Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005634 nucleus	IBA GO_REF:0000033	ACCEPT	Summary: CTBP1 is well established as a nuclear transcriptional corepressor. UniProt confirms nuclear localization (PMID:12679040). IBA is appropriate as this is conserved across the CtBP family.
GO:0003714 transcription corepressor activity	IBA GO_REF:0000033	ACCEPT	Summary: Transcription corepressor activity is the primary molecular function of CTBP1. It is recruited by PXDLS-motif-containing transcription factors and assembles HDAC/LSD1/CoREST complexes to silence gene expression. IBA is well-supported and represents the core function. Supporting Evidence: PMID:12419229 CtBP is an NAD(+)-regulated component of critical complexes for specific repression events in cells.
GO:0006357 regulation of transcription by RNA polymerase II	IBA GO_REF:0000033	ACCEPT	Summary: CTBP1 regulates RNA Pol II-dependent transcription as a corepressor. This is a core biological process annotation consistent with its well-established role. IBA annotation is well-supported.
GO:0140297 DNA-binding transcription factor binding	IBA GO_REF:0000033	ACCEPT	Summary: CTBP1 binds numerous DNA-binding transcription factors via their PXDLS motifs (ZEB1/2, KLFs, BCL6, MECOM, FOXP1, etc.). This is a core molecular function. IBA is well-supported. Supporting Evidence: PMID:10359772 ZEB represses transcription through interaction with the corepressor CtBP.
GO:0001221 transcription coregulator binding	IBA GO_REF:0000033	ACCEPT	Summary: CTBP1 binds other coregulators such as HDAC1/2, LSD1/KDM1A, RCOR1/CoREST within its corepressor complexes. It also heterodimerizes with CTBP2. IBA is appropriate.
GO:0003713 transcription coactivator activity	IBA GO_REF:0000033	ACCEPT	Summary: While CTBP1 is primarily a corepressor, there is evidence that CtBP proteins can also have coactivator functions in certain contexts. The IBA annotation suggests this is phylogenetically conserved. Chen 2021 describes both transrepression and transactivation roles for CtBPs. Accepting as a secondary function. Reason: Chen 2021 (J Mol Med) describes transactivation roles of CtBPs in certain pathways, supporting the IBA annotation of coactivator activity as a conserved property.
GO:0045893 positive regulation of DNA-templated transcription	IEA GO_REF:0000108	ACCEPT	Summary: IEA annotation consistent with the coactivator role noted above for CtBP family. Logically inferred from the coactivator activity annotation. Acceptable as a broader annotation.
GO:0003714 transcription corepressor activity	IEA GO_REF:0000002	ACCEPT	Summary: IEA annotation for transcription corepressor activity is redundant with the IBA (index 1) but correct. CTBP1 is well established as a transcriptional corepressor.
GO:0005634 nucleus	IEA GO_REF:0000120	ACCEPT	Summary: IEA annotation for nucleus is redundant with the IBA and IDA annotations but correct.
GO:0005737 cytoplasm	IEA GO_REF:0000044	ACCEPT	Summary: CTBP1 localizes to both nucleus and cytoplasm. UniProt confirms cytoplasmic localization (PMID:12679040). CTBP1/BARS has well-described cytoplasmic roles in Golgi membrane dynamics.
GO:0016491 oxidoreductase activity	IEA GO_REF:0000043	ACCEPT	Summary: CTBP1 has a D-2-hydroxyacid dehydrogenase domain and demonstrated dehydrogenase activity (PMID:12419229). This IEA is a parent term of the more specific GO:0016616 annotation and is correct. Supporting Evidence: PMID:12419229 CtBP is a functional dehydrogenase.
GO:0016616 oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor	IEA GO_REF:0000002	ACCEPT	Summary: Correct IEA annotation consistent with the IDA annotation from PMID:12419229. CTBP1 has demonstrated dehydrogenase activity with NAD as cofactor.
GO:0030154 cell differentiation	IEA GO_REF:0000043	KEEP AS NON CORE	Summary: CTBP1 is involved in differentiation processes (BAT/WAT differentiation, developmental programs) as a pleiotropic consequence of its transcriptional corepressor function. This is a very general term. Keeping as non-core. Reason: Cell differentiation is too general and represents pleiotropic effects of CTBP1 corepressor activity rather than a core function.
GO:0051287 NAD binding	IEA GO_REF:0000002	ACCEPT	Summary: NAD binding is well established for CTBP1. Its Rossmann fold binds NAD+/NADH, which allosterically regulates oligomerization and corepressor function. Supported by crystal structure (PMID:12419229).
GO:0005515 protein binding	IPI PMID:10359772 ZEB represses transcription through interaction with the cor...	MODIFY	Summary: PMID:10359772 demonstrates CTBP1 interaction with ZEB1, a DNA-binding transcription factor. "protein binding" is too vague. Should be annotated as DNA-binding transcription factor binding. Proposed replacements: DNA-binding transcription factor binding Supporting Evidence: PMID:10359772 ZEB represses transcription through interaction with the corepressor CtBP.
GO:0005515 protein binding	IPI PMID:10995736 The interaction of the carboxyl terminus-binding protein wit...	MODIFY	Summary: PMID:10995736 describes CTBP1 interaction with TGIF, a Smad corepressor/transcription factor. Should be annotated more specifically. Proposed replacements: DNA-binding transcription factor binding Supporting Evidence: PMID:10995736 The interaction of the carboxyl terminus-binding protein with the Smad corepressor TGIF is disrupted by a holoprosencephaly mutation in TGIF.
GO:0005515 protein binding	IPI PMID:11462050 Physical and functional interactions between the corepressor...	MODIFY	Summary: PMID:11462050 describes physical interaction between CTBP1 and Epstein-Barr virus EBNA3C. This is a viral protein interaction relevant to host-virus biology. Protein binding is too vague. Reason: EBNA3C is a viral transcriptional regulator that recruits CTBP1 corepressor activity. Proposed replacements: DNA-binding transcription factor binding Supporting Evidence: PMID:11462050 Physical and functional interactions between the corepressor CtBP and the Epstein-Barr virus nuclear antigen EBNA3C.
GO:0005515 protein binding	IPI PMID:16762039 A L225A substitution in the human tumour suppressor HIC1 abo...	MODIFY	Summary: PMID:16762039 demonstrates CTBP1 interaction with HIC1 tumor suppressor. HIC1 is a DNA-binding transcription factor. Protein binding is too vague. Proposed replacements: DNA-binding transcription factor binding Supporting Evidence: PMID:16762039 2006 Jun 7. A L225A substitution in the human tumour suppressor HIC1 abolishes its interaction with the corepressor CtBP.
GO:0005515 protein binding	IPI PMID:17085477 ZNF366 is an estrogen receptor corepressor that acts through...	MODIFY	Summary: PMID:17085477 shows ZNF366 is an estrogen receptor corepressor that acts through CtBP. ZNF366 is a DNA-binding zinc-finger transcription factor. Protein binding is too vague. Proposed replacements: DNA-binding transcription factor binding Supporting Evidence: PMID:17085477 ZNF366 is an estrogen receptor corepressor that acts through CtBP and histone deacetylases.
GO:0005515 protein binding	IPI PMID:19486893 HIC1 interacts with a specific subunit of SWI/SNF complexes,...	UNDECIDED	Summary: PMID:19486893 is about HIC1 interacting with SWI/SNF subunit ARID1A. The direct relevance to CTBP1 protein binding is unclear from the title alone. Unable to fully assess without reading the full publication. Reason: Cannot determine the specific CTBP1 interaction described in this paper from the available abstract alone. Supporting Evidence: PMID:19486893 HIC1 interacts with a specific subunit of SWI/SNF complexes, ARID1A/BAF250A.
GO:0005515 protein binding	IPI PMID:19751731 C-terminal binding proteins (CtBPs) attenuate KLF4-mediated ...	MODIFY	Summary: PMID:19751731 describes CtBPs attenuating KLF4-mediated transcriptional activation. KLF4 is a DNA-binding transcription factor. Protein binding is too vague. Proposed replacements: DNA-binding transcription factor binding Supporting Evidence: PMID:19751731 Epub 2009 Sep 12. C-terminal binding proteins (CtBPs) attenuate KLF4-mediated transcriptional activation.
GO:0005515 protein binding	IPI PMID:20098713 A role for non-covalent SUMO interaction motifs in Pc2/CBX4 ...	MODIFY	Summary: PMID:20098713 describes CTBP1 interaction with Pc2/CBX4 in the context of SUMOylation. CBX4 is a Polycomb group protein that SUMOylates CTBP1. This could be more specifically annotated. Reason: CBX4/Pc2 functions as a transcriptional coregulator and SUMO E3 ligase for CTBP1. Proposed replacements: transcription coregulator binding Supporting Evidence: PMID:20098713 A role for non-covalent SUMO interaction motifs in Pc2/CBX4 E3 activity.
GO:0005515 protein binding	IPI PMID:20211142 An atlas of combinatorial transcriptional regulation in mous...	MARK AS OVER ANNOTATED	Summary: PMID:20211142 is a large-scale atlas study of combinatorial transcriptional regulation. Protein binding from HTP studies is uninformative for CTBP1 annotation. Reason: High-throughput study; protein binding is too vague to be useful. Supporting Evidence: PMID:20211142 An atlas of combinatorial transcriptional regulation in mouse and man.
GO:0005515 protein binding	IPI PMID:21044950 Genome-wide YFP fluorescence complementation screen identifi...	MARK AS OVER ANNOTATED	Summary: PMID:21044950 is a genome-wide YFP fluorescence complementation screen for telomere signaling. CTBP1 is not primarily involved in telomere signaling. This is a HTP screen result. Reason: High-throughput screen; protein binding is too vague and telomere function is not core to CTBP1. Supporting Evidence: PMID:21044950 Epub 2010 Nov 2. Genome-wide YFP fluorescence complementation screen identifies new regulators for telomere signaling in human cells.
GO:0005515 protein binding	IPI PMID:21900206 A directed protein interaction network for investigating int...	MARK AS OVER ANNOTATED	Summary: PMID:21900206 is a directed protein interaction network study. Protein binding from HTP studies is uninformative. Reason: High-throughput study; protein binding is too vague. Supporting Evidence: PMID:21900206 A directed protein interaction network for investigating intracellular signal transduction.
GO:0005515 protein binding	IPI PMID:21903422 Mapping a dynamic innate immunity protein interaction networ...	MARK AS OVER ANNOTATED	Summary: PMID:21903422 is a HTP mapping study of innate immunity protein interaction network. Protein binding is uninformative. Reason: High-throughput study; protein binding is too vague. Supporting Evidence: PMID:21903422 2011 Sep 8. Mapping a dynamic innate immunity protein interaction network regulating type I interferon production.
GO:0005515 protein binding	IPI PMID:21988832 Toward an understanding of the protein interaction network o...	MARK AS OVER ANNOTATED	Summary: PMID:21988832 is a HTP protein interaction network study of human liver. Protein binding is uninformative. Reason: High-throughput study; protein binding is too vague. Supporting Evidence: PMID:21988832 Toward an understanding of the protein interaction network of the human liver.
GO:0005515 protein binding	IPI PMID:24722188 Protein interaction network of alternatively spliced isoform...	MARK AS OVER ANNOTATED	Summary: PMID:24722188 is a HTP isoform interaction network study from brain. Protein binding is uninformative. Reason: High-throughput study; protein binding is too vague. Supporting Evidence: PMID:24722188 Protein interaction network of alternatively spliced isoforms from brain links genetic risk factors for autism.
GO:0005515 protein binding	IPI PMID:24981860 Human-chromatin-related protein interactions identify a deme...	MODIFY	Summary: PMID:24981860 identifies chromatin-related protein interactions including a demethylase complex. CTBP1 is known to associate with chromatin-modifying complexes (LSD1/CoREST). More specifically annotated as transcription coregulator binding. Proposed replacements: transcription coregulator binding Supporting Evidence: PMID:24981860 2014 Jun 26. Human-chromatin-related protein interactions identify a demethylase complex required for chromosome segregation.
GO:0005515 protein binding	IPI PMID:26496610 A human interactome in three quantitative dimensions organiz...	MARK AS OVER ANNOTATED	Summary: PMID:26496610 is a large-scale quantitative interactome study. Protein binding is uninformative. Reason: High-throughput study; protein binding is too vague. Supporting Evidence: PMID:26496610 Oct 22. A human interactome in three quantitative dimensions organized by stoichiometries and abundances.
GO:0005515 protein binding	IPI PMID:26807646 EXD2 promotes homologous recombination by facilitating DNA e...	MARK AS OVER ANNOTATED	Summary: PMID:26807646 is about EXD2 promoting homologous recombination. CTBP1 is not primarily a DNA repair protein. This likely reflects a HTP interaction. Reason: Tangential interaction; protein binding is too vague. Supporting Evidence: PMID:26807646 EXD2 promotes homologous recombination by facilitating DNA end resection.
GO:0005515 protein binding	IPI PMID:27705803 A High-Density Map for Navigating the Human Polycomb Complex...	MODIFY	Summary: PMID:27705803 maps the Polycomb complexome. CTBP1 is known to interact with Polycomb proteins (CBX4/Pc2). More informative than generic protein binding. Proposed replacements: transcription coregulator binding Supporting Evidence: PMID:27705803 A High-Density Map for Navigating the Human Polycomb Complexome.
GO:0005515 protein binding	IPI PMID:28514442 Architecture of the human interactome defines protein commun...	MARK AS OVER ANNOTATED	Summary: PMID:28514442 is a large-scale interactome architecture study. Protein binding is uninformative. Reason: High-throughput study; protein binding is too vague. Supporting Evidence: PMID:28514442 Architecture of the human interactome defines protein communities and disease networks.
GO:0005515 protein binding	IPI PMID:28947780 ZNF516 suppresses EGFR by targeting the CtBP/LSD1/CoREST com...	MODIFY	Summary: PMID:28947780 shows ZNF516 suppresses EGFR by targeting the CtBP/LSD1/CoREST complex to chromatin. ZNF516 is a DNA-binding transcription factor recruiting the CTBP1 complex. Protein binding is too vague. Proposed replacements: DNA-binding transcription factor binding Supporting Evidence: PMID:28947780 ZNF516 suppresses EGFR by targeting the CtBP/LSD1/CoREST complex to chromatin.
GO:0005515 protein binding	IPI PMID:31041561 A pathogenic CtBP1 missense mutation causes altered cofactor...	MODIFY	Summary: PMID:31041561 describes a pathogenic CtBP1 missense mutation affecting cofactor binding and transcriptional activity. The protein binding here likely refers to self-association and partner interactions. Given CtBP1 forms homodimers, identical protein binding is already annotated. Protein binding is too vague. Proposed replacements: identical protein binding Supporting Evidence: PMID:31041561 2019 Apr 30. A pathogenic CtBP1 missense mutation causes altered cofactor binding and transcriptional activity.
GO:0005515 protein binding	IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari...	MARK AS OVER ANNOTATED	Summary: PMID:31515488 is a large-scale study of genetic variant effects on protein interactions. Protein binding is uninformative. Reason: High-throughput study; protein binding is too vague. Supporting Evidence: PMID:31515488 Extensive disruption of protein interactions by genetic variants across the allele frequency spectrum in human populations.
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	MARK AS OVER ANNOTATED	Summary: PMID:33961781 is a large-scale proteome network study. Protein binding is uninformative. Reason: High-throughput study; protein binding is too vague. Supporting Evidence: PMID:33961781 2021 May 6. Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
GO:0005515 protein binding	IPI PMID:35016035 Identification and functional characterization of transcript...	MARK AS OVER ANNOTATED	Summary: PMID:35016035 is a large-scale study identifying transcriptional activators. Protein binding from HTP is uninformative. Reason: High-throughput study; protein binding is too vague. Supporting Evidence: PMID:35016035 2022 Jan 10. Identification and functional characterization of transcriptional activators in human cells.
GO:0005515 protein binding	IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce...	MARK AS OVER ANNOTATED	Summary: PMID:35271311 is the OpenCell large-scale endogenous tagging study. Protein binding is uninformative. Reason: High-throughput study; protein binding is too vague. Supporting Evidence: PMID:35271311 2022 Mar 11. OpenCell: Endogenous tagging for the cartography of human cellular organization.
GO:0005515 protein binding	IPI PMID:36414381 ZBTB18 inhibits SREBP-dependent lipid synthesis by halting C...	MODIFY	Summary: PMID:36414381 shows ZBTB18 inhibits lipid synthesis by halting CTBPs and LSD1 activity in glioblastoma. ZBTB18 is a DNA-binding transcription factor. Protein binding is too vague. Proposed replacements: DNA-binding transcription factor binding Supporting Evidence: PMID:36414381 Print 2023 Jan. ZBTB18 inhibits SREBP-dependent lipid synthesis by halting CTBPs and LSD1 activity in glioblastoma.
GO:0005515 protein binding	IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func...	MARK AS OVER ANNOTATED	Summary: PMID:40205054 is a large-scale multimodal cell map study. Protein binding is uninformative. Reason: High-throughput study; protein binding is too vague. Supporting Evidence: PMID:40205054 Apr 9. Multimodal cell maps as a foundation for structural and functional genomics.
GO:0005515 protein binding	IPI PMID:7479821 Molecular cloning and characterization of a cellular phospho...	MODIFY	Summary: PMID:7479821 is the original cloning paper showing CTBP1 interacts with adenovirus E1A C-terminal domain. This is a specific viral protein interaction. Protein binding is too vague for this well-characterized interaction. Reason: E1A is a viral transcriptional regulator. The CTBP1-E1A interaction via PXDLS motif is the founding interaction for this protein. Proposed replacements: DNA-binding transcription factor binding Supporting Evidence: PMID:7479821 Molecular cloning and characterization of a cellular phosphoprotein that interacts with a conserved C-terminal domain of adenovirus E1A involved in negative modulation of oncogenic transformation.
GO:0005515 protein binding	IPI PMID:9535825 Interaction between a cellular protein that binds to the C-t...	MODIFY	Summary: PMID:9535825 describes the interaction between CTBP1 and a novel cellular protein (CtIP/RBBP8) disrupted by E1A through a PLDLS motif. This is a specific corepressor complex interaction. Reason: CtIP/RBBP8 participates in CtBP corepressor complexes. Proposed replacements: transcription coregulator binding Supporting Evidence: PMID:9535825 Interaction between a cellular protein that binds to the C-terminal region of adenovirus E1A (CtBP) and a novel cellular protein is disrupted by E1A through a conserved PLDLS motif.
GO:0042802 identical protein binding	IPI PMID:21988832 Toward an understanding of the protein interaction network o...	ACCEPT	Summary: CTBP1 forms homodimers, which is critical for its corepressor function. NAD/NADH binding promotes dimerization. Identical protein binding is well supported by crystal structures and biochemical data (PMID:12419229). Supporting Evidence: PMID:12419229 both a cofactor-dependent conformational change, with NAD(+) and NADH being equivalently effective, and the active site residues are linked to the binding of the PXDLS consensus recognition motif
GO:0042802 identical protein binding	IPI PMID:24722188 Protein interaction network of alternatively spliced isoform...	ACCEPT	Summary: CTBP1 homodimerization is well established. Duplicate evidence source is acceptable. Supporting Evidence: PMID:24722188 Protein interaction network of alternatively spliced isoforms from brain links genetic risk factors for autism.
GO:0042802 identical protein binding	IPI PMID:31041561 A pathogenic CtBP1 missense mutation causes altered cofactor...	ACCEPT	Summary: PMID:31041561 describes a pathogenic CTBP1 mutation affecting cofactor binding and transcriptional activity, which includes effects on self-association. Homodimerization is a core property. Supporting Evidence: PMID:31041561 2019 Apr 30. A pathogenic CtBP1 missense mutation causes altered cofactor binding and transcriptional activity.
GO:0042802 identical protein binding	IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari...	ACCEPT	Summary: Additional evidence for CTBP1 homodimerization from genetic variant disruption study. Homodimerization is well established. Supporting Evidence: PMID:31515488 Extensive disruption of protein interactions by genetic variants across the allele frequency spectrum in human populations.
GO:0003682 chromatin binding	IEA GO_REF:0000107	ACCEPT	Summary: CTBP1 associates with chromatin as part of its corepressor complexes containing HDAC1/2, LSD1, CoREST. While it does not bind DNA directly, it is recruited to chromatin by DNA-binding partners. IEA from Ensembl ortholog transfer is reasonable.
GO:0017053 transcription repressor complex	IEA GO_REF:0000107	ACCEPT	Summary: CTBP1 is a component of transcription repressor complexes. It assembles multi-protein corepressor complexes with HDAC1/2, LSD1/KDM1A, CoREST. IEA is consistent with IDA evidence from other annotations.
GO:0045892 negative regulation of DNA-templated transcription	IEA GO_REF:0000107	ACCEPT	Summary: CTBP1 negatively regulates transcription by assembling corepressor complexes. IEA is consistent with extensive experimental evidence including PMID:19162039, PMID:21102443, and PMID:16287852.
GO:0048488 synaptic vesicle endocytosis	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: CTBP1 has been reported to interact with presynaptic scaffold proteins (Bassoon) in neurons. Synaptic vesicle endocytosis is based on ortholog data. This is not the core function of CTBP1 but may reflect a specialized neuronal role. Reason: Neuronal-specific function transferred from mouse ortholog. Not a core function of CTBP1.
GO:0050872 white fat cell differentiation	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: CTBP1 interacts with PRDM16 to repress WAT-specific genes. UniProt notes it functions in BAT differentiation. This is a pleiotropic consequence of corepressor activity, not a core function. Reason: Differentiation role is a downstream consequence of corepressor function.
GO:0061629 RNA polymerase II-specific DNA-binding transcription factor binding	IEA GO_REF:0000107	ACCEPT	Summary: CTBP1 binds RNA Pol II-specific transcription factors like ZEB1/2, KLFs, BCL6 via PXDLS motifs. This is a more specific child of GO:0140297. IEA from Ensembl is appropriate.
GO:0097091 synaptic vesicle clustering	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: CTBP1 has reported synaptic roles through Bassoon interaction. This is a specialized neuronal function, not the core function of CTBP1. Reason: Neuronal-specific function. Not core to CTBP1.
GO:0098831 presynaptic active zone cytoplasmic component	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Based on ortholog evidence from mouse CTBP1 at presynaptic terminals via Bassoon interaction. Not a core localization for CTBP1. Reason: Neuronal-specific localization. Not core.
GO:0098978 glutamatergic synapse	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Synaptic localization is a specialized neuronal function of CTBP1, not its core localization. Reason: Neuronal-specific localization. Not core.
GO:0098982 GABA-ergic synapse	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Synaptic localization is a specialized neuronal function of CTBP1, not its core localization. Reason: Neuronal-specific localization. Not core.
GO:0106222 lncRNA binding	IEA GO_REF:0000107	UNDECIDED	Summary: lncRNA binding for CTBP1 is not well supported in the literature reviewed. This may come from ortholog evidence but lacks clear validation for human CTBP1. Reason: Insufficient evidence in the reviewed literature to confirm lncRNA binding as a function of CTBP1.
GO:0005654 nucleoplasm	IDA GO_REF:0000052	ACCEPT	Summary: Nucleoplasm localization is well supported by immunofluorescence data (HPA). CTBP1 is predominantly nuclear in its corepressor function.
GO:0016616 oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor	IDA PMID:12419229 Transcription corepressor CtBP is an NAD(+)-regulated dehydr...	ACCEPT	Summary: PMID:12419229 directly demonstrates CTBP1 dehydrogenase activity by biochemical and crystallographic methods. This is a core molecular function. Supporting Evidence: PMID:12419229 CtBP is a functional dehydrogenase. In addition, both a cofactor-dependent conformational change, with NAD(+) and NADH being equivalently effective, and the active site residues are linked to the binding of the PXDLS consensus recognition motif on repressors
GO:0051287 NAD binding	IDA PMID:12419229 Transcription corepressor CtBP is an NAD(+)-regulated dehydr...	ACCEPT	Summary: PMID:12419229 provides crystal structure (1.95A) of CTBP1 in complex with NAD, directly demonstrating NAD binding. This is a core molecular function. Supporting Evidence: PMID:12419229 CtBP is an NAD(+)-regulated component of critical complexes for specific repression events in cells.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-3108209	ACCEPT	Summary: Nucleoplasm localization from Reactome SUMOylation pathway. CTBP1 is SUMOylated at Lys-428 by CBX4 in the nucleus (PMID:12679040). Consistent with nuclear localization.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-3108203	ACCEPT	Summary: Same as above. Nucleoplasm is the site of CTBP1 SUMOylation events. Consistent with established nuclear localization.
GO:0140297 DNA-binding transcription factor binding	IPI PMID:16609867 The FoxP subclass in Xenopus laevis development.	ACCEPT	Summary: PMID:16609867 describes interaction of CTBP1 with FOXP1. UniProt confirms this interaction. FOXP1 is a DNA-binding transcription factor. Directly supports this annotation. Supporting Evidence: PMID:16609867 The FoxP subclass in Xenopus laevis development.
GO:0005515 protein binding	IPI PMID:23707407 PLEIAD/SIMC1/C5orf25, a novel autolysis regulator for a skel...	MODIFY	Summary: PMID:23707407 describes interaction between SIMC1 and CTBP1, where SIMC1 scaffolds CAPN3-mediated cleavage of CTBP1. This is a specific protein interaction but protein binding is too vague. Reason: SIMC1 interacts with CTBP1 through specific domains. UniProt confirms the interaction and identifies specific mutagenesis sites that disrupt it. Proposed replacements: protein domain specific binding Supporting Evidence: PMID:23707407 2013 May 21. PLEIAD/SIMC1/C5orf25, a novel autolysis regulator for a skeletal-muscle-specific calpain, CAPN3, scaffolds a CAPN3 substrate, CTBP1.
GO:0001222 transcription corepressor binding	IPI PMID:29628311 A Family of Vertebrate-Specific Polycombs Encoded by the LCO...	ACCEPT	Summary: PMID:29628311 describes LCOR/LCORL family as vertebrate-specific Polycombs that interact with CTBP1. LCOR functions as a corepressor. This annotation correctly captures CTBP1 binding to a transcription corepressor. Supporting Evidence: PMID:29628311 A Family of Vertebrate-Specific Polycombs Encoded by the LCOR/LCORL Genes Balance PRC2 Subtype Activities.
GO:0005515 protein binding	IPI PMID:25728771 MCRIP1, an ERK substrate, mediates ERK-induced gene silencin...	MODIFY	Summary: PMID:25728771 describes MCRIP1 as an ERK substrate that competitively inhibits CtBP-ZEB1 interaction via its PXDLS motif. This is a specific coregulator interaction. Protein binding is too vague. Reason: MCRIP1 regulates CTBP1 corepressor function through competitive binding. Proposed replacements: transcription coregulator binding Supporting Evidence: PMID:25728771 Feb 26. MCRIP1, an ERK substrate, mediates ERK-induced gene silencing during epithelial-mesenchymal transition by regulating the co-repressor CtBP.
GO:0005634 nucleus	IDA PMID:16702210 Zinc finger protein Wiz links G9a/GLP histone methyltransfer...	ACCEPT	Summary: PMID:16702210 shows CTBP1 in the nucleus via its interaction with WIZ, which links G9a/GLP histone methyltransferases to CTBP1. Nuclear localization is well established. Supporting Evidence: PMID:16702210 Zinc finger protein Wiz links G9a/GLP histone methyltransferases to the co-repressor molecule CtBP.
GO:0005515 protein binding	IPI PMID:16702210 Zinc finger protein Wiz links G9a/GLP histone methyltransfer...	MODIFY	Summary: PMID:16702210 demonstrates WIZ links G9a/GLP histone methyltransferases to CtBP. WIZ is a zinc finger protein functioning as a transcriptional coregulator. Protein binding is too vague. Proposed replacements: transcription coregulator binding Supporting Evidence: PMID:16702210 2006 May 15. Zinc finger protein Wiz links G9a/GLP histone methyltransferases to the co-repressor molecule CtBP.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-3361751	ACCEPT	Summary: Nucleoplasm localization from Reactome pathway Reactome:R-HSA-3361751. CTBP1 functions in the nucleoplasm as a transcriptional corepressor in Wnt signaling and other pathways.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-3364042	ACCEPT	Summary: Nucleoplasm localization from Reactome pathway Reactome:R-HSA-3364042. CTBP1 functions in the nucleoplasm as a transcriptional corepressor in Wnt signaling and other pathways.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-5334050	ACCEPT	Summary: Nucleoplasm localization from Reactome pathway Reactome:R-HSA-5334050. CTBP1 functions in the nucleoplasm as a transcriptional corepressor in Wnt signaling and other pathways.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-5334052	ACCEPT	Summary: Nucleoplasm localization from Reactome pathway Reactome:R-HSA-5334052. CTBP1 functions in the nucleoplasm as a transcriptional corepressor in Wnt signaling and other pathways.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-9765973	ACCEPT	Summary: Nucleoplasm localization from Reactome pathway Reactome:R-HSA-9765973. CTBP1 functions in the nucleoplasm as a transcriptional corepressor in Wnt signaling and other pathways.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-9765974	ACCEPT	Summary: Nucleoplasm localization from Reactome pathway Reactome:R-HSA-9765974. CTBP1 functions in the nucleoplasm as a transcriptional corepressor in Wnt signaling and other pathways.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-9768477	ACCEPT	Summary: Nucleoplasm localization from Reactome pathway Reactome:R-HSA-9768477. CTBP1 functions in the nucleoplasm as a transcriptional corepressor in Wnt signaling and other pathways.
GO:0003714 transcription corepressor activity	IDA PMID:19162039 Hepatoma-derived growth factor represses SET and MYND domain...	ACCEPT	Summary: PMID:19162039 directly demonstrates CTBP1 corepressor activity. HDGF represses SMYD1 gene transcription through interaction with CtBP. Over-expression of CtBP potentiated the trans-repressive activity of HDGF; knocking down CtBP attenuated the effect. Supporting Evidence: PMID:19162039 Over-expression of CtBP potentiated the trans-repressive activity of HDGF; on the other hand, knocking down CtBP attenuated the trans-repressive effect of HDGF.
GO:0140297 DNA-binding transcription factor binding	IPI PMID:19162039 Hepatoma-derived growth factor represses SET and MYND domain...	ACCEPT	Summary: PMID:19162039 demonstrates CTBP1 binding to HDGF via a non-canonical PXDLS motif (PKDLF). HDGF acts as a transcriptional repressor. Directly supports this annotation. Supporting Evidence: PMID:19162039 HDGF binds CtBP through a non-canonical binding motif (PKDLF) within the PWWP domain, as mutation of DL to AS abolished HDGF and CtBP interaction
GO:0000122 negative regulation of transcription by RNA polymerase II	IMP PMID:19162039 Hepatoma-derived growth factor represses SET and MYND domain...	ACCEPT	Summary: PMID:19162039 demonstrates CTBP1 participates in negative regulation of SMYD1 transcription. HDGF-CtBP complex represses SMYD1 promoter activity. IMP evidence is appropriate. Supporting Evidence: PMID:19162039 in G-7 myoblast cells, over-expression of a GFP-HDGF fusion specifically downregulated SMYD1 mRNA expression and the activity of the human SMYD1 promoter
GO:0017053 transcription repressor complex	IDA PMID:19162039 Hepatoma-derived growth factor represses SET and MYND domain...	ACCEPT	Summary: PMID:19162039 demonstrates CTBP1 forms a transcriptional complex with HDGF for gene repression. CTBP1 is a well-established component of transcription repressor complexes. Supporting Evidence: PMID:19162039 fluorescent microscopy showed that HDGF induced the nuclear accumulation of CtBP, suggesting that HDGF forms a transcriptional complex with CtBP
GO:0019904 protein domain specific binding	IDA PMID:19162039 Hepatoma-derived growth factor represses SET and MYND domain...	ACCEPT	Summary: PMID:19162039 demonstrates CTBP1 binds specifically to the PKDLF motif within the PWWP domain of HDGF. Mutation of this motif abolishes the interaction. This is protein domain specific binding. Supporting Evidence: PMID:19162039 HDGF binds CtBP through a non-canonical binding motif (PKDLF) within the PWWP domain, as mutation of DL to AS abolished HDGF and CtBP interaction
GO:0003714 transcription corepressor activity	IDA PMID:16287852 RBP-Jkappa/SHARP recruits CtIP/CtBP corepressors to silence ...	ACCEPT	Summary: PMID:16287852 demonstrates CtBP corepressor activity in the context of Notch signaling. CtBP augments SHARP-mediated repression and is required for repression of Notch target gene Hey1. Supporting Evidence: PMID:16287852 Transcriptional repression of the Notch target gene Hey1 is abolished in CtBP-deficient cells or after the functional knockout of CtBP.
GO:0005515 protein binding	IPI PMID:16287852 RBP-Jkappa/SHARP recruits CtIP/CtBP corepressors to silence ...	MODIFY	Summary: PMID:16287852 shows CTBP1 interaction with CtIP and SHARP within the RBP-Jkappa/SHARP corepressor complex. Protein binding is too vague for this specific corepressor complex interaction. Reason: CtIP and SHARP are corepressor complex components that interact with CTBP1. Proposed replacements: transcription coregulator binding Supporting Evidence: PMID:16287852 RBP-Jkappa/SHARP recruits CtIP/CtBP corepressors to silence Notch target genes.
GO:0017053 transcription repressor complex	IDA PMID:16287852 RBP-Jkappa/SHARP recruits CtIP/CtBP corepressors to silence ...	ACCEPT	Summary: PMID:16287852 directly demonstrates CTBP1 as a component of the RBP-Jkappa/SHARP-CtIP-CtBP corepressor complex that silences Notch target genes. Supporting Evidence: PMID:16287852 We identify the CtIP and CtBP corepressors as novel components of the human RBP-Jkappa/SHARP-corepressor complex
GO:0000122 negative regulation of transcription by RNA polymerase II	IMP PMID:21102443 Transcriptional regulation of BRCA1 expression by a metaboli...	ACCEPT	Summary: PMID:21102443 directly demonstrates CTBP1 negatively regulates BRCA1 transcription. CtBP assembles at the BRCA1 promoter as part of a corepressor complex containing HDAC1. CtBP depletion increases BRCA1 expression. Supporting Evidence: PMID:21102443 Silencing of CtBP expression in MCF-7 cells results in a significant increase in both BRCA1 protein and BRCA1 RNA message (nascent and mature).
GO:0051726 regulation of cell cycle	IMP PMID:21102443 Transcriptional regulation of BRCA1 expression by a metaboli...	KEEP AS NON CORE	Summary: PMID:21102443 shows CtBP depletion induces a cell cycle block in G2 phase, mimicking BRCA1 over-expression effects. This is a downstream consequence of CTBP1 corepressor activity on cell cycle regulators, not a direct cell cycle function. Reason: Cell cycle regulation is an indirect consequence of CTBP1 transcriptional corepression of BRCA1 and other targets. Supporting Evidence: PMID:21102443 CtBP depletion also mimics the functional influences of BRCA1 over-expression 12 by inducing a cell cycle block in G2 phase (Fig
GO:0005515 protein binding	IPI PMID:19505873 Complementary quantitative proteomics reveals that transcrip...	MODIFY	Summary: PMID:19505873 identifies CTBP1 in an AP-4 mediated transcriptional repression complex for HDM2. AP-4/TFAP4 is a DNA-binding transcription factor. Protein binding is too vague. Proposed replacements: DNA-binding transcription factor binding Supporting Evidence: PMID:19505873 Epub 2009 Jun 7. Complementary quantitative proteomics reveals that transcription factor AP-4 mediates E-box-dependent complex formation for transcriptional repression of HDM2.
GO:0005515 protein binding	IPI PMID:11568182 Interaction of EVI1 with cAMP-responsive element-binding pro...	MODIFY	Summary: PMID:11568182 describes CTBP1 interaction with MECOM/EVI1. MECOM is a DNA-binding transcription factor. Protein binding is too vague. Proposed replacements: DNA-binding transcription factor binding Supporting Evidence: PMID:11568182 2001 Sep 21. Interaction of EVI1 with cAMP-responsive element-binding protein-binding protein (CBP) and p300/CBP-associated factor (P/CAF) results in reversible acetylation of EVI1 and in co-localization in nuclear speckles.
GO:0005515 protein binding	IPI PMID:15897867 Oligomerization of Evi-1 regulated by the PR domain contribu...	MODIFY	Summary: PMID:15897867 shows oligomerization of Evi-1/MECOM regulated by the PR domain contributes to recruitment of corepressor CtBP. MECOM is a DNA-binding transcription factor. Protein binding is too vague. Proposed replacements: DNA-binding transcription factor binding Supporting Evidence: PMID:15897867 Oligomerization of Evi-1 regulated by the PR domain contributes to recruitment of corepressor CtBP.
GO:0051287 NAD binding	ISS GO_REF:0000024	ACCEPT	Summary: NAD binding is well established for CTBP1 by crystal structure and biochemistry (PMID:12419229). ISS annotation is consistent with IDA evidence.
GO:0019904 protein domain specific binding	IPI PMID:18374649 TBL1 and TBLR1 phosphorylation on regulated gene promoters o...	ACCEPT	Summary: PMID:18374649 describes TBL1/TBLR1 phosphorylation overcoming dual CtBP and NCoR/SMRT repression checkpoints. CTBP1 recognizes PXDLS domains specifically, supporting protein domain specific binding. Supporting Evidence: PMID:18374649 TBL1 and TBLR1 phosphorylation on regulated gene promoters overcomes dual CtBP and NCoR/SMRT transcriptional repression checkpoints.
GO:0005634 nucleus	ISS GO_REF:0000024	ACCEPT	Summary: Nuclear localization is well established for CTBP1. ISS is consistent with IDA and IBA evidence.
GO:0017053 transcription repressor complex	ISS GO_REF:0000024	ACCEPT	Summary: CTBP1 is a well-established component of transcription repressor complexes. ISS is consistent with IDA evidence from multiple publications.
GO:0045892 negative regulation of DNA-templated transcription	ISS GO_REF:0000024	ACCEPT	Summary: CTBP1 negatively regulates DNA-templated transcription. ISS is consistent with extensive experimental evidence.
GO:0050872 white fat cell differentiation	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: CTBP1 interacts with PRDM16 to repress WAT-specific genes. UniProt confirms function in BAT differentiation. This is a pleiotropic consequence of corepressor activity. Reason: WAT differentiation is a downstream consequence of CTBP1 corepressor function, not a core function.
GO:0019079 viral genome replication	TAS PMID:7479821 Molecular cloning and characterization of a cellular phospho...	MARK AS OVER ANNOTATED	Summary: PMID:7479821 describes CTBP1 interaction with adenovirus E1A and suggests a role in adenovirus replication. However, CTBP1 is not directly involved in viral genome replication; rather, the E1A-CtBP interaction modulates transformation and indirectly affects replication. The annotation over-attributes a direct viral replication function. Reason: CTBP1 does not directly participate in viral genome replication. The E1A interaction modulates cellular transcription. PMID:23747199 suggests the interaction potentiates viral replication but CTBP1 is a host transcriptional corepressor, not a replication factor. Supporting Evidence: PMID:7479821 These results suggest that interaction of CtBP with the E1A proteins may play a critical role in adenovirus replication and oncogenic transformation.
GO:0005515 protein binding	TAS PMID:8440238 A region in the C-terminus of adenovirus 2/5 E1a protein is ...	MODIFY	Summary: PMID:8440238 describes the interaction between CTBP1 and adenovirus E1A C-terminal domain. E1A is a viral transcriptional regulator. Protein binding is too vague. Proposed replacements: DNA-binding transcription factor binding Supporting Evidence: PMID:8440238 A region in the C-terminus of adenovirus 2/5 E1a protein is required for association with a cellular phosphoprotein and important for the negative modulation of T24-ras mediated transformation, tumorigenesis and metastasis.
GO:0006468 protein phosphorylation	TAS PMID:8440238 A region in the C-terminus of adenovirus 2/5 E1a protein is ...	REMOVE	Summary: MISANNOTATION: CTBP1 is a transcriptional corepressor, NOT a kinase. PMID:8440238 explicitly describes CTBP1 as being phosphorylated: "CtBP is a phosphoprotein and the level of phosphorylation of CtBP appears to be regulated during the cell cycle". UniProt shows CTBP1 is "phosphorylated by HIPK2" at Ser-422. CTBP1 is a SUBSTRATE of kinases, not an enzyme that performs phosphorylation. Supporting Evidence: PMID:8440238 A region in the C-terminus of adenovirus 2/5 E1a protein is required for association with a cellular phosphoprotein and important for the negative modulation of T24-ras mediated transformation, tumorigenesis and metastasis.
GO:0008285 negative regulation of cell population proliferation	TAS PMID:7479821 Molecular cloning and characterization of a cellular phospho...	MARK AS OVER ANNOTATED	Summary: PMID:7479821 describes CTBP1 in the context of E1A-mediated modulation of oncogenic transformation. The paper does not directly demonstrate CTBP1 negatively regulates cell proliferation; rather, the E1A-CtBP interaction modulates transformation. This over-attributes a direct antiproliferative function to CTBP1. Reason: The negative regulation of proliferation is attributed to the E1A-CtBP interaction in the context of transformation, not to CTBP1 alone. Supporting Evidence: PMID:7479821 a region located between residues 225 and 238 of the 243R E1A protein negatively modulates in vitro T24 ras cooperative transformation as well as the tumorigenic potential of E1A/T24 ras-transformed cells
GO:0005515 protein binding	IPI PMID:12052894 The human candidate tumor suppressor gene HIC1 recruits CtBP...	MODIFY	Summary: PMID:12052894 demonstrates CTBP1 interaction with HIC1 through a degenerate GLDLSKK motif. HIC1 is a DNA-binding transcription factor/tumor suppressor. Protein binding is too vague. Proposed replacements: DNA-binding transcription factor binding Supporting Evidence: PMID:12052894 The human candidate tumor suppressor gene HIC1 recruits CtBP through a degenerate GLDLSKK motif.

Core Functions

CTBP1 functions primarily as a transcriptional corepressor, recruited to target genes by DNA-binding transcription factors via PXDLS motifs. It scaffolds chromatin-modifying complexes containing HDAC1/2, LSD1/KDM1A, and RCOR1/CoREST.

Molecular Function:

transcription corepressor activity

CTBP1 binds diverse DNA-binding transcription factors (ZEB1/2, KLFs, BCL6, MECOM, HIC1, FOXP1, ZNF366, ZNF516) through recognition of PXDLS/PLDLS short linear motifs.

Molecular Function:

DNA-binding transcription factor binding

CTBP1 binds NAD+/NADH via its Rossmann fold domain. NADH binding allosterically promotes dimerization and corepressor complex assembly, making CTBP1 a metabolic/redox sensor.

Molecular Function:

NAD binding

CTBP1 is a functional D-2-hydroxyacid dehydrogenase, though the primary biological role centers on its corepressor/scaffolding function rather than catalytic activity.

Molecular Function:

oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000024

Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000043

Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

GO_REF:0000052

Gene Ontology annotation based on curation of immunofluorescence data

GO_REF:0000107

Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara

GO_REF:0000108

Automatic assignment of GO terms using logical inference, based on on inter-ontology links

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:10359772

ZEB represses transcription through interaction with the corepressor CtBP.

PMID:10995736

The interaction of the carboxyl terminus-binding protein with the Smad corepressor TGIF is disrupted by a holoprosencephaly mutation in TGIF.

PMID:11462050

Physical and functional interactions between the corepressor CtBP and the Epstein-Barr virus nuclear antigen EBNA3C.

PMID:11568182

Interaction of EVI1 with cAMP-responsive element-binding protein-binding protein (CBP) and p300/CBP-associated factor (P/CAF) results in reversible acetylation of EVI1 and in co-localization in nuclear speckles.

PMID:12052894

The human candidate tumor suppressor gene HIC1 recruits CtBP through a degenerate GLDLSKK motif.

PMID:12419229

Transcription corepressor CtBP is an NAD(+)-regulated dehydrogenase.

PMID:15897867

Oligomerization of Evi-1 regulated by the PR domain contributes to recruitment of corepressor CtBP.

PMID:16287852

RBP-Jkappa/SHARP recruits CtIP/CtBP corepressors to silence Notch target genes.

PMID:16609867

The FoxP subclass in Xenopus laevis development.

PMID:16702210

Zinc finger protein Wiz links G9a/GLP histone methyltransferases to the co-repressor molecule CtBP.

PMID:16762039

A L225A substitution in the human tumour suppressor HIC1 abolishes its interaction with the corepressor CtBP.

PMID:17085477

ZNF366 is an estrogen receptor corepressor that acts through CtBP and histone deacetylases.

PMID:18374649

TBL1 and TBLR1 phosphorylation on regulated gene promoters overcomes dual CtBP and NCoR/SMRT transcriptional repression checkpoints.

PMID:19162039

Hepatoma-derived growth factor represses SET and MYND domain containing 1 gene expression through interaction with C-terminal binding protein.

PMID:19486893

HIC1 interacts with a specific subunit of SWI/SNF complexes, ARID1A/BAF250A.

PMID:19505873

Complementary quantitative proteomics reveals that transcription factor AP-4 mediates E-box-dependent complex formation for transcriptional repression of HDM2.

PMID:19751731

C-terminal binding proteins (CtBPs) attenuate KLF4-mediated transcriptional activation.

PMID:20098713

A role for non-covalent SUMO interaction motifs in Pc2/CBX4 E3 activity.

PMID:20211142

An atlas of combinatorial transcriptional regulation in mouse and man.

PMID:21044950

Genome-wide YFP fluorescence complementation screen identifies new regulators for telomere signaling in human cells.

PMID:21102443

Transcriptional regulation of BRCA1 expression by a metabolic switch.

PMID:21900206

A directed protein interaction network for investigating intracellular signal transduction.

PMID:21903422

Mapping a dynamic innate immunity protein interaction network regulating type I interferon production.

PMID:21988832

Toward an understanding of the protein interaction network of the human liver.

PMID:23707407

PLEIAD/SIMC1/C5orf25, a novel autolysis regulator for a skeletal-muscle-specific calpain, CAPN3, scaffolds a CAPN3 substrate, CTBP1.

PMID:24722188

Protein interaction network of alternatively spliced isoforms from brain links genetic risk factors for autism.

PMID:24981860

Human-chromatin-related protein interactions identify a demethylase complex required for chromosome segregation.

PMID:25728771

MCRIP1, an ERK substrate, mediates ERK-induced gene silencing during epithelial-mesenchymal transition by regulating the co-repressor CtBP.

PMID:26496610

A human interactome in three quantitative dimensions organized by stoichiometries and abundances.

PMID:26807646

EXD2 promotes homologous recombination by facilitating DNA end resection.

PMID:27705803

A High-Density Map for Navigating the Human Polycomb Complexome.

PMID:28514442

Architecture of the human interactome defines protein communities and disease networks.

PMID:28947780

ZNF516 suppresses EGFR by targeting the CtBP/LSD1/CoREST complex to chromatin.

PMID:29628311

A Family of Vertebrate-Specific Polycombs Encoded by the LCOR/LCORL Genes Balance PRC2 Subtype Activities.

PMID:31041561

A pathogenic CtBP1 missense mutation causes altered cofactor binding and transcriptional activity.

PMID:31515488

Extensive disruption of protein interactions by genetic variants across the allele frequency spectrum in human populations.

PMID:33961781

Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.

PMID:35016035

Identification and functional characterization of transcriptional activators in human cells.

PMID:35271311

OpenCell: Endogenous tagging for the cartography of human cellular organization.

PMID:36414381

ZBTB18 inhibits SREBP-dependent lipid synthesis by halting CTBPs and LSD1 activity in glioblastoma.

PMID:40205054

Multimodal cell maps as a foundation for structural and functional genomics.

PMID:7479821

Molecular cloning and characterization of a cellular phosphoprotein that interacts with a conserved C-terminal domain of adenovirus E1A involved in negative modulation of oncogenic transformation.

PMID:8440238

A region in the C-terminus of adenovirus 2/5 E1a protein is required for association with a cellular phosphoprotein and important for the negative modulation of T24-ras mediated transformation, tumorigenesis and metastasis.

PMID:9535825

Interaction between a cellular protein that binds to the C-terminal region of adenovirus E1A (CtBP) and a novel cellular protein is disrupted by E1A through a conserved PLDLS motif.

Reactome:R-HSA-3108203

PRC1 SUMOylates CTBP1 with SUMO2,3

Reactome:R-HSA-3108209

PRC1 SUMOylates CTBP1 with SUMO1

Reactome:R-HSA-3361751

beta-catenin is replaced by repression complexes at the promoter

Reactome:R-HSA-3364042

APC promotes disassembly of beta-catenin transactivation complex

Reactome:R-HSA-5334050

TCF7L2/TCF7L1 bind CTBP1 to repress WNT target genes

Reactome:R-HSA-5334052

TFC7L2 mutants don't bind CTBP

Reactome:R-HSA-9765973

CTBP1,CTBP2 binds ZEB1

Reactome:R-HSA-9765974

MCRIP1 binds CTBP1

Reactome:R-HSA-9768477

CTBP1,CTBP2 binds CDH1 gene promoter

📚 Additional Documentation

Deep Research Falcon

(CTBP1-deep-research-falcon.md)

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gene_info: Name=CTBP1; Synonyms=CTBP;
organism_full: Homo sapiens (Human).
protein_family: Belongs to the D-isomer specific 2-hydroxyacid
protein_domains: CtBP. (IPR043322); CTBP_dehydrogenase. (IPR051638); D-isomer_2_OHA_DH_cat_dom.
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Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: Q13363
Protein Description: RecName: Full=C-terminal-binding protein 1; Short=CtBP1; EC=1.1.1.-;
Gene Information: Name=CTBP1; Synonyms=CTBP;
Organism (full): Homo sapiens (Human).
Protein Family: Belongs to the D-isomer specific 2-hydroxyacid
Key Domains: CtBP. (IPR043322); CTBP_dehydrogenase. (IPR051638); D-isomer_2_OHA_DH_cat_dom. (IPR006139); D-isomer_DH_CS. (IPR029753); D-isomer_DH_CS1. (IPR029752)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "CTBP1" matches the protein description above
Verify the organism is correct: Homo sapiens (Human).
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE. Instead:
- State clearly: "The gene symbol 'CTBP1' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information

Research Target:

Please provide a comprehensive research report on the gene CTBP1 (gene ID: CTBP1, UniProt: Q13363) in human.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Output

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on:
1. Key concepts and definitions with current understanding
2. Recent developments and latest research (prioritize 2023-2024 sources)
3. Current applications and real-world implementations
4. Expert opinions and analysis from authoritative sources
5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available.
Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: Q13363
Protein Description: RecName: Full=C-terminal-binding protein 1; Short=CtBP1; EC=1.1.1.-;
Gene Information: Name=CTBP1; Synonyms=CTBP;
Organism (full): Homo sapiens (Human).
Protein Family: Belongs to the D-isomer specific 2-hydroxyacid
Key Domains: CtBP. (IPR043322); CTBP_dehydrogenase. (IPR051638); D-isomer_2_OHA_DH_cat_dom. (IPR006139); D-isomer_DH_CS. (IPR029753); D-isomer_DH_CS1. (IPR029752)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "CTBP1" matches the protein description above
Verify the organism is correct: Homo sapiens (Human).
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Please provide a comprehensive research report on the gene CTBP1 (gene ID: CTBP1, UniProt: Q13363) in human.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Comprehensive Research Report: Human CTBP1 (UniProt Q13363) – Functional Annotation

0. Target verification (mandatory)

The research target is human C-terminal-binding protein 1 (CtBP1) encoded by CTBP1 (UniProt Q13363). The retrieved literature consistently describes CtBP1 as a D-isomer–specific 2‑hydroxyacid dehydrogenase (D2‑HDH)-like protein that contains an NAD(H)-binding Rossmann fold and a protein–protein interaction cleft that recognizes PXDLS/PLDLS short motifs in transcriptional regulators, matching the UniProt description and domain architecture provided (CtBP/CTBP_dehydrogenase/D‑isomer‑2‑hydroxyacid dehydrogenase family features). (huang2024cterminalbindingprotein pages 2-4, chen2021thetransrepressionand pages 1-2)

Category	Key details	Representative evidence (with citation IDs)	Publication info (first author year journal and URL/DOI)
Identity/domains	Human CtBP1 (UniProt Q13363); D-2-hydroxyacid dehydrogenase-like protein with NAD(H)-binding Rossmann fold; recognizes PXDLS short linear motifs on partner proteins	(huang2024cterminalbindingprotein pages 2-4, chen2021thetransrepressionand pages 1-2)	Huang 2024 Viruses https://doi.org/10.3390/v16060988; Chen 2021 J Mol Med https://doi.org/10.1007/s00109-021-02107-w
Corepressor mechanism	DNA-binding partners recruit CtBP1 via PXDLS; assembles chromatin-modifying complexes (HDAC1/2, LSD1/KDM1A, RCOR1/CoREST); antagonizes p300/CBP to repress transcription	(chen2021thetransrepressionand pages 1-2, chen2021thetransrepressionand pages 5-7, lee2025usingtheallen pages 6-8)	Chen 2021 J Mol Med https://doi.org/10.1007/s00109-021-02107-w; Lee 2025 Biologics https://doi.org/10.3390/biologics5020014
Ligand/enzyme activity	NADH allosterically regulates binding and oligomerization; MTOB (4-methylthio-2-oxobutyric acid) binds active site; CtBP family is D-2-hydroxyacid dehydrogenase-like	(chen2021thetransrepressionand pages 1-2, lee2025usingtheallen pages 9-11)	Nichols 2021 J Biol Chem https://doi.org/10.1016/j.jbc.2021.100351; Chen 2021 J Mol Med https://doi.org/10.1007/s00109-021-02107-w
Oligomerization/regulation	NADH promotes dimer/tetramer assembly; RAI2 tandem SLiMs induce CtBP polymerization/filaments and functional inactivation; ISGylation of CtBP1 increases affinity for LSD1/HDAC1 and enhances repression	(lee2025usingtheallen pages 9-11, goradia2024mastercorepressorinactivation pages 4-8, goradia2024mastercorepressorinactivation pages 1-4, goradia2024mastercorepressorinactivation pages 8-11, lim2024transcriptionalcorepressoractivity pages 3-7)	Nichols 2021 J Biol Chem https://doi.org/10.1016/j.jbc.2021.100351; Goradia 2024 Nat Commun https://doi.org/10.1101/2023.06.16.545227; Lim 2024 Anim Cells Syst https://doi.org/10.1080/19768354.2024.2321354
Key partners/complexes	Recruited by ZEB1/2, KLFs; forms complexes with CtIP/RBBP8, HDAC1/2, LSD1/KDM1A, RCOR1/CoREST; partners include E1A, MECOM	(lee2025usingtheallen pages 6-8, chen2021thetransrepressionand pages 1-2, chen2021thetransrepressionand pages 5-7)	Lee 2025 Biologics https://doi.org/10.3390/biologics5020014; Chen 2021 J Mol Med https://doi.org/10.1007/s00109-021-02107-w
Localization	Predominantly nuclear as corepressor; cytoplasmic/presynaptic roles described in neurons; shuttles between nucleus and cytoplasm depending on context	(lee2025usingtheallen pages 1-2)	Lee 2025 Biologics https://doi.org/10.3390/biologics5020014
Pathways/biological roles	Transcriptional repression of tumor suppressors; metabolism sensing via NADH; EMT and developmental programs; regulation of DNA damage response genes via corepressor assemblies	(huang2024cterminalbindingprotein pages 2-4, chen2021thetransrepressionand pages 5-7, lee2025usingtheallen pages 1-2)	Huang 2024 Viruses https://doi.org/10.3390/v16060988; Chen 2021 J Mol Med https://doi.org/10.1007/s00109-021-02107-w; Lee 2025 Biologics https://doi.org/10.3390/biologics5020014
Recent 2024 mechanistic updates	RAI2 contains tandem ALDLS SLiMs that drive CtBP polymerization into filaments; polymerization creates nuclear foci and relieves CtBP repression (e.g., CDKN1A upregulation); clinical link: RAI2 expression decreases with prostate cancer progression	(goradia2024mastercorepressorinactivation pages 4-8, goradia2024mastercorepressorinactivation pages 1-4, goradia2024mastercorepressorinactivation pages 8-11)	Goradia 2024 Nat Commun https://doi.org/10.1101/2023.06.16.545227
Translational inhibitors/therapeutics	Comp.11 selectively targets CtBP1/BARS Rossmann fold (Kd ~0.66 µM), alters oligomerization and partner binding; in vivo melanoma growth reduction; classical substrate-competitive inhibitors (MTOB, HIPP) reported with lower potency	(filograna2024identificationandcharacterization pages 22-25, filograna2024identificationandcharacterization pages 9-11, filograna2024identificationandcharacterization pages 25-27, filograna2024identificationandcharacterization pages 27-28, filograna2024identificationandcharacterization pages 2-4, filograna2024identificationandcharacterization pages 11-14, filograna2024identificationandcharacterization pages 8-9, huang2024cterminalbindingprotein pages 2-4, chen2021thetransrepressionand pages 5-7)	Filograna 2024 J Exp Clin Cancer Res https://doi.org/10.1186/s13046-024-03044-5; Huang 2024 Viruses https://doi.org/10.3390/v16060988; Chen 2021 J Mol Med https://doi.org/10.1007/s00109-021-02107-w
Quantitative stats/data points	Comp.11 binding: Kd 0.66 ± 0.20 µM (ITC); melanoma xenograft: −39.39% tumor change at day 14 (20 mg/kg) with significant inhibition; RAI2 CTC positivity declines with progression: 89% CRPC → 35% AVPC → 19% NEPC; ISGylation increases CtBP1 binding to LSD1/HDAC1	(filograna2024identificationandcharacterization pages 9-11, filograna2024identificationandcharacterization pages 25-27, filograna2024identificationandcharacterization media a3db0a0a, filograna2024identificationandcharacterization media 4353de2d, filograna2024identificationandcharacterization media 440b0878, goradia2024mastercorepressorinactivation pages 11-14, lim2024transcriptionalcorepressoractivity pages 3-7, lim2024transcriptionalcorepressoractivity pages 7-8)	Filograna 2024 J Exp Clin Cancer Res https://doi.org/10.1186/s13046-024-03044-5; Goradia 2024 Nat Commun https://doi.org/10.1101/2023.06.16.545227; Lim 2024 Anim Cells Syst https://doi.org/10.1080/19768354.2024.2321354

Table: Concise, evidence-mapped summary of CTBP1 (Q13363) covering mechanisms, partners, regulation, 2024 updates, and translational inhibitors with quantitative data. Citations point to primary and review sources supporting each entry.

1. Key concepts and definitions (current understanding)

1.1 What CtBP1 is

CtBP1 is best understood as a transcriptional coregulator (primarily a corepressor) that lacks intrinsic DNA-binding capacity and instead is recruited to chromatin by DNA-binding transcription factors and repressors that present PXDLS/PLDLS-like short linear motifs (SLiMs). (huang2024cterminalbindingprotein pages 2-4, chen2021thetransrepressionand pages 1-2)

1.2 How CtBP1 represses transcription

Mechanistically, CtBP1 functions as a scaffold that nucleates multi-protein corepressor assemblies. It binds PXDLS-bearing DNA-binding proteins and recruits chromatin-modifying enzymes including histone deacetylases (HDACs) and other epigenetic regulators (e.g., LSD1/KDM1A, RCOR1/CoREST, and methylation-related machinery), resulting in histone modification changes that favor transcriptional repression. (huang2024cterminalbindingprotein pages 2-4, chen2021thetransrepressionand pages 1-2, lee2025usingtheallen pages 6-8)

1.3 A “metabolic sensor” corepressor

A defining conceptual feature is that CtBP1 corepressor function is coupled to cellular redox/metabolic status through binding of NADH (and NAD+/related nucleotides) at its Rossmann fold. NADH binding promotes CtBP1 multimerization states (dimer/tetramer assemblies) that are linked to corepressor activity. This forms a molecular basis for CtBP1’s frequent description as a metabolic/redox sensor in transcriptional control. (chen2021thetransrepressionand pages 1-2, lee2025usingtheallen pages 1-2)

1.4 Enzyme-like domain: what is (and isn’t) established

CtBP1 is homologous to D2‑hydroxyacid dehydrogenases and contains a substrate-binding domain (SBD) plus a Rossmann fold. Small molecules such as MTOB (4‑methylthio‑2‑oxobutyric acid) bind in the active-site region; however, much of CtBP1 biology depends on its corepressor/scaffolding function rather than a well-defined, physiology-dominant metabolic catalytic reaction in vivo. (chen2021thetransrepressionand pages 1-2, chen2021thetransrepressionand pages 5-7)

2. Molecular functions, partners, pathways, and localization (evidence-based)

2.1 Interaction logic: PXDLS recruitment plus non-PXDLS partner binding

CtBP1 recognizes PXDLS-like motifs and can also associate with other partners through additional interfaces, enabling assembly of large transcriptional complexes. A 2024 review highlights both PXDLS recognition and interactions with non-PXDLS partners, including chromatin and DNA-damage-related factors. (huang2024cterminalbindingprotein pages 2-4)

2.2 Representative complex components and interactors

Evidence across the included sources supports CtBP1 association with:
- HDAC1/HDAC2 and LSD1/KDM1A with RCOR1/CoREST as a repressive chromatin module (lee2025usingtheallen pages 6-8)
- CtIP/RBBP8 as a component in CtBP-containing repression complexes relevant to DNA repair gene control in at least some settings (lee2025usingtheallen pages 6-8)
- DNA-binding transcriptional regulators such as ZEB1/2 and KLF family proteins that recruit CtBP via motif interactions (chen2021thetransrepressionand pages 1-2, lee2025usingtheallen pages 6-8)

2.3 Subcellular localization: nucleus ↔ cytoplasm/Golgi and specialized roles

CtBP1 is functionally nuclear as a corepressor, but also has well-described non-nuclear roles. CtBP1/BARS is described as having both transcriptional corepressor activity and a membrane fission function relevant to membrane trafficking and Golgi dynamics, linking localization to cell-cycle and secretory phenotypes. (huang2024cterminalbindingprotein pages 2-4, filograna2024identificationandcharacterization pages 1-2)

In neuronal contexts, CtBP1 can shuttle between nucleus and cytoplasm and has reported interactions with presynaptic scaffold proteins (e.g., Bassoon/Piccolo), supporting specialized synaptic roles alongside transcriptional regulation. (lee2025usingtheallen pages 9-11)

2.4 Pathways and biological processes most directly supported by this evidence set

Across the cited works, CtBP1 is most directly implicated in:
- Epithelial–mesenchymal transition (EMT) and malignant transcriptional programs via repression of epithelial genes and/or modulation of EMT-related networks (chen2021thetransrepressionand pages 1-2, filograna2024identificationandcharacterization pages 22-25)
- Apoptosis/cell survival programs, via repression of pro-apoptotic genes and tumor-suppressor pathways in cancer contexts (lim2024transcriptionalcorepressoractivity pages 3-7, filograna2024identificationandcharacterization pages 25-27)
- DNA damage response (DDR) gene regulation through transcriptional control (distinct from direct enzymatic repair), including repression of DDR-related genes in cancer cell models (lee2025usingtheallen pages 6-8)

3. Recent developments (prioritizing 2023–2024)

3.1 2024 structural/mechanistic breakthrough: RAI2-driven CtBP polymerization inactivates corepressor function

A 2024 Nature Communications study reports a mechanism whereby RAI2, a largely intrinsically disordered protein, contains two tandem ALDLS (PxDLS-like) SLiMs that bind CtBP and drive multivalent interaction–induced polymerization of CtBP into filamentous assemblies (stacked tetrameric layers). The study connects polymerization to nuclear CtBP foci and functional inactivation of CtBP corepressor activity, including relief of repression at CDKN1A (p21) with increased promoter activity (~2.5-fold) and decreased H3K27me3 at the promoter in RAI2-present settings. Methods include cryo-EM (3.0 Å structure for filaments), X-ray crystallography, SAXS, NMR, and SEC. (goradia2024mastercorepressorinactivation pages 1-4, goradia2024mastercorepressorinactivation pages 8-11, goradia2024mastercorepressorinactivation pages 4-8)

Clinical association within the same work indicates that RAI2 decreases in advanced treatment-resistant prostate cancer subtypes and reports circulating tumor cell (CTC) positivity rates consistent with progression: RAI2 detected in 89% of CRPC CTCs vs 35% in AVPC vs 19% in NEPC, supporting RAI2 loss as linked to aggressive disease phenotypes and suggesting a disease-relevant shift away from RAI2-mediated CtBP inactivation. (goradia2024mastercorepressorinactivation pages 11-14)

3.2 2024 post-translational regulation: CtBP1 ISGylation increases partner affinity and repression potency

A 2024 study reports that CtBP1 is modified by ISG15 (ISGylation) following interferon-α stimulation and that this modification is regulated by an ISGylation E3 ligase (EFP) and reversed by the deISGylase (USP18). Functionally, ISGylation increases CtBP1 binding to HDAC1 and LSD1, while not changing CtBP1 association with HDAC4, and enhances CtBP1 transcriptional repression of genes linked to EMT and apoptosis (including E-cadherin, Bax, Noxa in their tested system). The authors note that the CtBP1 ISGylation site(s) remain to be identified. (lim2024transcriptionalcorepressoractivity pages 1-2, lim2024transcriptionalcorepressoractivity pages 3-7, lim2024transcriptionalcorepressoractivity pages 7-8)

3.3 2024 translational inhibitor development: targeting CtBP1/BARS Rossmann fold with “Comp.11”

A 2024 Journal of Experimental & Clinical Cancer Research paper reports a structure-guided discovery of Comp.11 (N-(3,4-dichlorophenyl)-4-{[(4-nitrophenyl)carbamoyl]amino}benzenesulfonamide) as a potent and selective inhibitor of CtBP1/BARS (not CtBP2) that binds the Rossmann fold near the NADH-binding region and forms a ternary complex with NADH, altering oligomerization and preventing productive partner interactions. (filograna2024identificationandcharacterization pages 1-2, filograna2024identificationandcharacterization pages 9-11, filograna2024identificationandcharacterization pages 25-27)

Quantitative binding: ITC reports Kd = 0.66 ± 0.20 μM for Comp.11 binding (with one ligand per protein in their model). (filograna2024identificationandcharacterization pages 9-11, filograna2024identificationandcharacterization media a3db0a0a)

Mechanistic cellular effects: Comp.11 promotes redistribution of CtBP1/BARS from nucleus to cytoplasm/Golgi, disrupts partner interactions (including transcriptional and membrane fission partners), induces Golgi tubulation consistent with impaired fission, blocks mitotic entry and secretion-related functions, and shifts transcriptional programs toward a more epithelial phenotype with reduced invasion. (filograna2024identificationandcharacterization pages 9-11, filograna2024identificationandcharacterization pages 11-14, filograna2024identificationandcharacterization pages 22-25)

In vivo efficacy (mouse xenograft): In an A375MM melanoma xenograft model, Comp.11 at 20 mg/kg produced significant tumor growth inhibition with reported reductions in tumor-burden metrics and significant tumor weight reduction (p-values reported around 0.02–0.03), with percent change in tumor burden reported as ~39.39% (day 14, 20 mg/kg) versus a smaller effect at 10 mg/kg; treatment was described as well tolerated with maintained body weight. (filograna2024identificationandcharacterization pages 22-25, filograna2024identificationandcharacterization media a3db0a0a, filograna2024identificationandcharacterization media 4353de2d, filograna2024identificationandcharacterization media 440b0878)

4. Current applications and real-world implementations

4.1 Preclinical oncology targeting

The most concrete real-world implementation in this evidence set is preclinical pharmacologic targeting of CtBP1/BARS with Comp.11 in melanoma models (cell lines and mouse xenografts), providing a translational path toward CtBP1-directed therapies. (filograna2024identificationandcharacterization pages 22-25, filograna2024identificationandcharacterization pages 9-11)

4.2 Biomarker/clinical stratification concepts

The RAI2–CtBP polymerization work provides a clinically oriented application: RAI2 expression in CTCs and tumor progression states may serve as a biomarker axis reflecting CtBP repression states in prostate cancer subtypes (CRPC vs AVPC vs NEPC). (goradia2024mastercorepressorinactivation pages 11-14)

4.3 Virus–cancer interface (emerging application area)

A 2024 review frames CtBP proteins as regulators at the intersection of viral infection and tumorigenesis, synthesizing evidence that CtBP proteins contribute to oncogenic transcriptional programs and may be exploitable for antiviral/anticancer strategies; it also emphasizes that antiviral applications remain comparatively less developed. (huang2024cterminalbindingprotein pages 2-4)

5. Expert opinions/authoritative analysis (as expressed in reviews and mechanistic papers)

5.1 CtBP1 as an actionable hub: why experts consider it druggable

Authoritative synthesis emphasizes CtBP1’s D2‑HDH-like Rossmann fold and ligand-binding pocket as an attractive intervention site, and frames inhibitor development as feasible via structure-guided design targeting the Rossmann fold or substrate-binding region, with the expectation that blocking CtBP1 oligomerization/partner binding can reprogram transcriptional outputs in disease. (huang2024cterminalbindingprotein pages 2-4, filograna2024identificationandcharacterization pages 1-2)

5.2 Regulatory layers beyond NADH: polymerization and ISGylation

The 2024 Nature Communications study proposes polymerization as an additional structural/regulatory layer that can switch CtBP from an active tetrameric corepressor assembly to an inactivated filament/foci state, suggesting new ways to modulate CtBP activity beyond classic competitive inhibition. (goradia2024mastercorepressorinactivation pages 1-4, goradia2024mastercorepressorinactivation pages 8-11)

The 2024 ISGylation work provides a distinct perspective: immune signaling (IFN-α) can potentiate CtBP1 repression by increasing its affinity for specific epigenetic enzymes, implying that CtBP1 activity is integrated with inflammatory signaling states. (lim2024transcriptionalcorepressoractivity pages 1-2, lim2024transcriptionalcorepressoractivity pages 3-7)

6. Statistics and data highlights from recent studies

Comp.11 binding affinity: CtBP1/BARS Kd = 0.66 ± 0.20 μM by ITC. (filograna2024identificationandcharacterization pages 9-11, filograna2024identificationandcharacterization media a3db0a0a)
Melanoma xenograft response: Comp.11 shows significant growth inhibition at 20 mg/kg, with reported tumor-burden percent change metrics including ~39.39% (day 14, 20 mg/kg) and significant tumor weight reduction. (filograna2024identificationandcharacterization pages 22-25, filograna2024identificationandcharacterization media 4353de2d)
Prostate cancer CTC RAI2 positivity across progression: 89% CRPC, 35% AVPC, 19% NEPC. (goradia2024mastercorepressorinactivation pages 11-14)

7. Evidence gaps and interpretation boundaries

While CtBP1 is enzyme-homologous and ligandable, the present evidence set supports a well-established binding pocket and dehydrogenase-like fold and substrate/inhibitor binding (e.g., MTOB), but does not fully establish a single dominant physiological catalytic reaction as the primary biological role; instead, the strongest experimental narrative centers on transcriptional corepressor scaffolding regulated by NADH and oligomeric state. (chen2021thetransrepressionand pages 1-2, chen2021thetransrepressionand pages 5-7)
Many pathway-level claims about broad disease roles exist in the literature; this report prioritizes mechanistic and experimentally anchored functions supported by the retrieved primary studies and reviews.

Key 2024 sources (URLs and publication dates)

Filograna et al. May 2024, Journal of Experimental & Clinical Cancer Research: “Identification and characterization of a new potent inhibitor targeting CtBP1/BARS in melanoma cells.” https://doi.org/10.1186/s13046-024-03044-5 (filograna2024identificationandcharacterization pages 1-2)
Goradia et al. May 2024, Nature Communications: “Master corepressor inactivation through multivalent SLiM-induced polymerization mediated by the oncogene suppressor RAI2.” https://doi.org/10.1101/2023.06.16.545227 (goradia2024mastercorepressorinactivation pages 1-4)
Lim et al. Feb 2024, Animal Cells and Systems: “Transcriptional corepressor activity of CtBP1 is regulated by ISG15 modification.” https://doi.org/10.1080/19768354.2024.2321354 (lim2024transcriptionalcorepressoractivity pages 1-2)
Huang et al. Jun 2024, Viruses: “C-Terminal Binding Protein: Regulator between Viral Infection and Tumorigenesis.” https://doi.org/10.3390/v16060988 (huang2024cterminalbindingprotein pages 2-4)

References

(huang2024cterminalbindingprotein pages 2-4): Meihui Huang, Yucong Li, Yuxiao Li, and Shuiping Liu. C-terminal binding protein: regulator between viral infection and tumorigenesis. Viruses, 16:988, Jun 2024. URL: https://doi.org/10.3390/v16060988, doi:10.3390/v16060988. This article has 3 citations.
(chen2021thetransrepressionand pages 1-2): Zhi Chen. The transrepression and transactivation roles of ctbps in the pathogenesis of different diseases. Journal of Molecular Medicine, 99:1335-1347, Jul 2021. URL: https://doi.org/10.1007/s00109-021-02107-w, doi:10.1007/s00109-021-02107-w. This article has 30 citations.
(chen2021thetransrepressionand pages 5-7): Zhi Chen. The transrepression and transactivation roles of ctbps in the pathogenesis of different diseases. Journal of Molecular Medicine, 99:1335-1347, Jul 2021. URL: https://doi.org/10.1007/s00109-021-02107-w, doi:10.1007/s00109-021-02107-w. This article has 30 citations.
(lee2025usingtheallen pages 6-8): Suhjin Lee and Uthayashanker R. Ezekiel. Using the allen brain cell atlas of the human brain to gain insights into c-terminal-binding protein 1 (ctbp1)’s potential function. Biologics, 5:14, May 2025. URL: https://doi.org/10.3390/biologics5020014, doi:10.3390/biologics5020014. This article has 1 citations and is from a peer-reviewed journal.
(lee2025usingtheallen pages 9-11): Suhjin Lee and Uthayashanker R. Ezekiel. Using the allen brain cell atlas of the human brain to gain insights into c-terminal-binding protein 1 (ctbp1)’s potential function. Biologics, 5:14, May 2025. URL: https://doi.org/10.3390/biologics5020014, doi:10.3390/biologics5020014. This article has 1 citations and is from a peer-reviewed journal.
(goradia2024mastercorepressorinactivation pages 4-8): Nishit Goradia, Stefan Werner, Edukondalu Mullapudi, Sarah Greimeier, Lina Merkens, Andras Lang, Haydyn Mertens, Aleksandra Węglarz, Simon Sander, Grzegorz Chojnowski, Harriet Wikman, Oliver Ohlenschläger, Gunhild von Amsberg, Klaus Pantel, and Matthias Wilmanns. Master corepressor inactivation through multivalent slim-induced polymerization mediated by the oncogene suppressor rai2. Nature Communications, May 2024. URL: https://doi.org/10.1101/2023.06.16.545227, doi:10.1101/2023.06.16.545227. This article has 1 citations and is from a highest quality peer-reviewed journal.
(goradia2024mastercorepressorinactivation pages 1-4): Nishit Goradia, Stefan Werner, Edukondalu Mullapudi, Sarah Greimeier, Lina Merkens, Andras Lang, Haydyn Mertens, Aleksandra Węglarz, Simon Sander, Grzegorz Chojnowski, Harriet Wikman, Oliver Ohlenschläger, Gunhild von Amsberg, Klaus Pantel, and Matthias Wilmanns. Master corepressor inactivation through multivalent slim-induced polymerization mediated by the oncogene suppressor rai2. Nature Communications, May 2024. URL: https://doi.org/10.1101/2023.06.16.545227, doi:10.1101/2023.06.16.545227. This article has 1 citations and is from a highest quality peer-reviewed journal.
(goradia2024mastercorepressorinactivation pages 8-11): Nishit Goradia, Stefan Werner, Edukondalu Mullapudi, Sarah Greimeier, Lina Merkens, Andras Lang, Haydyn Mertens, Aleksandra Węglarz, Simon Sander, Grzegorz Chojnowski, Harriet Wikman, Oliver Ohlenschläger, Gunhild von Amsberg, Klaus Pantel, and Matthias Wilmanns. Master corepressor inactivation through multivalent slim-induced polymerization mediated by the oncogene suppressor rai2. Nature Communications, May 2024. URL: https://doi.org/10.1101/2023.06.16.545227, doi:10.1101/2023.06.16.545227. This article has 1 citations and is from a highest quality peer-reviewed journal.
(lim2024transcriptionalcorepressoractivity pages 3-7): Yun Hwan Lim, Yoon Jin Park, Jieun Lee, and Jung Hwa Kim. Transcriptional corepressor activity of ctbp1 is regulated by isg15 modification. Animal Cells and Systems, 28:66-74, Feb 2024. URL: https://doi.org/10.1080/19768354.2024.2321354, doi:10.1080/19768354.2024.2321354. This article has 5 citations and is from a peer-reviewed journal.
(lee2025usingtheallen pages 1-2): Suhjin Lee and Uthayashanker R. Ezekiel. Using the allen brain cell atlas of the human brain to gain insights into c-terminal-binding protein 1 (ctbp1)’s potential function. Biologics, 5:14, May 2025. URL: https://doi.org/10.3390/biologics5020014, doi:10.3390/biologics5020014. This article has 1 citations and is from a peer-reviewed journal.
(filograna2024identificationandcharacterization pages 22-25): Angela Filograna, Stefano De Tito, Matteo Lo Monte, Rosario Oliva, Francesca Bruzzese, Maria Serena Roca, Antonella Zannetti, Adelaide Greco, Daniela Spano, Inmaculada Ayala, Assunta Liberti, Luigi Petraccone, Nina Dathan, Giuliana Catara, Laura Schembri, Antonino Colanzi, Alfredo Budillon, Andrea Rosario Beccari, Pompea Del Vecchio, Alberto Luini, Daniela Corda, and Carmen Valente. Identification and characterization of a new potent inhibitor targeting ctbp1/bars in melanoma cells. Journal of Experimental & Clinical Cancer Research, May 2024. URL: https://doi.org/10.1186/s13046-024-03044-5, doi:10.1186/s13046-024-03044-5. This article has 6 citations and is from a domain leading peer-reviewed journal.
(filograna2024identificationandcharacterization pages 9-11): Angela Filograna, Stefano De Tito, Matteo Lo Monte, Rosario Oliva, Francesca Bruzzese, Maria Serena Roca, Antonella Zannetti, Adelaide Greco, Daniela Spano, Inmaculada Ayala, Assunta Liberti, Luigi Petraccone, Nina Dathan, Giuliana Catara, Laura Schembri, Antonino Colanzi, Alfredo Budillon, Andrea Rosario Beccari, Pompea Del Vecchio, Alberto Luini, Daniela Corda, and Carmen Valente. Identification and characterization of a new potent inhibitor targeting ctbp1/bars in melanoma cells. Journal of Experimental & Clinical Cancer Research, May 2024. URL: https://doi.org/10.1186/s13046-024-03044-5, doi:10.1186/s13046-024-03044-5. This article has 6 citations and is from a domain leading peer-reviewed journal.
(filograna2024identificationandcharacterization pages 25-27): Angela Filograna, Stefano De Tito, Matteo Lo Monte, Rosario Oliva, Francesca Bruzzese, Maria Serena Roca, Antonella Zannetti, Adelaide Greco, Daniela Spano, Inmaculada Ayala, Assunta Liberti, Luigi Petraccone, Nina Dathan, Giuliana Catara, Laura Schembri, Antonino Colanzi, Alfredo Budillon, Andrea Rosario Beccari, Pompea Del Vecchio, Alberto Luini, Daniela Corda, and Carmen Valente. Identification and characterization of a new potent inhibitor targeting ctbp1/bars in melanoma cells. Journal of Experimental & Clinical Cancer Research, May 2024. URL: https://doi.org/10.1186/s13046-024-03044-5, doi:10.1186/s13046-024-03044-5. This article has 6 citations and is from a domain leading peer-reviewed journal.
(filograna2024identificationandcharacterization pages 27-28): Angela Filograna, Stefano De Tito, Matteo Lo Monte, Rosario Oliva, Francesca Bruzzese, Maria Serena Roca, Antonella Zannetti, Adelaide Greco, Daniela Spano, Inmaculada Ayala, Assunta Liberti, Luigi Petraccone, Nina Dathan, Giuliana Catara, Laura Schembri, Antonino Colanzi, Alfredo Budillon, Andrea Rosario Beccari, Pompea Del Vecchio, Alberto Luini, Daniela Corda, and Carmen Valente. Identification and characterization of a new potent inhibitor targeting ctbp1/bars in melanoma cells. Journal of Experimental & Clinical Cancer Research, May 2024. URL: https://doi.org/10.1186/s13046-024-03044-5, doi:10.1186/s13046-024-03044-5. This article has 6 citations and is from a domain leading peer-reviewed journal.
(filograna2024identificationandcharacterization pages 2-4): Angela Filograna, Stefano De Tito, Matteo Lo Monte, Rosario Oliva, Francesca Bruzzese, Maria Serena Roca, Antonella Zannetti, Adelaide Greco, Daniela Spano, Inmaculada Ayala, Assunta Liberti, Luigi Petraccone, Nina Dathan, Giuliana Catara, Laura Schembri, Antonino Colanzi, Alfredo Budillon, Andrea Rosario Beccari, Pompea Del Vecchio, Alberto Luini, Daniela Corda, and Carmen Valente. Identification and characterization of a new potent inhibitor targeting ctbp1/bars in melanoma cells. Journal of Experimental & Clinical Cancer Research, May 2024. URL: https://doi.org/10.1186/s13046-024-03044-5, doi:10.1186/s13046-024-03044-5. This article has 6 citations and is from a domain leading peer-reviewed journal.
(filograna2024identificationandcharacterization pages 11-14): Angela Filograna, Stefano De Tito, Matteo Lo Monte, Rosario Oliva, Francesca Bruzzese, Maria Serena Roca, Antonella Zannetti, Adelaide Greco, Daniela Spano, Inmaculada Ayala, Assunta Liberti, Luigi Petraccone, Nina Dathan, Giuliana Catara, Laura Schembri, Antonino Colanzi, Alfredo Budillon, Andrea Rosario Beccari, Pompea Del Vecchio, Alberto Luini, Daniela Corda, and Carmen Valente. Identification and characterization of a new potent inhibitor targeting ctbp1/bars in melanoma cells. Journal of Experimental & Clinical Cancer Research, May 2024. URL: https://doi.org/10.1186/s13046-024-03044-5, doi:10.1186/s13046-024-03044-5. This article has 6 citations and is from a domain leading peer-reviewed journal.
(filograna2024identificationandcharacterization pages 8-9): Angela Filograna, Stefano De Tito, Matteo Lo Monte, Rosario Oliva, Francesca Bruzzese, Maria Serena Roca, Antonella Zannetti, Adelaide Greco, Daniela Spano, Inmaculada Ayala, Assunta Liberti, Luigi Petraccone, Nina Dathan, Giuliana Catara, Laura Schembri, Antonino Colanzi, Alfredo Budillon, Andrea Rosario Beccari, Pompea Del Vecchio, Alberto Luini, Daniela Corda, and Carmen Valente. Identification and characterization of a new potent inhibitor targeting ctbp1/bars in melanoma cells. Journal of Experimental & Clinical Cancer Research, May 2024. URL: https://doi.org/10.1186/s13046-024-03044-5, doi:10.1186/s13046-024-03044-5. This article has 6 citations and is from a domain leading peer-reviewed journal.
(filograna2024identificationandcharacterization media a3db0a0a): Angela Filograna, Stefano De Tito, Matteo Lo Monte, Rosario Oliva, Francesca Bruzzese, Maria Serena Roca, Antonella Zannetti, Adelaide Greco, Daniela Spano, Inmaculada Ayala, Assunta Liberti, Luigi Petraccone, Nina Dathan, Giuliana Catara, Laura Schembri, Antonino Colanzi, Alfredo Budillon, Andrea Rosario Beccari, Pompea Del Vecchio, Alberto Luini, Daniela Corda, and Carmen Valente. Identification and characterization of a new potent inhibitor targeting ctbp1/bars in melanoma cells. Journal of Experimental & Clinical Cancer Research, May 2024. URL: https://doi.org/10.1186/s13046-024-03044-5, doi:10.1186/s13046-024-03044-5. This article has 6 citations and is from a domain leading peer-reviewed journal.
(filograna2024identificationandcharacterization media 4353de2d): Angela Filograna, Stefano De Tito, Matteo Lo Monte, Rosario Oliva, Francesca Bruzzese, Maria Serena Roca, Antonella Zannetti, Adelaide Greco, Daniela Spano, Inmaculada Ayala, Assunta Liberti, Luigi Petraccone, Nina Dathan, Giuliana Catara, Laura Schembri, Antonino Colanzi, Alfredo Budillon, Andrea Rosario Beccari, Pompea Del Vecchio, Alberto Luini, Daniela Corda, and Carmen Valente. Identification and characterization of a new potent inhibitor targeting ctbp1/bars in melanoma cells. Journal of Experimental & Clinical Cancer Research, May 2024. URL: https://doi.org/10.1186/s13046-024-03044-5, doi:10.1186/s13046-024-03044-5. This article has 6 citations and is from a domain leading peer-reviewed journal.
(filograna2024identificationandcharacterization media 440b0878): Angela Filograna, Stefano De Tito, Matteo Lo Monte, Rosario Oliva, Francesca Bruzzese, Maria Serena Roca, Antonella Zannetti, Adelaide Greco, Daniela Spano, Inmaculada Ayala, Assunta Liberti, Luigi Petraccone, Nina Dathan, Giuliana Catara, Laura Schembri, Antonino Colanzi, Alfredo Budillon, Andrea Rosario Beccari, Pompea Del Vecchio, Alberto Luini, Daniela Corda, and Carmen Valente. Identification and characterization of a new potent inhibitor targeting ctbp1/bars in melanoma cells. Journal of Experimental & Clinical Cancer Research, May 2024. URL: https://doi.org/10.1186/s13046-024-03044-5, doi:10.1186/s13046-024-03044-5. This article has 6 citations and is from a domain leading peer-reviewed journal.
(goradia2024mastercorepressorinactivation pages 11-14): Nishit Goradia, Stefan Werner, Edukondalu Mullapudi, Sarah Greimeier, Lina Merkens, Andras Lang, Haydyn Mertens, Aleksandra Węglarz, Simon Sander, Grzegorz Chojnowski, Harriet Wikman, Oliver Ohlenschläger, Gunhild von Amsberg, Klaus Pantel, and Matthias Wilmanns. Master corepressor inactivation through multivalent slim-induced polymerization mediated by the oncogene suppressor rai2. Nature Communications, May 2024. URL: https://doi.org/10.1101/2023.06.16.545227, doi:10.1101/2023.06.16.545227. This article has 1 citations and is from a highest quality peer-reviewed journal.
(lim2024transcriptionalcorepressoractivity pages 7-8): Yun Hwan Lim, Yoon Jin Park, Jieun Lee, and Jung Hwa Kim. Transcriptional corepressor activity of ctbp1 is regulated by isg15 modification. Animal Cells and Systems, 28:66-74, Feb 2024. URL: https://doi.org/10.1080/19768354.2024.2321354, doi:10.1080/19768354.2024.2321354. This article has 5 citations and is from a peer-reviewed journal.
(filograna2024identificationandcharacterization pages 1-2): Angela Filograna, Stefano De Tito, Matteo Lo Monte, Rosario Oliva, Francesca Bruzzese, Maria Serena Roca, Antonella Zannetti, Adelaide Greco, Daniela Spano, Inmaculada Ayala, Assunta Liberti, Luigi Petraccone, Nina Dathan, Giuliana Catara, Laura Schembri, Antonino Colanzi, Alfredo Budillon, Andrea Rosario Beccari, Pompea Del Vecchio, Alberto Luini, Daniela Corda, and Carmen Valente. Identification and characterization of a new potent inhibitor targeting ctbp1/bars in melanoma cells. Journal of Experimental & Clinical Cancer Research, May 2024. URL: https://doi.org/10.1186/s13046-024-03044-5, doi:10.1186/s13046-024-03044-5. This article has 6 citations and is from a domain leading peer-reviewed journal.
(lim2024transcriptionalcorepressoractivity pages 1-2): Yun Hwan Lim, Yoon Jin Park, Jieun Lee, and Jung Hwa Kim. Transcriptional corepressor activity of ctbp1 is regulated by isg15 modification. Animal Cells and Systems, 28:66-74, Feb 2024. URL: https://doi.org/10.1080/19768354.2024.2321354, doi:10.1080/19768354.2024.2321354. This article has 5 citations and is from a peer-reviewed journal.

Citations

lee2025usingtheallen pages 1-2
huang2024cterminalbindingprotein pages 2-4
lee2025usingtheallen pages 6-8
lee2025usingtheallen pages 9-11
goradia2024mastercorepressorinactivation pages 11-14
filograna2024identificationandcharacterization pages 1-2
goradia2024mastercorepressorinactivation pages 1-4
lim2024transcriptionalcorepressoractivity pages 1-2
chen2021thetransrepressionand pages 1-2
chen2021thetransrepressionand pages 5-7
goradia2024mastercorepressorinactivation pages 4-8
goradia2024mastercorepressorinactivation pages 8-11
lim2024transcriptionalcorepressoractivity pages 3-7
filograna2024identificationandcharacterization pages 22-25
filograna2024identificationandcharacterization pages 9-11
filograna2024identificationandcharacterization pages 25-27
filograna2024identificationandcharacterization pages 27-28
filograna2024identificationandcharacterization pages 2-4
filograna2024identificationandcharacterization pages 11-14
filograna2024identificationandcharacterization pages 8-9
lim2024transcriptionalcorepressoractivity pages 7-8
(4-nitrophenyl)carbamoyl
https://doi.org/10.3390/v16060988;
https://doi.org/10.1007/s00109-021-02107-w
https://doi.org/10.1007/s00109-021-02107-w;
https://doi.org/10.3390/biologics5020014
https://doi.org/10.1016/j.jbc.2021.100351;
https://doi.org/10.1101/2023.06.16.545227;
https://doi.org/10.1080/19768354.2024.2321354
https://doi.org/10.3390/biologics5020014;
https://doi.org/10.1101/2023.06.16.545227
https://doi.org/10.1186/s13046-024-03044-5;
https://doi.org/10.1186/s13046-024-03044-5
https://doi.org/10.3390/v16060988
https://doi.org/10.3390/v16060988,
https://doi.org/10.1007/s00109-021-02107-w,
https://doi.org/10.3390/biologics5020014,
https://doi.org/10.1101/2023.06.16.545227,
https://doi.org/10.1080/19768354.2024.2321354,
https://doi.org/10.1186/s13046-024-03044-5,

📄 View Raw YAML

id: Q13363
gene_symbol: CTBP1
product_type: PROTEIN
status: IN_PROGRESS
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: CTBP1 (C-terminal-binding protein 1) is a transcriptional corepressor that functions as a
  scaffold to nucleate multi-protein chromatin-modifying complexes. It lacks intrinsic DNA-binding activity
  and is instead recruited to target gene promoters by DNA-binding transcription factors (e.g. ZEB1/2,
  KLFs, BCL6, MECOM) that present PXDLS/PLDLS short linear motifs. Once recruited, CTBP1 assembles corepressor
  complexes containing HDAC1/2, LSD1/KDM1A, and RCOR1/CoREST to mediate transcriptional silencing through
  histone modification. CTBP1 contains a D-isomer-specific 2-hydroxyacid dehydrogenase-like domain with
  a Rossmann fold that binds NAD+/NADH, and NADH binding allosterically promotes dimerization/oligomerization
  critical for corepressor function, establishing CTBP1 as a metabolic/redox sensor in transcriptional
  regulation. CTBP1 also has roles in Golgi membrane fission (as CtBP1/BARS) and has been reported at
  presynaptic terminals in neurons. It is predominantly nuclear but shuttles between nucleus and cytoplasm
  depending on cellular context.
alternative_products:
- id: Q13363-1
  name: '1'
- id: Q13363-2
  name: '2'
existing_annotations:
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: CTBP1 is well established as a nuclear transcriptional corepressor. UniProt confirms nuclear
      localization (PMID:12679040). IBA is appropriate as this is conserved across the CtBP family.
    action: ACCEPT
- term:
    id: GO:0003714
    label: transcription corepressor activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Transcription corepressor activity is the primary molecular function of CTBP1. It is recruited
      by PXDLS-motif-containing transcription factors and assembles HDAC/LSD1/CoREST complexes to silence
      gene expression. IBA is well-supported and represents the core function.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:12419229
      supporting_text: CtBP is an NAD(+)-regulated component of critical complexes for specific repression
        events in cells.
- term:
    id: GO:0006357
    label: regulation of transcription by RNA polymerase II
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: CTBP1 regulates RNA Pol II-dependent transcription as a corepressor. This is a core biological
      process annotation consistent with its well-established role. IBA annotation is well-supported.
    action: ACCEPT
- term:
    id: GO:0140297
    label: DNA-binding transcription factor binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: CTBP1 binds numerous DNA-binding transcription factors via their PXDLS motifs (ZEB1/2, KLFs,
      BCL6, MECOM, FOXP1, etc.). This is a core molecular function. IBA is well-supported.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:10359772
      supporting_text: ZEB represses transcription through interaction with the corepressor CtBP.
- term:
    id: GO:0001221
    label: transcription coregulator binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: CTBP1 binds other coregulators such as HDAC1/2, LSD1/KDM1A, RCOR1/CoREST within its corepressor
      complexes. It also heterodimerizes with CTBP2. IBA is appropriate.
    action: ACCEPT
- term:
    id: GO:0003713
    label: transcription coactivator activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: While CTBP1 is primarily a corepressor, there is evidence that CtBP proteins can also have
      coactivator functions in certain contexts. The IBA annotation suggests this is phylogenetically
      conserved. Chen 2021 describes both transrepression and transactivation roles for CtBPs. Accepting
      as a secondary function.
    action: ACCEPT
    reason: Chen 2021 (J Mol Med) describes transactivation roles of CtBPs in certain pathways, supporting
      the IBA annotation of coactivator activity as a conserved property.
- term:
    id: GO:0045893
    label: positive regulation of DNA-templated transcription
  evidence_type: IEA
  original_reference_id: GO_REF:0000108
  review:
    summary: IEA annotation consistent with the coactivator role noted above for CtBP family. Logically
      inferred from the coactivator activity annotation. Acceptable as a broader annotation.
    action: ACCEPT
- term:
    id: GO:0003714
    label: transcription corepressor activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: IEA annotation for transcription corepressor activity is redundant with the IBA (index 1)
      but correct. CTBP1 is well established as a transcriptional corepressor.
    action: ACCEPT
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: IEA annotation for nucleus is redundant with the IBA and IDA annotations but correct.
    action: ACCEPT
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: CTBP1 localizes to both nucleus and cytoplasm. UniProt confirms cytoplasmic localization
      (PMID:12679040). CTBP1/BARS has well-described cytoplasmic roles in Golgi membrane dynamics.
    action: ACCEPT
- term:
    id: GO:0016491
    label: oxidoreductase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: CTBP1 has a D-2-hydroxyacid dehydrogenase domain and demonstrated dehydrogenase activity
      (PMID:12419229). This IEA is a parent term of the more specific GO:0016616 annotation and is correct.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:12419229
      supporting_text: CtBP is a functional dehydrogenase.
- term:
    id: GO:0016616
    label: oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: Correct IEA annotation consistent with the IDA annotation from PMID:12419229. CTBP1 has demonstrated
      dehydrogenase activity with NAD as cofactor.
    action: ACCEPT
- term:
    id: GO:0030154
    label: cell differentiation
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: CTBP1 is involved in differentiation processes (BAT/WAT differentiation, developmental programs)
      as a pleiotropic consequence of its transcriptional corepressor function. This is a very general
      term. Keeping as non-core.
    action: KEEP_AS_NON_CORE
    reason: Cell differentiation is too general and represents pleiotropic effects of CTBP1 corepressor
      activity rather than a core function.
- term:
    id: GO:0051287
    label: NAD binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: NAD binding is well established for CTBP1. Its Rossmann fold binds NAD+/NADH, which allosterically
      regulates oligomerization and corepressor function. Supported by crystal structure (PMID:12419229).
    action: ACCEPT
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:10359772
  review:
    summary: PMID:10359772 demonstrates CTBP1 interaction with ZEB1, a DNA-binding transcription factor.
      "protein binding" is too vague. Should be annotated as DNA-binding transcription factor binding.
    action: MODIFY
    supported_by:
    - reference_id: PMID:10359772
      supporting_text: ZEB represses transcription through interaction with the corepressor CtBP.
    proposed_replacement_terms:
    - id: GO:0140297
      label: DNA-binding transcription factor binding
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:10995736
  review:
    summary: PMID:10995736 describes CTBP1 interaction with TGIF, a Smad corepressor/transcription factor.
      Should be annotated more specifically.
    action: MODIFY
    supported_by:
    - reference_id: PMID:10995736
      supporting_text: The interaction of the carboxyl terminus-binding protein with the Smad corepressor
        TGIF is disrupted by a holoprosencephaly mutation in TGIF.
    proposed_replacement_terms:
    - id: GO:0140297
      label: DNA-binding transcription factor binding
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:11462050
  review:
    summary: PMID:11462050 describes physical interaction between CTBP1 and Epstein-Barr virus EBNA3C.
      This is a viral protein interaction relevant to host-virus biology. Protein binding is too vague.
    action: MODIFY
    supported_by:
    - reference_id: PMID:11462050
      supporting_text: Physical and functional interactions between the corepressor CtBP and the Epstein-Barr
        virus nuclear antigen EBNA3C.
    reason: EBNA3C is a viral transcriptional regulator that recruits CTBP1 corepressor activity.
    proposed_replacement_terms:
    - id: GO:0140297
      label: DNA-binding transcription factor binding
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16762039
  review:
    summary: PMID:16762039 demonstrates CTBP1 interaction with HIC1 tumor suppressor. HIC1 is a DNA-binding
      transcription factor. Protein binding is too vague.
    action: MODIFY
    supported_by:
    - reference_id: PMID:16762039
      supporting_text: 2006 Jun 7. A L225A substitution in the human tumour suppressor HIC1 abolishes
        its interaction with the corepressor CtBP.
    proposed_replacement_terms:
    - id: GO:0140297
      label: DNA-binding transcription factor binding
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17085477
  review:
    summary: PMID:17085477 shows ZNF366 is an estrogen receptor corepressor that acts through CtBP. ZNF366
      is a DNA-binding zinc-finger transcription factor. Protein binding is too vague.
    action: MODIFY
    supported_by:
    - reference_id: PMID:17085477
      supporting_text: ZNF366 is an estrogen receptor corepressor that acts through CtBP and histone deacetylases.
    proposed_replacement_terms:
    - id: GO:0140297
      label: DNA-binding transcription factor binding
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19486893
  review:
    summary: PMID:19486893 is about HIC1 interacting with SWI/SNF subunit ARID1A. The direct relevance
      to CTBP1 protein binding is unclear from the title alone. Unable to fully assess without reading
      the full publication.
    action: UNDECIDED
    supported_by:
    - reference_id: PMID:19486893
      supporting_text: HIC1 interacts with a specific subunit of SWI/SNF complexes, ARID1A/BAF250A.
    reason: Cannot determine the specific CTBP1 interaction described in this paper from the available
      abstract alone.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19751731
  review:
    summary: PMID:19751731 describes CtBPs attenuating KLF4-mediated transcriptional activation. KLF4
      is a DNA-binding transcription factor. Protein binding is too vague.
    action: MODIFY
    supported_by:
    - reference_id: PMID:19751731
      supporting_text: Epub 2009 Sep 12. C-terminal binding proteins (CtBPs) attenuate KLF4-mediated transcriptional
        activation.
    proposed_replacement_terms:
    - id: GO:0140297
      label: DNA-binding transcription factor binding
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20098713
  review:
    summary: PMID:20098713 describes CTBP1 interaction with Pc2/CBX4 in the context of SUMOylation. CBX4
      is a Polycomb group protein that SUMOylates CTBP1. This could be more specifically annotated.
    action: MODIFY
    supported_by:
    - reference_id: PMID:20098713
      supporting_text: A role for non-covalent SUMO interaction motifs in Pc2/CBX4 E3 activity.
    reason: CBX4/Pc2 functions as a transcriptional coregulator and SUMO E3 ligase for CTBP1.
    proposed_replacement_terms:
    - id: GO:0001221
      label: transcription coregulator binding
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20211142
  review:
    summary: PMID:20211142 is a large-scale atlas study of combinatorial transcriptional regulation. Protein
      binding from HTP studies is uninformative for CTBP1 annotation.
    action: MARK_AS_OVER_ANNOTATED
    supported_by:
    - reference_id: PMID:20211142
      supporting_text: An atlas of combinatorial transcriptional regulation in mouse and man.
    reason: High-throughput study; protein binding is too vague to be useful.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21044950
  review:
    summary: PMID:21044950 is a genome-wide YFP fluorescence complementation screen for telomere signaling.
      CTBP1 is not primarily involved in telomere signaling. This is a HTP screen result.
    action: MARK_AS_OVER_ANNOTATED
    supported_by:
    - reference_id: PMID:21044950
      supporting_text: Epub 2010 Nov 2. Genome-wide YFP fluorescence complementation screen identifies
        new regulators for telomere signaling in human cells.
    reason: High-throughput screen; protein binding is too vague and telomere function is not core to
      CTBP1.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21900206
  review:
    summary: PMID:21900206 is a directed protein interaction network study. Protein binding from HTP studies
      is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    supported_by:
    - reference_id: PMID:21900206
      supporting_text: A directed protein interaction network for investigating intracellular signal transduction.
    reason: High-throughput study; protein binding is too vague.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21903422
  review:
    summary: PMID:21903422 is a HTP mapping study of innate immunity protein interaction network. Protein
      binding is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    supported_by:
    - reference_id: PMID:21903422
      supporting_text: 2011 Sep 8. Mapping a dynamic innate immunity protein interaction network regulating
        type I interferon production.
    reason: High-throughput study; protein binding is too vague.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21988832
  review:
    summary: PMID:21988832 is a HTP protein interaction network study of human liver. Protein binding
      is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    supported_by:
    - reference_id: PMID:21988832
      supporting_text: Toward an understanding of the protein interaction network of the human liver.
    reason: High-throughput study; protein binding is too vague.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24722188
  review:
    summary: PMID:24722188 is a HTP isoform interaction network study from brain. Protein binding is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    supported_by:
    - reference_id: PMID:24722188
      supporting_text: Protein interaction network of alternatively spliced isoforms from brain links
        genetic risk factors for autism.
    reason: High-throughput study; protein binding is too vague.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24981860
  review:
    summary: PMID:24981860 identifies chromatin-related protein interactions including a demethylase complex.
      CTBP1 is known to associate with chromatin-modifying complexes (LSD1/CoREST). More specifically
      annotated as transcription coregulator binding.
    action: MODIFY
    supported_by:
    - reference_id: PMID:24981860
      supporting_text: 2014 Jun 26. Human-chromatin-related protein interactions identify a demethylase
        complex required for chromosome segregation.
    proposed_replacement_terms:
    - id: GO:0001221
      label: transcription coregulator binding
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26496610
  review:
    summary: PMID:26496610 is a large-scale quantitative interactome study. Protein binding is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    supported_by:
    - reference_id: PMID:26496610
      supporting_text: Oct 22. A human interactome in three quantitative dimensions organized by stoichiometries
        and abundances.
    reason: High-throughput study; protein binding is too vague.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26807646
  review:
    summary: PMID:26807646 is about EXD2 promoting homologous recombination. CTBP1 is not primarily a
      DNA repair protein. This likely reflects a HTP interaction.
    action: MARK_AS_OVER_ANNOTATED
    supported_by:
    - reference_id: PMID:26807646
      supporting_text: EXD2 promotes homologous recombination by facilitating DNA end resection.
    reason: Tangential interaction; protein binding is too vague.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:27705803
  review:
    summary: PMID:27705803 maps the Polycomb complexome. CTBP1 is known to interact with Polycomb proteins
      (CBX4/Pc2). More informative than generic protein binding.
    action: MODIFY
    supported_by:
    - reference_id: PMID:27705803
      supporting_text: A High-Density Map for Navigating the Human Polycomb Complexome.
    proposed_replacement_terms:
    - id: GO:0001221
      label: transcription coregulator binding
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  review:
    summary: PMID:28514442 is a large-scale interactome architecture study. Protein binding is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    supported_by:
    - reference_id: PMID:28514442
      supporting_text: Architecture of the human interactome defines protein communities and disease networks.
    reason: High-throughput study; protein binding is too vague.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28947780
  review:
    summary: PMID:28947780 shows ZNF516 suppresses EGFR by targeting the CtBP/LSD1/CoREST complex to chromatin.
      ZNF516 is a DNA-binding transcription factor recruiting the CTBP1 complex. Protein binding is too
      vague.
    action: MODIFY
    supported_by:
    - reference_id: PMID:28947780
      supporting_text: ZNF516 suppresses EGFR by targeting the CtBP/LSD1/CoREST complex to chromatin.
    proposed_replacement_terms:
    - id: GO:0140297
      label: DNA-binding transcription factor binding
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31041561
  review:
    summary: PMID:31041561 describes a pathogenic CtBP1 missense mutation affecting cofactor binding and
      transcriptional activity. The protein binding here likely refers to self-association and partner
      interactions. Given CtBP1 forms homodimers, identical protein binding is already annotated. Protein
      binding is too vague.
    action: MODIFY
    supported_by:
    - reference_id: PMID:31041561
      supporting_text: 2019 Apr 30. A pathogenic CtBP1 missense mutation causes altered cofactor binding
        and transcriptional activity.
    proposed_replacement_terms:
    - id: GO:0042802
      label: identical protein binding
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31515488
  review:
    summary: PMID:31515488 is a large-scale study of genetic variant effects on protein interactions.
      Protein binding is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    supported_by:
    - reference_id: PMID:31515488
      supporting_text: Extensive disruption of protein interactions by genetic variants across the allele
        frequency spectrum in human populations.
    reason: High-throughput study; protein binding is too vague.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  review:
    summary: PMID:33961781 is a large-scale proteome network study. Protein binding is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    supported_by:
    - reference_id: PMID:33961781
      supporting_text: 2021 May 6. Dual proteome-scale networks reveal cell-specific remodeling of the
        human interactome.
    reason: High-throughput study; protein binding is too vague.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35016035
  review:
    summary: PMID:35016035 is a large-scale study identifying transcriptional activators. Protein binding
      from HTP is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    supported_by:
    - reference_id: PMID:35016035
      supporting_text: 2022 Jan 10. Identification and functional characterization of transcriptional
        activators in human cells.
    reason: High-throughput study; protein binding is too vague.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35271311
  review:
    summary: PMID:35271311 is the OpenCell large-scale endogenous tagging study. Protein binding is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    supported_by:
    - reference_id: PMID:35271311
      supporting_text: '2022 Mar 11. OpenCell: Endogenous tagging for the cartography of human cellular
        organization.'
    reason: High-throughput study; protein binding is too vague.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:36414381
  review:
    summary: PMID:36414381 shows ZBTB18 inhibits lipid synthesis by halting CTBPs and LSD1 activity in
      glioblastoma. ZBTB18 is a DNA-binding transcription factor. Protein binding is too vague.
    action: MODIFY
    supported_by:
    - reference_id: PMID:36414381
      supporting_text: Print 2023 Jan. ZBTB18 inhibits SREBP-dependent lipid synthesis by halting CTBPs
        and LSD1 activity in glioblastoma.
    proposed_replacement_terms:
    - id: GO:0140297
      label: DNA-binding transcription factor binding
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40205054
  review:
    summary: PMID:40205054 is a large-scale multimodal cell map study. Protein binding is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    supported_by:
    - reference_id: PMID:40205054
      supporting_text: Apr 9. Multimodal cell maps as a foundation for structural and functional genomics.
    reason: High-throughput study; protein binding is too vague.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:7479821
  review:
    summary: PMID:7479821 is the original cloning paper showing CTBP1 interacts with adenovirus E1A C-terminal
      domain. This is a specific viral protein interaction. Protein binding is too vague for this well-characterized
      interaction.
    action: MODIFY
    supported_by:
    - reference_id: PMID:7479821
      supporting_text: Molecular cloning and characterization of a cellular phosphoprotein that interacts
        with a conserved C-terminal domain of adenovirus E1A involved in negative modulation of oncogenic
        transformation.
    reason: E1A is a viral transcriptional regulator. The CTBP1-E1A interaction via PXDLS motif is the
      founding interaction for this protein.
    proposed_replacement_terms:
    - id: GO:0140297
      label: DNA-binding transcription factor binding
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:9535825
  review:
    summary: PMID:9535825 describes the interaction between CTBP1 and a novel cellular protein (CtIP/RBBP8)
      disrupted by E1A through a PLDLS motif. This is a specific corepressor complex interaction.
    action: MODIFY
    supported_by:
    - reference_id: PMID:9535825
      supporting_text: Interaction between a cellular protein that binds to the C-terminal region of adenovirus
        E1A (CtBP) and a novel cellular protein is disrupted by E1A through a conserved PLDLS motif.
    reason: CtIP/RBBP8 participates in CtBP corepressor complexes.
    proposed_replacement_terms:
    - id: GO:0001221
      label: transcription coregulator binding
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:21988832
  review:
    summary: CTBP1 forms homodimers, which is critical for its corepressor function. NAD/NADH binding
      promotes dimerization. Identical protein binding is well supported by crystal structures and biochemical
      data (PMID:12419229).
    action: ACCEPT
    supported_by:
    - reference_id: PMID:12419229
      supporting_text: both a cofactor-dependent conformational change, with NAD(+) and NADH being equivalently
        effective, and the active site residues are linked to the binding of the PXDLS consensus recognition
        motif
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:24722188
  review:
    summary: CTBP1 homodimerization is well established. Duplicate evidence source is acceptable.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:24722188
      supporting_text: Protein interaction network of alternatively spliced isoforms from brain links
        genetic risk factors for autism.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:31041561
  review:
    summary: PMID:31041561 describes a pathogenic CTBP1 mutation affecting cofactor binding and transcriptional
      activity, which includes effects on self-association. Homodimerization is a core property.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:31041561
      supporting_text: 2019 Apr 30. A pathogenic CtBP1 missense mutation causes altered cofactor binding
        and transcriptional activity.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:31515488
  review:
    summary: Additional evidence for CTBP1 homodimerization from genetic variant disruption study. Homodimerization
      is well established.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:31515488
      supporting_text: Extensive disruption of protein interactions by genetic variants across the allele
        frequency spectrum in human populations.
- term:
    id: GO:0003682
    label: chromatin binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: CTBP1 associates with chromatin as part of its corepressor complexes containing HDAC1/2,
      LSD1, CoREST. While it does not bind DNA directly, it is recruited to chromatin by DNA-binding partners.
      IEA from Ensembl ortholog transfer is reasonable.
    action: ACCEPT
- term:
    id: GO:0017053
    label: transcription repressor complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: CTBP1 is a component of transcription repressor complexes. It assembles multi-protein corepressor
      complexes with HDAC1/2, LSD1/KDM1A, CoREST. IEA is consistent with IDA evidence from other annotations.
    action: ACCEPT
- term:
    id: GO:0045892
    label: negative regulation of DNA-templated transcription
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: CTBP1 negatively regulates transcription by assembling corepressor complexes. IEA is consistent
      with extensive experimental evidence including PMID:19162039, PMID:21102443, and PMID:16287852.
    action: ACCEPT
- term:
    id: GO:0048488
    label: synaptic vesicle endocytosis
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: CTBP1 has been reported to interact with presynaptic scaffold proteins (Bassoon) in neurons.
      Synaptic vesicle endocytosis is based on ortholog data. This is not the core function of CTBP1 but
      may reflect a specialized neuronal role.
    action: KEEP_AS_NON_CORE
    reason: Neuronal-specific function transferred from mouse ortholog. Not a core function of CTBP1.
- term:
    id: GO:0050872
    label: white fat cell differentiation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: CTBP1 interacts with PRDM16 to repress WAT-specific genes. UniProt notes it functions in
      BAT differentiation. This is a pleiotropic consequence of corepressor activity, not a core function.
    action: KEEP_AS_NON_CORE
    reason: Differentiation role is a downstream consequence of corepressor function.
- term:
    id: GO:0061629
    label: RNA polymerase II-specific DNA-binding transcription factor binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: CTBP1 binds RNA Pol II-specific transcription factors like ZEB1/2, KLFs, BCL6 via PXDLS motifs.
      This is a more specific child of GO:0140297. IEA from Ensembl is appropriate.
    action: ACCEPT
- term:
    id: GO:0097091
    label: synaptic vesicle clustering
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: CTBP1 has reported synaptic roles through Bassoon interaction. This is a specialized neuronal
      function, not the core function of CTBP1.
    action: KEEP_AS_NON_CORE
    reason: Neuronal-specific function. Not core to CTBP1.
- term:
    id: GO:0098831
    label: presynaptic active zone cytoplasmic component
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Based on ortholog evidence from mouse CTBP1 at presynaptic terminals via Bassoon interaction.
      Not a core localization for CTBP1.
    action: KEEP_AS_NON_CORE
    reason: Neuronal-specific localization. Not core.
- term:
    id: GO:0098978
    label: glutamatergic synapse
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Synaptic localization is a specialized neuronal function of CTBP1, not its core localization.
    action: KEEP_AS_NON_CORE
    reason: Neuronal-specific localization. Not core.
- term:
    id: GO:0098982
    label: GABA-ergic synapse
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Synaptic localization is a specialized neuronal function of CTBP1, not its core localization.
    action: KEEP_AS_NON_CORE
    reason: Neuronal-specific localization. Not core.
- term:
    id: GO:0106222
    label: lncRNA binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: lncRNA binding for CTBP1 is not well supported in the literature reviewed. This may come
      from ortholog evidence but lacks clear validation for human CTBP1.
    action: UNDECIDED
    reason: Insufficient evidence in the reviewed literature to confirm lncRNA binding as a function of
      CTBP1.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  review:
    summary: Nucleoplasm localization is well supported by immunofluorescence data (HPA). CTBP1 is predominantly
      nuclear in its corepressor function.
    action: ACCEPT
- term:
    id: GO:0016616
    label: oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor
  evidence_type: IDA
  original_reference_id: PMID:12419229
  review:
    summary: PMID:12419229 directly demonstrates CTBP1 dehydrogenase activity by biochemical and crystallographic
      methods. This is a core molecular function.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:12419229
      supporting_text: CtBP is a functional dehydrogenase. In addition, both a cofactor-dependent conformational
        change, with NAD(+) and NADH being equivalently effective, and the active site residues are linked
        to the binding of the PXDLS consensus recognition motif on repressors
- term:
    id: GO:0051287
    label: NAD binding
  evidence_type: IDA
  original_reference_id: PMID:12419229
  review:
    summary: PMID:12419229 provides crystal structure (1.95A) of CTBP1 in complex with NAD, directly demonstrating
      NAD binding. This is a core molecular function.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:12419229
      supporting_text: CtBP is an NAD(+)-regulated component of critical complexes for specific repression
        events in cells.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3108209
  review:
    summary: Nucleoplasm localization from Reactome SUMOylation pathway. CTBP1 is SUMOylated at Lys-428
      by CBX4 in the nucleus (PMID:12679040). Consistent with nuclear localization.
    action: ACCEPT
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3108203
  review:
    summary: Same as above. Nucleoplasm is the site of CTBP1 SUMOylation events. Consistent with established
      nuclear localization.
    action: ACCEPT
- term:
    id: GO:0140297
    label: DNA-binding transcription factor binding
  evidence_type: IPI
  original_reference_id: PMID:16609867
  review:
    summary: PMID:16609867 describes interaction of CTBP1 with FOXP1. UniProt confirms this interaction.
      FOXP1 is a DNA-binding transcription factor. Directly supports this annotation.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:16609867
      supporting_text: The FoxP subclass in Xenopus laevis development.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23707407
  review:
    summary: PMID:23707407 describes interaction between SIMC1 and CTBP1, where SIMC1 scaffolds CAPN3-mediated
      cleavage of CTBP1. This is a specific protein interaction but protein binding is too vague.
    action: MODIFY
    supported_by:
    - reference_id: PMID:23707407
      supporting_text: 2013 May 21. PLEIAD/SIMC1/C5orf25, a novel autolysis regulator for a skeletal-muscle-specific
        calpain, CAPN3, scaffolds a CAPN3 substrate, CTBP1.
    reason: SIMC1 interacts with CTBP1 through specific domains. UniProt confirms the interaction and
      identifies specific mutagenesis sites that disrupt it.
    proposed_replacement_terms:
    - id: GO:0019904
      label: protein domain specific binding
- term:
    id: GO:0001222
    label: transcription corepressor binding
  evidence_type: IPI
  original_reference_id: PMID:29628311
  review:
    summary: PMID:29628311 describes LCOR/LCORL family as vertebrate-specific Polycombs that interact
      with CTBP1. LCOR functions as a corepressor. This annotation correctly captures CTBP1 binding to
      a transcription corepressor.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:29628311
      supporting_text: A Family of Vertebrate-Specific Polycombs Encoded by the LCOR/LCORL Genes Balance
        PRC2 Subtype Activities.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25728771
  review:
    summary: PMID:25728771 describes MCRIP1 as an ERK substrate that competitively inhibits CtBP-ZEB1
      interaction via its PXDLS motif. This is a specific coregulator interaction. Protein binding is
      too vague.
    action: MODIFY
    supported_by:
    - reference_id: PMID:25728771
      supporting_text: Feb 26. MCRIP1, an ERK substrate, mediates ERK-induced gene silencing during epithelial-mesenchymal
        transition by regulating the co-repressor CtBP.
    reason: MCRIP1 regulates CTBP1 corepressor function through competitive binding.
    proposed_replacement_terms:
    - id: GO:0001221
      label: transcription coregulator binding
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:16702210
  review:
    summary: PMID:16702210 shows CTBP1 in the nucleus via its interaction with WIZ, which links G9a/GLP
      histone methyltransferases to CTBP1. Nuclear localization is well established.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:16702210
      supporting_text: Zinc finger protein Wiz links G9a/GLP histone methyltransferases to the co-repressor
        molecule CtBP.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16702210
  review:
    summary: PMID:16702210 demonstrates WIZ links G9a/GLP histone methyltransferases to CtBP. WIZ is a
      zinc finger protein functioning as a transcriptional coregulator. Protein binding is too vague.
    action: MODIFY
    supported_by:
    - reference_id: PMID:16702210
      supporting_text: 2006 May 15. Zinc finger protein Wiz links G9a/GLP histone methyltransferases to
        the co-repressor molecule CtBP.
    proposed_replacement_terms:
    - id: GO:0001221
      label: transcription coregulator binding
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3361751
  review:
    summary: Nucleoplasm localization from Reactome pathway Reactome:R-HSA-3361751. CTBP1 functions in
      the nucleoplasm as a transcriptional corepressor in Wnt signaling and other pathways.
    action: ACCEPT
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3364042
  review:
    summary: Nucleoplasm localization from Reactome pathway Reactome:R-HSA-3364042. CTBP1 functions in
      the nucleoplasm as a transcriptional corepressor in Wnt signaling and other pathways.
    action: ACCEPT
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5334050
  review:
    summary: Nucleoplasm localization from Reactome pathway Reactome:R-HSA-5334050. CTBP1 functions in
      the nucleoplasm as a transcriptional corepressor in Wnt signaling and other pathways.
    action: ACCEPT
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5334052
  review:
    summary: Nucleoplasm localization from Reactome pathway Reactome:R-HSA-5334052. CTBP1 functions in
      the nucleoplasm as a transcriptional corepressor in Wnt signaling and other pathways.
    action: ACCEPT
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9765973
  review:
    summary: Nucleoplasm localization from Reactome pathway Reactome:R-HSA-9765973. CTBP1 functions in
      the nucleoplasm as a transcriptional corepressor in Wnt signaling and other pathways.
    action: ACCEPT
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9765974
  review:
    summary: Nucleoplasm localization from Reactome pathway Reactome:R-HSA-9765974. CTBP1 functions in
      the nucleoplasm as a transcriptional corepressor in Wnt signaling and other pathways.
    action: ACCEPT
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9768477
  review:
    summary: Nucleoplasm localization from Reactome pathway Reactome:R-HSA-9768477. CTBP1 functions in
      the nucleoplasm as a transcriptional corepressor in Wnt signaling and other pathways.
    action: ACCEPT
- term:
    id: GO:0003714
    label: transcription corepressor activity
  evidence_type: IDA
  original_reference_id: PMID:19162039
  review:
    summary: PMID:19162039 directly demonstrates CTBP1 corepressor activity. HDGF represses SMYD1 gene
      transcription through interaction with CtBP. Over-expression of CtBP potentiated the trans-repressive
      activity of HDGF; knocking down CtBP attenuated the effect.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:19162039
      supporting_text: Over-expression of CtBP potentiated the trans-repressive activity of HDGF; on the
        other hand, knocking down CtBP attenuated the trans-repressive effect of HDGF.
- term:
    id: GO:0140297
    label: DNA-binding transcription factor binding
  evidence_type: IPI
  original_reference_id: PMID:19162039
  review:
    summary: PMID:19162039 demonstrates CTBP1 binding to HDGF via a non-canonical PXDLS motif (PKDLF).
      HDGF acts as a transcriptional repressor. Directly supports this annotation.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:19162039
      supporting_text: HDGF binds CtBP through a non-canonical binding motif (PKDLF) within the PWWP domain,
        as mutation of DL to AS abolished HDGF and CtBP interaction
- term:
    id: GO:0000122
    label: negative regulation of transcription by RNA polymerase II
  evidence_type: IMP
  original_reference_id: PMID:19162039
  review:
    summary: PMID:19162039 demonstrates CTBP1 participates in negative regulation of SMYD1 transcription.
      HDGF-CtBP complex represses SMYD1 promoter activity. IMP evidence is appropriate.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:19162039
      supporting_text: in G-7 myoblast cells, over-expression of a GFP-HDGF fusion specifically downregulated
        SMYD1 mRNA expression and the activity of the human SMYD1 promoter
- term:
    id: GO:0017053
    label: transcription repressor complex
  evidence_type: IDA
  original_reference_id: PMID:19162039
  review:
    summary: PMID:19162039 demonstrates CTBP1 forms a transcriptional complex with HDGF for gene repression.
      CTBP1 is a well-established component of transcription repressor complexes.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:19162039
      supporting_text: fluorescent microscopy showed that HDGF induced the nuclear accumulation of CtBP,
        suggesting that HDGF forms a transcriptional complex with CtBP
- term:
    id: GO:0019904
    label: protein domain specific binding
  evidence_type: IDA
  original_reference_id: PMID:19162039
  review:
    summary: PMID:19162039 demonstrates CTBP1 binds specifically to the PKDLF motif within the PWWP domain
      of HDGF. Mutation of this motif abolishes the interaction. This is protein domain specific binding.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:19162039
      supporting_text: HDGF binds CtBP through a non-canonical binding motif (PKDLF) within the PWWP domain,
        as mutation of DL to AS abolished HDGF and CtBP interaction
- term:
    id: GO:0003714
    label: transcription corepressor activity
  evidence_type: IDA
  original_reference_id: PMID:16287852
  review:
    summary: PMID:16287852 demonstrates CtBP corepressor activity in the context of Notch signaling. CtBP
      augments SHARP-mediated repression and is required for repression of Notch target gene Hey1.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:16287852
      supporting_text: Transcriptional repression of the Notch target gene Hey1 is abolished in CtBP-deficient
        cells or after the functional knockout of CtBP.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16287852
  review:
    summary: PMID:16287852 shows CTBP1 interaction with CtIP and SHARP within the RBP-Jkappa/SHARP corepressor
      complex. Protein binding is too vague for this specific corepressor complex interaction.
    action: MODIFY
    supported_by:
    - reference_id: PMID:16287852
      supporting_text: RBP-Jkappa/SHARP recruits CtIP/CtBP corepressors to silence Notch target genes.
    reason: CtIP and SHARP are corepressor complex components that interact with CTBP1.
    proposed_replacement_terms:
    - id: GO:0001221
      label: transcription coregulator binding
- term:
    id: GO:0017053
    label: transcription repressor complex
  evidence_type: IDA
  original_reference_id: PMID:16287852
  review:
    summary: PMID:16287852 directly demonstrates CTBP1 as a component of the RBP-Jkappa/SHARP-CtIP-CtBP
      corepressor complex that silences Notch target genes.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:16287852
      supporting_text: We identify the CtIP and CtBP corepressors as novel components of the human RBP-Jkappa/SHARP-corepressor
        complex
- term:
    id: GO:0000122
    label: negative regulation of transcription by RNA polymerase II
  evidence_type: IMP
  original_reference_id: PMID:21102443
  review:
    summary: PMID:21102443 directly demonstrates CTBP1 negatively regulates BRCA1 transcription. CtBP
      assembles at the BRCA1 promoter as part of a corepressor complex containing HDAC1. CtBP depletion
      increases BRCA1 expression.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:21102443
      supporting_text: Silencing of CtBP expression in MCF-7 cells results in a significant increase in
        both BRCA1 protein and BRCA1 RNA message (nascent and mature).
- term:
    id: GO:0051726
    label: regulation of cell cycle
  evidence_type: IMP
  original_reference_id: PMID:21102443
  review:
    summary: PMID:21102443 shows CtBP depletion induces a cell cycle block in G2 phase, mimicking BRCA1
      over-expression effects. This is a downstream consequence of CTBP1 corepressor activity on cell
      cycle regulators, not a direct cell cycle function.
    action: KEEP_AS_NON_CORE
    supported_by:
    - reference_id: PMID:21102443
      supporting_text: CtBP depletion also mimics the functional influences of BRCA1 over-expression 12
        by inducing a cell cycle block in G2 phase (Fig
    reason: Cell cycle regulation is an indirect consequence of CTBP1 transcriptional corepression of
      BRCA1 and other targets.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19505873
  review:
    summary: PMID:19505873 identifies CTBP1 in an AP-4 mediated transcriptional repression complex for
      HDM2. AP-4/TFAP4 is a DNA-binding transcription factor. Protein binding is too vague.
    action: MODIFY
    supported_by:
    - reference_id: PMID:19505873
      supporting_text: Epub 2009 Jun 7. Complementary quantitative proteomics reveals that transcription
        factor AP-4 mediates E-box-dependent complex formation for transcriptional repression of HDM2.
    proposed_replacement_terms:
    - id: GO:0140297
      label: DNA-binding transcription factor binding
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:11568182
  review:
    summary: PMID:11568182 describes CTBP1 interaction with MECOM/EVI1. MECOM is a DNA-binding transcription
      factor. Protein binding is too vague.
    action: MODIFY
    supported_by:
    - reference_id: PMID:11568182
      supporting_text: 2001 Sep 21. Interaction of EVI1 with cAMP-responsive element-binding protein-binding
        protein (CBP) and p300/CBP-associated factor (P/CAF) results in reversible acetylation of EVI1
        and in co-localization in nuclear speckles.
    proposed_replacement_terms:
    - id: GO:0140297
      label: DNA-binding transcription factor binding
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:15897867
  review:
    summary: PMID:15897867 shows oligomerization of Evi-1/MECOM regulated by the PR domain contributes
      to recruitment of corepressor CtBP. MECOM is a DNA-binding transcription factor. Protein binding
      is too vague.
    action: MODIFY
    supported_by:
    - reference_id: PMID:15897867
      supporting_text: Oligomerization of Evi-1 regulated by the PR domain contributes to recruitment
        of corepressor CtBP.
    proposed_replacement_terms:
    - id: GO:0140297
      label: DNA-binding transcription factor binding
- term:
    id: GO:0051287
    label: NAD binding
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: NAD binding is well established for CTBP1 by crystal structure and biochemistry (PMID:12419229).
      ISS annotation is consistent with IDA evidence.
    action: ACCEPT
- term:
    id: GO:0019904
    label: protein domain specific binding
  evidence_type: IPI
  original_reference_id: PMID:18374649
  review:
    summary: PMID:18374649 describes TBL1/TBLR1 phosphorylation overcoming dual CtBP and NCoR/SMRT repression
      checkpoints. CTBP1 recognizes PXDLS domains specifically, supporting protein domain specific binding.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:18374649
      supporting_text: TBL1 and TBLR1 phosphorylation on regulated gene promoters overcomes dual CtBP
        and NCoR/SMRT transcriptional repression checkpoints.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Nuclear localization is well established for CTBP1. ISS is consistent with IDA and IBA evidence.
    action: ACCEPT
- term:
    id: GO:0017053
    label: transcription repressor complex
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: CTBP1 is a well-established component of transcription repressor complexes. ISS is consistent
      with IDA evidence from multiple publications.
    action: ACCEPT
- term:
    id: GO:0045892
    label: negative regulation of DNA-templated transcription
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: CTBP1 negatively regulates DNA-templated transcription. ISS is consistent with extensive
      experimental evidence.
    action: ACCEPT
- term:
    id: GO:0050872
    label: white fat cell differentiation
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: CTBP1 interacts with PRDM16 to repress WAT-specific genes. UniProt confirms function in BAT
      differentiation. This is a pleiotropic consequence of corepressor activity.
    action: KEEP_AS_NON_CORE
    reason: WAT differentiation is a downstream consequence of CTBP1 corepressor function, not a core
      function.
- term:
    id: GO:0019079
    label: viral genome replication
  evidence_type: TAS
  original_reference_id: PMID:7479821
  review:
    summary: PMID:7479821 describes CTBP1 interaction with adenovirus E1A and suggests a role in adenovirus
      replication. However, CTBP1 is not directly involved in viral genome replication; rather, the E1A-CtBP
      interaction modulates transformation and indirectly affects replication. The annotation over-attributes
      a direct viral replication function.
    action: MARK_AS_OVER_ANNOTATED
    supported_by:
    - reference_id: PMID:7479821
      supporting_text: These results suggest that interaction of CtBP with the E1A proteins may play a
        critical role in adenovirus replication and oncogenic transformation.
    reason: CTBP1 does not directly participate in viral genome replication. The E1A interaction modulates
      cellular transcription. PMID:23747199 suggests the interaction potentiates viral replication but
      CTBP1 is a host transcriptional corepressor, not a replication factor.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: TAS
  original_reference_id: PMID:8440238
  review:
    summary: PMID:8440238 describes the interaction between CTBP1 and adenovirus E1A C-terminal domain.
      E1A is a viral transcriptional regulator. Protein binding is too vague.
    action: MODIFY
    supported_by:
    - reference_id: PMID:8440238
      supporting_text: A region in the C-terminus of adenovirus 2/5 E1a protein is required for association
        with a cellular phosphoprotein and important for the negative modulation of T24-ras mediated transformation,
        tumorigenesis and metastasis.
    proposed_replacement_terms:
    - id: GO:0140297
      label: DNA-binding transcription factor binding
- term:
    id: GO:0006468
    label: protein phosphorylation
  evidence_type: TAS
  original_reference_id: PMID:8440238
  review:
    summary: 'MISANNOTATION: CTBP1 is a transcriptional corepressor, NOT a kinase. PMID:8440238 explicitly
      describes CTBP1 as being phosphorylated: "CtBP is a phosphoprotein and the level of phosphorylation
      of CtBP appears to be regulated during the cell cycle". UniProt shows CTBP1 is "phosphorylated by
      HIPK2" at Ser-422. CTBP1 is a SUBSTRATE of kinases, not an enzyme that performs phosphorylation.'
    action: REMOVE
    supported_by:
    - reference_id: PMID:8440238
      supporting_text: A region in the C-terminus of adenovirus 2/5 E1a protein is required for association
        with a cellular phosphoprotein and important for the negative modulation of T24-ras mediated transformation,
        tumorigenesis and metastasis.
- term:
    id: GO:0008285
    label: negative regulation of cell population proliferation
  evidence_type: TAS
  original_reference_id: PMID:7479821
  review:
    summary: PMID:7479821 describes CTBP1 in the context of E1A-mediated modulation of oncogenic transformation.
      The paper does not directly demonstrate CTBP1 negatively regulates cell proliferation; rather, the
      E1A-CtBP interaction modulates transformation. This over-attributes a direct antiproliferative function
      to CTBP1.
    action: MARK_AS_OVER_ANNOTATED
    supported_by:
    - reference_id: PMID:7479821
      supporting_text: a region located between residues 225 and 238 of the 243R E1A protein negatively
        modulates in vitro T24 ras cooperative transformation as well as the tumorigenic potential of
        E1A/T24 ras-transformed cells
    reason: The negative regulation of proliferation is attributed to the E1A-CtBP interaction in the
      context of transformation, not to CTBP1 alone.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:12052894
  review:
    summary: PMID:12052894 demonstrates CTBP1 interaction with HIC1 through a degenerate GLDLSKK motif.
      HIC1 is a DNA-binding transcription factor/tumor suppressor. Protein binding is too vague.
    action: MODIFY
    supported_by:
    - reference_id: PMID:12052894
      supporting_text: The human candidate tumor suppressor gene HIC1 recruits CtBP through a degenerate
        GLDLSKK motif.
    proposed_replacement_terms:
    - id: GO:0140297
      label: DNA-binding transcription factor binding
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator
    judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000043
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping,
    accompanied by conservative changes to GO terms applied by UniProt
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl
    Compara
  findings: []
- id: GO_REF:0000108
  title: Automatic assignment of GO terms using logical inference, based on on inter-ontology links
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:10359772
  title: ZEB represses transcription through interaction with the corepressor CtBP.
  findings: []
- id: PMID:10995736
  title: The interaction of the carboxyl terminus-binding protein with the Smad corepressor TGIF is disrupted
    by a holoprosencephaly mutation in TGIF.
  findings: []
- id: PMID:11462050
  title: Physical and functional interactions between the corepressor CtBP and the Epstein-Barr virus
    nuclear antigen EBNA3C.
  findings: []
- id: PMID:11568182
  title: Interaction of EVI1 with cAMP-responsive element-binding protein-binding protein (CBP) and p300/CBP-associated
    factor (P/CAF) results in reversible acetylation of EVI1 and in co-localization in nuclear speckles.
  findings: []
- id: PMID:12052894
  title: The human candidate tumor suppressor gene HIC1 recruits CtBP through a degenerate GLDLSKK motif.
  findings: []
- id: PMID:12419229
  title: Transcription corepressor CtBP is an NAD(+)-regulated dehydrogenase.
  findings: []
- id: PMID:15897867
  title: Oligomerization of Evi-1 regulated by the PR domain contributes to recruitment of corepressor
    CtBP.
  findings: []
- id: PMID:16287852
  title: RBP-Jkappa/SHARP recruits CtIP/CtBP corepressors to silence Notch target genes.
  findings: []
- id: PMID:16609867
  title: The FoxP subclass in Xenopus laevis development.
  findings: []
- id: PMID:16702210
  title: Zinc finger protein Wiz links G9a/GLP histone methyltransferases to the co-repressor molecule
    CtBP.
  findings: []
- id: PMID:16762039
  title: A L225A substitution in the human tumour suppressor HIC1 abolishes its interaction with the corepressor
    CtBP.
  findings: []
- id: PMID:17085477
  title: ZNF366 is an estrogen receptor corepressor that acts through CtBP and histone deacetylases.
  findings: []
- id: PMID:18374649
  title: TBL1 and TBLR1 phosphorylation on regulated gene promoters overcomes dual CtBP and NCoR/SMRT
    transcriptional repression checkpoints.
  findings: []
- id: PMID:19162039
  title: Hepatoma-derived growth factor represses SET and MYND domain containing 1 gene expression through
    interaction with C-terminal binding protein.
  findings: []
- id: PMID:19486893
  title: HIC1 interacts with a specific subunit of SWI/SNF complexes, ARID1A/BAF250A.
  findings: []
- id: PMID:19505873
  title: Complementary quantitative proteomics reveals that transcription factor AP-4 mediates E-box-dependent
    complex formation for transcriptional repression of HDM2.
  findings: []
- id: PMID:19751731
  title: C-terminal binding proteins (CtBPs) attenuate KLF4-mediated transcriptional activation.
  findings: []
- id: PMID:20098713
  title: A role for non-covalent SUMO interaction motifs in Pc2/CBX4 E3 activity.
  findings: []
- id: PMID:20211142
  title: An atlas of combinatorial transcriptional regulation in mouse and man.
  findings: []
- id: PMID:21044950
  title: Genome-wide YFP fluorescence complementation screen identifies new regulators for telomere signaling
    in human cells.
  findings: []
- id: PMID:21102443
  title: Transcriptional regulation of BRCA1 expression by a metabolic switch.
  findings: []
- id: PMID:21900206
  title: A directed protein interaction network for investigating intracellular signal transduction.
  findings: []
- id: PMID:21903422
  title: Mapping a dynamic innate immunity protein interaction network regulating type I interferon production.
  findings: []
- id: PMID:21988832
  title: Toward an understanding of the protein interaction network of the human liver.
  findings: []
- id: PMID:23707407
  title: PLEIAD/SIMC1/C5orf25, a novel autolysis regulator for a skeletal-muscle-specific calpain, CAPN3,
    scaffolds a CAPN3 substrate, CTBP1.
  findings: []
- id: PMID:24722188
  title: Protein interaction network of alternatively spliced isoforms from brain links genetic risk factors
    for autism.
  findings: []
- id: PMID:24981860
  title: Human-chromatin-related protein interactions identify a demethylase complex required for chromosome
    segregation.
  findings: []
- id: PMID:25728771
  title: MCRIP1, an ERK substrate, mediates ERK-induced gene silencing during epithelial-mesenchymal transition
    by regulating the co-repressor CtBP.
  findings: []
- id: PMID:26496610
  title: A human interactome in three quantitative dimensions organized by stoichiometries and abundances.
  findings: []
- id: PMID:26807646
  title: EXD2 promotes homologous recombination by facilitating DNA end resection.
  findings: []
- id: PMID:27705803
  title: A High-Density Map for Navigating the Human Polycomb Complexome.
  findings: []
- id: PMID:28514442
  title: Architecture of the human interactome defines protein communities and disease networks.
  findings: []
- id: PMID:28947780
  title: ZNF516 suppresses EGFR by targeting the CtBP/LSD1/CoREST complex to chromatin.
  findings: []
- id: PMID:29628311
  title: A Family of Vertebrate-Specific Polycombs Encoded by the LCOR/LCORL Genes Balance PRC2 Subtype
    Activities.
  findings: []
- id: PMID:31041561
  title: A pathogenic CtBP1 missense mutation causes altered cofactor binding and transcriptional activity.
  findings: []
- id: PMID:31515488
  title: Extensive disruption of protein interactions by genetic variants across the allele frequency
    spectrum in human populations.
  findings: []
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
  findings: []
- id: PMID:35016035
  title: Identification and functional characterization of transcriptional activators in human cells.
  findings: []
- id: PMID:35271311
  title: 'OpenCell: Endogenous tagging for the cartography of human cellular organization.'
  findings: []
- id: PMID:36414381
  title: ZBTB18 inhibits SREBP-dependent lipid synthesis by halting CTBPs and LSD1 activity in glioblastoma.
  findings: []
- id: PMID:40205054
  title: Multimodal cell maps as a foundation for structural and functional genomics.
  findings: []
- id: PMID:7479821
  title: Molecular cloning and characterization of a cellular phosphoprotein that interacts with a conserved
    C-terminal domain of adenovirus E1A involved in negative modulation of oncogenic transformation.
  findings: []
- id: PMID:8440238
  title: A region in the C-terminus of adenovirus 2/5 E1a protein is required for association with a cellular
    phosphoprotein and important for the negative modulation of T24-ras mediated transformation, tumorigenesis
    and metastasis.
  findings: []
- id: PMID:9535825
  title: Interaction between a cellular protein that binds to the C-terminal region of adenovirus E1A
    (CtBP) and a novel cellular protein is disrupted by E1A through a conserved PLDLS motif.
  findings: []
- id: Reactome:R-HSA-3108203
  title: PRC1 SUMOylates CTBP1 with SUMO2,3
  findings: []
- id: Reactome:R-HSA-3108209
  title: PRC1 SUMOylates CTBP1 with SUMO1
  findings: []
- id: Reactome:R-HSA-3361751
  title: beta-catenin is replaced by repression complexes at the promoter
  findings: []
- id: Reactome:R-HSA-3364042
  title: APC promotes disassembly of beta-catenin transactivation complex
  findings: []
- id: Reactome:R-HSA-5334050
  title: TCF7L2/TCF7L1 bind CTBP1 to repress WNT target genes
  findings: []
- id: Reactome:R-HSA-5334052
  title: TFC7L2 mutants don't bind CTBP
  findings: []
- id: Reactome:R-HSA-9765973
  title: CTBP1,CTBP2 binds ZEB1
  findings: []
- id: Reactome:R-HSA-9765974
  title: MCRIP1 binds CTBP1
  findings: []
- id: Reactome:R-HSA-9768477
  title: CTBP1,CTBP2 binds CDH1 gene promoter
  findings: []
core_functions:
- description: CTBP1 functions primarily as a transcriptional corepressor, recruited to target genes by
    DNA-binding transcription factors via PXDLS motifs. It scaffolds chromatin-modifying complexes containing
    HDAC1/2, LSD1/KDM1A, and RCOR1/CoREST.
  molecular_function:
    id: GO:0003714
    label: transcription corepressor activity
- description: CTBP1 binds diverse DNA-binding transcription factors (ZEB1/2, KLFs, BCL6, MECOM, HIC1,
    FOXP1, ZNF366, ZNF516) through recognition of PXDLS/PLDLS short linear motifs.
  molecular_function:
    id: GO:0140297
    label: DNA-binding transcription factor binding
- description: CTBP1 binds NAD+/NADH via its Rossmann fold domain. NADH binding allosterically promotes
    dimerization and corepressor complex assembly, making CTBP1 a metabolic/redox sensor.
  molecular_function:
    id: GO:0051287
    label: NAD binding
- description: CTBP1 is a functional D-2-hydroxyacid dehydrogenase, though the primary biological role
    centers on its corepressor/scaffolding function rather than catalytic activity.
  molecular_function:
    id: GO:0016616
    label: oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor

CTBP1

Gene Description

Existing Annotations Review

Core Functions

CTBP1 functions primarily as a transcriptional corepressor, recruited to target genes by DNA-binding transcription factors via PXDLS motifs. It scaffolds chromatin-modifying complexes containing HDAC1/2, LSD1/KDM1A, and RCOR1/CoREST.

CTBP1 binds diverse DNA-binding transcription factors (ZEB1/2, KLFs, BCL6, MECOM, HIC1, FOXP1, ZNF366, ZNF516) through recognition of PXDLS/PLDLS short linear motifs.

CTBP1 binds NAD+/NADH via its Rossmann fold domain. NADH binding allosterically promotes dimerization and corepressor complex assembly, making CTBP1 a metabolic/redox sensor.

CTBP1 is a functional D-2-hydroxyacid dehydrogenase, though the primary biological role centers on its corepressor/scaffolding function rather than catalytic activity.

References

📚 Additional Documentation

Deep Research Falcon

Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

MANDATORY VERIFICATION STEPS:

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Output

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

MANDATORY VERIFICATION STEPS:

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Comprehensive Research Report: Human CTBP1 (UniProt Q13363) – Functional Annotation

0. Target verification (mandatory)

1. Key concepts and definitions (current understanding)

1.1 What CtBP1 is

1.2 How CtBP1 represses transcription

1.3 A “metabolic sensor” corepressor

1.4 Enzyme-like domain: what is (and isn’t) established

2. Molecular functions, partners, pathways, and localization (evidence-based)

2.1 Interaction logic: PXDLS recruitment plus non-PXDLS partner binding

2.2 Representative complex components and interactors

2.3 Subcellular localization: nucleus ↔ cytoplasm/Golgi and specialized roles

2.4 Pathways and biological processes most directly supported by this evidence set

3. Recent developments (prioritizing 2023–2024)

3.1 2024 structural/mechanistic breakthrough: RAI2-driven CtBP polymerization inactivates corepressor function

3.2 2024 post-translational regulation: CtBP1 ISGylation increases partner affinity and repression potency

3.3 2024 translational inhibitor development: targeting CtBP1/BARS Rossmann fold with “Comp.11”

4. Current applications and real-world implementations

4.1 Preclinical oncology targeting

4.2 Biomarker/clinical stratification concepts

4.3 Virus–cancer interface (emerging application area)

5. Expert opinions/authoritative analysis (as expressed in reviews and mechanistic papers)

5.1 CtBP1 as an actionable hub: why experts consider it druggable

5.2 Regulatory layers beyond NADH: polymerization and ISGylation

6. Statistics and data highlights from recent studies

7. Evidence gaps and interpretation boundaries

Key 2024 sources (URLs and publication dates)

Citations

📄 View Raw YAML