaction network for human inherited at... | MODIFY | Summary: CIC binds the transcription corepressor ATXN1. Reason: Five exact human CIC–ATXN1 records from the original ataxia screen report two-hybrid positives, including a sufficient-region construct. The records do not resolve every fragment to a current CIC product. ATXN1 acts as a transcriptional corepressor through protein interactions: co-expression enhances CIC-site reporter repression. This class refinement identifies the bound partner, without transferring ATXN1 activity to CIC or making the interaction a separate core function. Proposed replacements: transcription corepressor binding Supporting Evidence: PMID:20628574 synergistic co-repression of this luciferase reporter |
| GO:0005515 protein binding | IPI PMID:16713569 A protein-protein interaction network for human inherited at... | MODIFY | Summary: Refine the CENPJ interaction to cytoskeletal protein binding. Reason: The exact human CIC–CENPJ records include a two-hybrid positive with CIC residues 2210–2517 and a tagged pull-down. The original Methods use human brain/ORFeome libraries and HEK293T co-affinity validation. CENPJ/CPAP is an established centriole-associated microtubule regulator associated with the gamma-tubulin complex, supporting the partner class; current GOA also records part_of the gamma-tubulin complex (NAS, PMID:11003675). This does not establish CIC localization or a native role at centrioles, and the tested fragment is not an assay of both complete CIC products. Proposed replacements: cytoskeletal protein binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:18337722 Opposing effects of polyglutamine expansion on native protei... | MODIFY | Summary: CIC forms an ATXN1-containing repressor complex. Reason: The original full Results distinguish ATXN1–CIC from ATXN1–RBM17 complexes in mouse cerebellum and HEK293T cells, with competition and fractionation experiments. The selected main cache is abstract-only; an independently retained genuine normal full variant supplies the Methods and Results. ATXN1 acts as a transcriptional corepressor through protein interactions: co-expression enhances CIC-site reporter repression. This class refinement identifies the bound partner, without transferring ATXN1 activity to CIC or making the interaction a separate core function. Proposed replacements: transcription corepressor binding |
| GO:0005515 protein binding | IPI PMID:25959826 Quantitative interaction proteomics of neurodegenerative dis... | MODIFY | Summary: CIC associates with the transcription corepressor ATXN1. Reason: Quantitative AP-MS in HEK293T cells specifically recovers CIC with ATXN1-Q30 relative to vector controls, and preferentially with Q30 over Q82 in the variant comparison. The authors explicitly note that AP-MS can enrich indirect members of a complex. ATXN1 acts as a transcriptional corepressor through protein interactions: co-expression enhances CIC-site reporter repression. This class refinement identifies the bound partner, without transferring ATXN1 activity to CIC or making the interaction a separate core function. Proposed replacements: transcription corepressor binding |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | MODIFY | Summary: The BioPlex ATXN1 association supports corepressor binding. Reason: The exact target pair is recorded as anti-tag co-immunoprecipitation with C-terminally tagged ATXN1. The original BioPlex pipeline uses sequence-validated human ORFeome baits and affinity purification, not purified binary affinity measurements. ATXN1 acts as a transcriptional corepressor through protein interactions: co-expression enhances CIC-site reporter repression. This class refinement identifies the bound partner, without transferring ATXN1 activity to CIC or making the interaction a separate core function. Proposed replacements: transcription corepressor binding |
| GO:0005515 protein binding | IPI PMID:29568061 An AP-MS- and BioID-compatible MAC-tag enables comprehensive... | KEEP AS NON CORE | Summary: Retain the GOLGA2 association with a proximity-labeling caveat. Reason: The original record is BioID proximity, not a binary binding assay. It places CIC near tagged GOLGA2/GM130; independent HuRI two-hybrid evidence supports the same pair. GOLGA2 has positive spindle-localization and microtubule-capture evidence, but its membership in the cytoskeletal-component class required by GO:0008092 is unresolved at the assayed-product scope. Generic binding is retained as non-core without denying those associations or treating a missing part_of annotation as negative evidence. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: The CIC–GOLGA2 two-hybrid interaction is supported. Reason: Three literal HuRI records comprise validated, pooling and array two-hybrid evidence; the GOLGA2 sufficient region is 13–1002. GOLGA2 associates with the spindle and captures nascent microtubules, but these findings do not settle whether this product is a cytoskeletal component in the sense of GO:0008092. Retain the positive pair as non-core with unresolved class specificity. Neither partner activity nor a native CIC Golgi or spindle mechanism is inferred. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MODIFY | Summary: The BioPlex ATXN1 association supports corepressor binding. Reason: The current exact pair record is anti-tag co-immunoprecipitation with C-terminally tagged ATXN1 and an association classification. The selected cache contains the abstract, Introduction and Discussion, rather than complete Results and Methods despite its full-text metadata. The literal pair and independently established ATXN1–CIC work support the refinement. ATXN1 acts as a transcriptional corepressor through protein interactions: co-expression enhances CIC-site reporter repression. This class refinement identifies the bound partner, without transferring ATXN1 activity to CIC or making the interaction a separate core function. Proposed replacements: transcription corepressor binding |
| GO:0005634 nucleus | IBA GO_REF:0000033 | ACCEPT | Summary: CIC performs transcriptional repression in the nucleus. Reason: Human GFP-CIC nuclear localization, promoter occupancy and reporter repression corroborate the inherited is_active_in relation. The current PTN000990637 source and actual fly/human donor identities are retained; the target occurring among source entities is legitimate grounding, not circularity. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000990637 SUPPORTS TRANSFER The current nuclear source chain and exact PTN000990637 are retained. Human target nuclear localization and activity are independently supported. Target self-evidence is valid grounding; historical PAINT placement and the alignment were not reconstructed. Supporting Evidence: |
| GO:0005634 nucleus | IEA GO_REF:0000044 | ACCEPT | Summary: CIC is a nuclear protein. Reason: The UniProt subcellular-location mapping agrees with the independently inspected human GFP-CIC localization and promoter-occupancy experiments. This source does not assert exclusive nuclear localization in every condition. Supporting Evidence: |
| GO:0005654 nucleoplasm | IDA GO_REF:0000052 | ACCEPT | Summary: The nucleoplasmic location is consistent with CIC transcriptional activity. Reason: Retain the curated immunofluorescence IDA at its stated gene-product scope. The original HPA image series was not independently re-read; nuclear localization and endogenous promoter occupancy in human cells provide separate corroboration. No localization is assigned uniquely to either product. |
| GO:0006357 regulation of transcription by RNA polymerase II | IBA GO_REF:0000033 | MODIFY | Summary: CIC negatively regulates Pol II transcription. Reason: The demonstrated direction is repression of Pol-II target reporters by human CIC. Negative regulation of transcription by RNA polymerase II is more informative than unqualified regulation. CIC performs the regulatory step through sequence-dependent occupancy and repression; no new process assertion is needed. Historical IBD placement remains uninspected. Propagation Review Root cause: TERM SCOPING PROBLEM Sources checked: PANTHER:PTN000990637 SUPPORTS TRANSFER Current mouse Cic/Q924A2 is officially cross-referenced to MGI:1918972 and has experimental negative-transcription evidence; human promoter/reporter assays also support transfer. The negative Pol II refinement is a target judgment, not a changed ancestral assertion. Proposed replacements: negative regulation of transcription by RNA polymerase II |
| GO:0007420 brain development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: CIC-dependent transcription supports brain development. Reason: The exact donor is mouse Cic/Q924A2, whose current experimental annotation cites PMID:28288114. Forebrain conditional deletion reduces upper cortical layers and dendritic complexity, with post-mitotic maturation or maintenance defects rather than reduced embryonic progenitor proliferation. Human truncating variants support neurodevelopmental relevance. Preserve this existing orthology assertion as a developmental context of repression, without adding a new process from necessity alone. Supporting Evidence: |
| GO:0007420 brain development | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: CIC-dependent transcription supports brain development. Reason: The exact donor is mouse Cic/Q924A2, whose current experimental annotation cites PMID:28288114. Forebrain conditional deletion reduces upper cortical layers and dendritic complexity, with post-mitotic maturation or maintenance defects rather than reduced embryonic progenitor proliferation. Human truncating variants support neurodevelopmental relevance. Preserve this existing orthology assertion as a developmental context of repression, without adding a new process from necessity alone. Supporting Evidence: |
| GO:0007612 learning | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Learning phenotypes are a contextual consequence of CIC loss. Reason: Mouse Emx1-lineage Cic deletion impairs fear-conditioning performance, particularly contextual freezing. The same study separates these forebrain effects from Otp-lineage social phenotypes. Retain the experimentally grounded mouse-to-human assertion as a behavioral context; it does not identify a separate learning-specific molecular activity. Supporting Evidence: PMID:28288114 impaired learning and memory |
| GO:0007612 learning | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Learning phenotypes are a contextual consequence of CIC loss. Reason: Mouse Emx1-lineage Cic deletion impairs fear-conditioning performance, particularly contextual freezing. The same study separates these forebrain effects from Otp-lineage social phenotypes. Retain the experimentally grounded mouse-to-human assertion as a behavioral context; it does not identify a separate learning-specific molecular activity. Supporting Evidence: |
| GO:0007613 memory | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: CIC-dependent neural transcription influences memory. Reason: The authenticated mouse Cic donor carries IMP evidence from conditional forebrain deletion and reduced contextual fear memory. Developmental, circuit and performance effects are not separated into an acute mnemonic mechanism by these assays. The existing orthology-based memory term is retained outside the molecular core. Supporting Evidence: |
| GO:0007613 memory | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: CIC-dependent neural transcription influences memory. Reason: The authenticated mouse Cic donor carries IMP evidence from conditional forebrain deletion and reduced contextual fear memory. Developmental, circuit and performance effects are not separated into an acute mnemonic mechanism by these assays. The existing orthology-based memory term is retained outside the molecular core. Supporting Evidence: |
| GO:0032991 protein-containing complex | IEA GO_REF:0000107 | MODIFY | Summary: Specify the CIC-containing transcription repressor complex. Reason: The original mouse complex annotation is supported by native fractionation and co-immunoprecipitation, with corresponding ATXN1–CIC complexes in human cells. CIC-site reporter experiments establish repressive activity of the associated factors. GO:0017053 captures that demonstrated complex role more informatively than an unspecified protein-containing complex, without assigning a fixed stoichiometry or requiring every CIC molecule to be ATXN1-bound. Proposed replacements: transcription repressor complex |
| GO:0035176 social behavior | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: CIC affects social behavior through region-specific neural functions. Reason: Mouse Otp-lineage Cic deletion in hypothalamic and medial-amygdala neurons reduces social interactions and increases aggression, while the Emx1-lineage deletion has a different behavioral profile. The exact mouse IMP donor supports the existing human orthology assertion at this contextual level. It does not demonstrate an autonomous social-behavior effector function of CIC. Supporting Evidence: PMID:28288114 prominent social interaction deficits |
| GO:0035176 social behavior | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: CIC affects social behavior through region-specific neural functions. Reason: Mouse Otp-lineage Cic deletion in hypothalamic and medial-amygdala neurons reduces social interactions and increases aggression, while the Emx1-lineage deletion has a different behavioral profile. The exact mouse IMP donor supports the existing human orthology assertion at this contextual level. It does not demonstrate an autonomous social-behavior effector function of CIC. Supporting Evidence: |
| GO:0045892 negative regulation of DNA-templated transcription | IEA GO_REF:0000107 | MODIFY | Summary: Refine negative transcriptional regulation to the demonstrated Pol II context. Reason: The broader negative DNA-templated-transcription claim is supported; direct human reporter and ETV-promoter studies identify Pol-II repression more precisely. This specificity refinement preserves the original mouse Ensembl source rather than claiming that the original broader function is false. Proposed replacements: negative regulation of transcription by RNA polymerase II |
| GO:0045892 negative regulation of DNA-templated transcription | ISS GO_REF:0000024 | MODIFY | Summary: Human repression experiments corroborate and refine the mouse orthology transfer. Reason: The mouse-supported negative-transcription assertion agrees with direct human CIC repression evidence. Pol-II-specific negative regulation is the informative refinement, supported by the 2017 reporter and promoter-occupancy experiments; the original ISS source remains exact. Proposed replacements: negative regulation of transcription by RNA polymerase II |
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Download this section (compressed HTML)Q: How do the distinct N-terminal regions of full-length CIC-L and CIC-S alter cofactor recruitment and repression at endogenous targets?
Q: Why do engineered CIC HMG–C1 variants show different binding behavior across EMSA, MST and linker lengths, and which measurements predict repression by complete CIC proteins?
Q: Do the screened CENPJ and GOLGA2 interactions occur for endogenous CIC in a defined physiological context, and what molecular consequence follows?
Experiment: Compare sequence-verified full-length Q96RK0-1 and Q96RK0-2 at matched expression in human cells using target occupancy, reporter repression and endogenous transcript measurements. Include intact versus disrupted CIC sites and ATXN1/ATXN1L perturbations.
Experiment: Test endogenous CIC–CENPJ and CIC–GOLGA2 interactions with reciprocal, compartment-resolved assays and knockout controls, separating proximity from stable association before assigning a cellular mechanism.
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