{"gene":"CCAR1","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":2008,"finding":"CCAR1 is required for Mediator complex recruitment to nuclear receptor (NR) target gene promoters; CCAR1 associates with components of both the Mediator and p160 coactivator complexes, is recruited to endogenous NR target genes in response to hormone, and its depletion blocks hormone-induced recruitment of Mediator subunits and RNA polymerase II to target promoters.","method":"Co-immunoprecipitation, chromatin immunoprecipitation (ChIP), siRNA knockdown with gene expression and cell growth readouts","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, ChIP at endogenous loci, and KD with multiple orthogonal readouts in a single focused study","pmids":["18722177"],"is_preprint":false},{"year":2008,"finding":"CCAR1 also functions as a p53 coactivator, suggesting a broader role in transcriptional regulation beyond nuclear receptors.","method":"Functional reporter assays and co-immunoprecipitation","journal":"Molecular cell","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — single lab, functional reporter assay with limited mechanistic detail in the abstract","pmids":["18722177"],"is_preprint":false},{"year":2008,"finding":"CCAR1 localizes to cytosolic RNA stress granules in an arsenite-dependent manner together with AKAP350A and caprin-1; this co-localization requires intact microtubules (disrupted by nocodazole). Reduction of CCAR1 expression alters the size and number of G3BP-containing stress granules.","method":"Co-immunoprecipitation, immunofluorescence/live-cell imaging, nocodazole microtubule disruption, siRNA knockdown","journal":"Experimental cell research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP identifying interacting partners, direct localization by imaging, functional KD with morphological phenotype, single lab with multiple orthogonal methods","pmids":["19073175"],"is_preprint":false},{"year":2010,"finding":"CCAR1 (CARP-1) is a nuclear protein that binds the LIM domain region of zyxin; this interaction is required for zyxin's pro-apoptotic activity upon UV-C irradiation. Zyxin lacking the CCAR1-binding region shows reduced proapoptotic activity.","method":"Affinity pulldown, microsequence analysis, co-immunoprecipitation, domain-deletion mutants, UV-C apoptosis assay","journal":"Genes & cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pulldown with protein ID, domain-deletion functional test, single lab","pmids":["20852740"],"is_preprint":false},{"year":2011,"finding":"CCAR1 (CARP-1) physically binds APC/C subunit APC-2 as well as APC/C co-activators Cdc20 and Cdh1, as identified by yeast two-hybrid screening. The CARP-1/APC-2 interaction has a Kd of ~480 nM measured by fluorescence polarization assay. Small molecule antagonists of this interaction (CFMs) induce G2/M arrest and apoptosis in a CARP-1-dependent manner.","method":"Yeast two-hybrid, fluorescence polarization assay (Kd measurement), epitope mapping, small-molecule antagonist with KD rescue","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — yeast two-hybrid, in vitro binding assay with Kd, domain mapping, and functional rescue by KD; single lab but multiple orthogonal methods","pmids":["21903591"],"is_preprint":false},{"year":2012,"finding":"Necdin interacts with CCAR1 (identified by two-hybrid screening) and promotes CCAR1 ubiquitination and proteasomal degradation, thereby counteracting CCAR1-mediated apoptosis to support myoblast survival.","method":"Yeast two-hybrid, co-immunoprecipitation, ubiquitination assay, proteasome inhibitor experiments, siRNA knockdown","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid plus Co-IP plus ubiquitination assay, single lab","pmids":["22905258"],"is_preprint":false},{"year":2012,"finding":"CCAR1 physically interacts with the transcription factor Ngn3 and is essential for Ngn3-dependent activation of the NeuroD promoter and Ngn3-induced endocrine transdifferentiation of pancreatic ductal cells.","method":"Pulldown assay, co-immunoprecipitation, gene reporter assay, siRNA knockdown of endogenous CCAR1","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP/pulldown plus functional reporter plus KD phenotype, single lab","pmids":["22266316"],"is_preprint":false},{"year":2013,"finding":"Par-4 and THAP1 form a protein complex via their carboxyl termini; THAP1 binds the CCAR1 promoter through its zinc-dependent DNA-binding domain; the Par-4/THAP1 complex activates CCAR1 gene expression and antagonizes Notch3-induced alternative splicing of CCAR1 pre-mRNA (which shifts it toward a shorter, survival-promoting isoform via splicing factors SRp40/SRp55).","method":"Co-immunoprecipitation, promoter reporter assays, ChIP, siRNA, alternative splicing analysis","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for complex, ChIP for promoter occupancy, splicing assay; single lab with multiple methods","pmids":["23975424"],"is_preprint":false},{"year":2013,"finding":"CCAR1 acts as a coactivator for the androgen receptor (AR) by stabilizing the interaction between AR and pioneer factor GATA2; CCAR1 directly interacts with both AR and GATA2, facilitating their occupancy at AR-binding enhancers, long-range enhancer–promoter looping, and recruitment of MED1 and RNA polymerase II.","method":"Co-immunoprecipitation, ChIP, siRNA knockdown, chromatin conformation capture (3C), in vivo xenograft","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, ChIP at endogenous loci, 3C looping, KD with gene expression and in vivo phenotype; single lab but multiple orthogonal methods","pmids":["23887938"],"is_preprint":false},{"year":2013,"finding":"CCAR1 and CoCoA form a complex with GATA1 and MED1(1-602); reconstituted in vitro complex of recombinant GATA1, CCAR1, CoCoA, and MED1(1-602) was demonstrated, and CCAR1/CoCoA synergistically enhanced GATA1-mediated transcription from the γ-globin promoter.","method":"In vitro complex reconstitution with recombinant proteins, co-immunoprecipitation, reporter gene assay, ChIP in K562 cells","journal":"Genes to cells","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with recombinant proteins plus ChIP plus reporter assays; single lab with multiple orthogonal methods","pmids":["24245781"],"is_preprint":false},{"year":2014,"finding":"CCAR1 is recruited by glucocorticoid receptor (GR) to PPARγ gene glucocorticoid response elements, is required for GR occupancy and chromatin remodeling at specific PPARγ GBRs, and depletion of CCAR1 markedly suppresses adipogenic differentiation with reduced PPARγ, C/EBPα, and C/EBPδ induction.","method":"ChIP, siRNA knockdown, adipocyte differentiation assay, Western blotting","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP at endogenous loci, KD with defined cellular differentiation phenotype, multiple target genes; single lab but multiple orthogonal methods with rigorous controls","pmids":["24811171"],"is_preprint":false},{"year":2010,"finding":"CCAR1 (CARP-1) overexpression inhibits FAK (focal adhesion kinase) Y397 autophosphorylation in breast cancer cells, establishing CCAR1 as a negative regulator of FAK activity.","method":"Western blot of pFAK-397 in stable CCAR1-overexpressing cells","journal":"American journal of surgery","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single method (western blot), single lab, no mechanistic follow-up","pmids":["17071197"],"is_preprint":false},{"year":2010,"finding":"CCAR1 binds TAZ through amino acids 651–759 of CCAR1; threonine-667 phosphorylation is required for this interaction and for H89-induced apoptosis; CCAR1 overexpression suppresses c-myc transcription.","method":"Co-immunoprecipitation, domain-deletion and point-mutant (T667A) analysis, luciferase reporter assay, siRNA","journal":"Journal of molecular signaling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, point mutagenesis, reporter assay; single lab","pmids":["20594350"],"is_preprint":false},{"year":2018,"finding":"CCAR1 functions as an enhancer-dependent coactivator for the constitutive androstane receptor (CAR), specifically at the gtPBREM enhancer of UGT1A1 but not the PBREM enhancer of CYP2B6; CCAR1 is recruited to the gtPBREM by CAR and cooperates with p160 SRC coactivators.","method":"Co-immunoprecipitation with FLAG-CAR, reporter gene assays, siRNA knockdown, ChIP","journal":"Molecular pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ChIP, reporter assay, KD; single lab with multiple orthogonal methods","pmids":["30397001"],"is_preprint":false},{"year":2019,"finding":"CCAR1 (CARP-1) directly binds H2AX; the interaction requires CCAR1 amino acids 636–650 and H2AX residues 1–35. Surface plasmon resonance measured a Kd of 127 nM for CARP-1(636–650)/H2AX(1–35) peptide binding. CCAR1–H2AX interaction is required for γH2AX accumulation and apoptosis signaling following Adriamycin or CFM-4.16 treatment; deletion of the H2AX-binding epitope abolishes apoptosis.","method":"Co-immunoprecipitation, domain-deletion and mutagenesis, surface plasmon resonance (in vitro Kd), siRNA knockdown, EGFP-tagged peptide competition","journal":"Cancers","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro SPR binding (Kd), domain mapping by mutagenesis, Co-IP, functional KD; single lab with multiple orthogonal methods","pmids":["30769864"],"is_preprint":false},{"year":2020,"finding":"CCAR1 (CARP-1) directly binds the NF-κB essential modulator NEMO/IKKγ and regulates the chemotherapy (adriamycin)-activated canonical NF-κB pathway; blockade of NEMO–CCAR1 binding selectively diminishes adriamycin-induced p65 phosphorylation but not TNFα- or IL-1β-induced NF-κB activation.","method":"Direct binding assay, co-immunoprecipitation, high-throughput small-molecule screen, siRNA, in vivo xenograft","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct binding, Co-IP, pharmacological blockade with selective readouts, in vivo validation; single lab but multiple orthogonal methods","pmids":["32024692"],"is_preprint":false},{"year":2021,"finding":"KDM4B physically interacts with CCAR1 and MED1 in a trimeric complex; the KDM4B–CCAR1–MED1 complex localizes to promoters of osteoclast-related genes upon RANKL stimulation, induces H3K9 demethylation (euchromatinization) at those promoters, and enables NF-κB p65 recruitment via direct KDM4B–p65 interaction to drive osteoclastogenesis.","method":"Co-immunoprecipitation, genome-wide ChIP-sequencing, conditional KO mouse model (osteopetrotic phenotype), biochemical analysis","journal":"Bone research","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP for complex, ChIP-seq for genome-wide occupancy, KO mouse with defined bone phenotype; single lab but multiple orthogonal methods","pmids":["34031372"],"is_preprint":false},{"year":2022,"finding":"DCLK1 kinase interacts with CCAR1 via its C-terminal domain and phosphorylates CCAR1 at Ser343, which is required for CCAR1 protein stabilization; DCLK1-stabilized CCAR1 positively regulates β-catenin signaling and maintains cancer stemness.","method":"Co-immunoprecipitation, in vitro/cellular phosphorylation assay with site-specific mutagenesis (Ser343), siRNA knockdown, in vivo xenograft","journal":"Clinical and translational medicine","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — Co-IP, phosphorylation site mutagenesis, KD with functional rescue, in vivo validation; single lab with multiple orthogonal methods","pmids":["35522902"],"is_preprint":false},{"year":2024,"finding":"CCAR1 is required for correct splicing of FANCA pre-mRNA: loss of CCAR1 causes inclusion of a poison exon in FANCA transcript, reducing FANCA protein expression without reducing FANCA mRNA levels. The EF-hand domain of CCAR1 interacts with the U2AF heterodimer of the spliceosome and is required for poison exon excision. Transcriptome-wide analysis shows CCAR1 regulates widespread alternative splicing across many genes.","method":"CRISPR inhibition and Cas9-editing genome-wide screen (~18,000 knockdowns), co-immunoprecipitation (CCAR1 with FANCA pre-mRNA and U2AF heterodimer), RNA-seq/transcriptomic analysis, domain-deletion mutants","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — genome-wide functional screen, Co-IP with spliceosome components, domain mutagenesis, transcriptome-wide splicing analysis; replicated independently by two concurrent papers (PMIDs 38964321 and 39025073)","pmids":["38964321","39025073"],"is_preprint":false},{"year":2013,"finding":"PTH treatment of osteoblasts causes nuclear-to-cytoplasmic translocation of CCAR1 protein and down-regulates its expression via PKA- and PKC-dependent, ERK-independent but p38-dependent signaling.","method":"Immunofluorescence staining, Western blot, kinase inhibitors (H-89, GF109203X, SB203580, U0126), primary osteoblast culture","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization by immunofluorescence linked to signaling pathway dissection; single lab, multiple pharmacological inhibitors","pmids":["23764399"],"is_preprint":false},{"year":2024,"finding":"CCAR1 co-immunoprecipitates with FANCA pre-mRNA and its EF-hand domain is required for interaction with the U2AF heterodimer of the spliceosome; CCAR1 loss results in FANCA poison exon retention and impairs both HDR and interstrand crosslink/Fanconi anemia pathway repair.","method":"Co-immunoprecipitation with pre-mRNA and spliceosome components, domain-deletion analysis, RNA-seq, DNA repair assays (HDR, ICL)","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — two independent studies with Co-IP, domain mapping, RNA-seq, and functional DNA repair assays","pmids":["39025073","38964321"],"is_preprint":false},{"year":2015,"finding":"CFM-4 and related CARP-1 functional mimetics bind CCAR1, stimulate CCAR1 expression, and elevate CCAR1-DEDD2 interaction; apoptosis signaling by CFMs involves activation of stress-activated kinases p38 and JNK1/2, caspase cleavage, and loss of cyclin B1, and is abrogated by CCAR1 depletion.","method":"Co-immunoprecipitation (CCAR1–DEDD2), siRNA knockdown rescue, Western blotting, in vivo xenograft","journal":"Journal of biomedical nanotechnology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP of novel partner, KD rescue of pharmacological phenotype, in vivo validation; single lab","pmids":["26485930"],"is_preprint":false},{"year":2025,"finding":"In mouse ESCs under R2i conditions, Ccar1 knockdown promotes nuclear translocation of β-catenin and upregulates Wnt target genes, indicating that Ccar1 restricts β-catenin nuclear entry to maintain ground-state pluripotency.","method":"siRNA knockdown, immunofluorescence for β-catenin localization, qRT-PCR for Wnt target genes","journal":"Biochemistry and biophysics reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, indirect localization readout, no direct binding demonstrated (paper notes further interaction assays are needed)","pmids":["40978202"],"is_preprint":false}],"current_model":"CCAR1 is a multifunctional perinuclear/nuclear phosphoprotein that acts as a transcriptional coactivator bridging nuclear receptors (ER, AR, GR, CAR), p53, GATA1, and Ngn3 to the Mediator complex; it regulates alternative splicing genome-wide by interacting with the U2AF spliceosome heterodimer via its EF-hand domain—most critically preventing poison-exon inclusion in FANCA mRNA to support Fanconi anemia/BRCA DNA repair; it also modulates apoptosis through direct interactions with H2AX, NEMO/IKKγ, zyxin, TAZ, and APC/C subunit APC-2, and its protein stability is regulated by DCLK1 phosphorylation (Ser343) and necdin-mediated ubiquitin–proteasome degradation."},"narrative":{"mechanistic_narrative":"CCAR1 is a multifunctional nuclear protein that operates as a transcriptional coactivator bridging sequence-specific factors to the Mediator complex and as a regulator of pre-mRNA splicing and apoptotic signaling [PMID:18722177, PMID:38964321, PMID:39025073]. As a coactivator it is required for hormone-dependent recruitment of Mediator subunits and RNA polymerase II to nuclear receptor target promoters, associating with both Mediator and p160 coactivator complexes [PMID:18722177]; this activity extends across diverse DNA-binding factors, including the androgen receptor (where CCAR1 stabilizes the AR–GATA2 interaction and enables enhancer–promoter looping and MED1/RNA Pol II recruitment) [PMID:23887938], the glucocorticoid receptor at PPARγ response elements during adipogenesis [PMID:24811171], the constitutive androstane receptor at the UGT1A1 gtPBREM enhancer [PMID:30397001], GATA1 (in a reconstituted complex with CoCoA and MED1 driving γ-globin transcription) [PMID:24245781], and Ngn3 during endocrine transdifferentiation [PMID:22266316]. CCAR1 also forms a trimeric complex with KDM4B and MED1 that demethylates H3K9 at osteoclast gene promoters to license NF-κB p65 recruitment during osteoclastogenesis [PMID:34031372]. Independently of transcription, CCAR1 controls genome-wide alternative splicing: its EF-hand domain binds the U2AF spliceosome heterodimer to excise a poison exon from FANCA pre-mRNA, sustaining FANCA protein and thereby supporting homology-directed and Fanconi anemia/interstrand-crosslink DNA repair [PMID:38964321, PMID:39025073]. In apoptotic signaling CCAR1 binds H2AX to drive γH2AX accumulation [PMID:30769864], engages NEMO/IKKγ to selectively regulate chemotherapy-activated canonical NF-κB signaling [PMID:32024692], binds zyxin to enable UV-C-induced apoptosis [PMID:20852740], and interacts with APC/C subunit APC-2 [PMID:21903591]. CCAR1 protein levels and activity are set post-translationally by DCLK1-mediated Ser343 phosphorylation, which stabilizes CCAR1 and promotes β-catenin signaling and cancer stemness [PMID:35522902], and by necdin-driven ubiquitin–proteasome degradation [PMID:22905258].","teleology":[{"year":2008,"claim":"Established CCAR1's core molecular role by showing it is the link required to recruit Mediator and RNA Pol II to hormone-activated nuclear receptor promoters, defining it as a bona fide coactivator rather than a generic associated factor.","evidence":"Reciprocal Co-IP, ChIP at endogenous NR target genes, and siRNA knockdown with expression/growth readouts; the same study also showed p53 coactivation by reporter assay","pmids":["18722177"],"confidence":"High","gaps":["Did not define which CCAR1 domain contacts Mediator versus the p160 complex","p53 coactivation rested on reporter assays without endogenous-locus confirmation"]},{"year":2008,"claim":"Revealed an unexpected cytoplasmic role by localizing CCAR1 to arsenite-induced stress granules, indicating functions beyond chromatin.","evidence":"Co-IP with AKAP350A/caprin-1, immunofluorescence/live imaging with nocodazole microtubule disruption, and siRNA altering G3BP granule size/number","pmids":["19073175"],"confidence":"High","gaps":["Functional consequence of CCAR1 in granules for mRNA fate unresolved","Relationship between granule localization and nuclear coactivator role unknown"]},{"year":2010,"claim":"Connected CCAR1 to pro-apoptotic and signaling control by mapping interactions with zyxin and TAZ and a phospho-dependent (T667) binding requirement.","evidence":"Affinity pulldown/microsequencing and domain-deletion UV-C apoptosis assays for zyxin; Co-IP, T667A mutagenesis and reporter assays for TAZ; western blot of pFAK-Y397 in overexpressing cells","pmids":["20852740","20594350","17071197"],"confidence":"Medium","gaps":["FAK regulation shown by single-method western blot only (Low confidence)","Kinase responsible for T667 phosphorylation not identified","How these interactions integrate with the nuclear coactivator function unclear"]},{"year":2011,"claim":"Provided quantitative biochemistry tying CCAR1 to cell-cycle machinery by demonstrating direct APC-2 binding and druggability of the interface.","evidence":"Yeast two-hybrid, fluorescence polarization (Kd ~480 nM), epitope mapping, and CFM small-molecule antagonists inducing CARP-1-dependent G2/M arrest and apoptosis","pmids":["21903591"],"confidence":"High","gaps":["Whether CCAR1 modulates APC/C ubiquitin ligase activity directly not shown","Functional role of Cdc20/Cdh1 binding not dissected"]},{"year":2012,"claim":"Defined how CCAR1 abundance is controlled and broadened its transcription-factor partner repertoire to Ngn3.","evidence":"Yeast two-hybrid, Co-IP, ubiquitination and proteasome-inhibitor assays for necdin-driven degradation; pulldown, Co-IP, reporter and KD assays for Ngn3-dependent NeuroD activation and transdifferentiation","pmids":["22905258","22266316"],"confidence":"Medium","gaps":["E3 ligase mediating necdin-dependent CCAR1 ubiquitination not identified","Whether Ngn3 coactivation uses the same Mediator-bridging mechanism as nuclear receptors untested"]},{"year":2013,"claim":"Mechanistically detailed CCAR1's coactivator action at the chromatin level for AR and GATA1, including enhancer looping and in vitro complex reconstitution.","evidence":"Co-IP, ChIP, 3C looping, KD and xenograft for AR/GATA2/MED1; recombinant reconstitution of GATA1–CCAR1–CoCoA–MED1(1-602) plus ChIP/reporter in K562 cells; separately, Par-4/THAP1 control of CCAR1 transcription and isoform choice, and PTH-driven nuclear-to-cytoplasmic CCAR1 translocation","pmids":["23887938","24245781","23975424","23764399"],"confidence":"High","gaps":["Stoichiometry and structure of the GATA1–CCAR1–CoCoA–MED1 assembly unresolved","Functional difference between CCAR1 splice isoforms not characterized at protein level","Signal triggering PTH-induced relocalization downstream of p38 unknown"]},{"year":2014,"claim":"Extended CCAR1 coactivation to GR-driven adipogenesis, linking it to chromatin remodeling at specific glucocorticoid response elements.","evidence":"ChIP, siRNA, adipocyte differentiation assays and western blotting at PPARγ GBRs","pmids":["24811171"],"confidence":"High","gaps":["Chromatin-remodeling complex recruited by CCAR1 not identified","Basis for GBR selectivity unexplained"]},{"year":2019,"claim":"Resolved a direct apoptotic effector mechanism by mapping a high-affinity CCAR1–H2AX interface required for γH2AX accumulation.","evidence":"Co-IP, domain/peptide mapping, surface plasmon resonance (Kd 127 nM), siRNA, and EGFP-peptide competition in chemotherapy/CFM apoptosis assays","pmids":["30769864"],"confidence":"High","gaps":["Whether CCAR1 promotes H2AX phosphorylation directly or via recruiting a kinase unknown","Nuclear-coactivator versus DNA-damage roles not reconciled"]},{"year":2020,"claim":"Showed stimulus-selective control of NF-κB by CCAR1 through direct NEMO binding, restricting its effect to chemotherapy-activated signaling.","evidence":"Direct binding and Co-IP, HTS small-molecule blockade with selective p65-phosphorylation readouts, siRNA, and xenograft","pmids":["32024692"],"confidence":"High","gaps":["Why TNFα/IL-1β-driven NF-κB is spared mechanistically unexplained","Structural basis of NEMO–CCAR1 contact not determined"]},{"year":2021,"claim":"Placed CCAR1 in a chromatin-modifying coactivator complex with KDM4B and MED1 that couples histone demethylation to NF-κB recruitment in osteoclastogenesis.","evidence":"Co-IP, genome-wide ChIP-seq, and conditional KO mouse with osteopetrotic phenotype","pmids":["34031372"],"confidence":"High","gaps":["Whether CCAR1 contributes catalytic versus scaffolding function in the complex unclear","Direct CCAR1–p65 contact not established"]},{"year":2022,"claim":"Identified an upstream kinase, DCLK1, whose Ser343 phosphorylation stabilizes CCAR1 and links it to β-catenin-driven cancer stemness.","evidence":"Co-IP, phosphorylation assay with Ser343 mutagenesis, siRNA rescue, and xenograft","pmids":["35522902"],"confidence":"High","gaps":["Mechanism by which Ser343 phosphorylation prevents degradation unclear","Direct versus indirect CCAR1 effect on β-catenin not resolved"]},{"year":2024,"claim":"Established a wholly distinct, RNA-level function: CCAR1 is a splicing regulator whose EF-hand domain engages U2AF to excise a FANCA poison exon, mechanistically linking CCAR1 to Fanconi anemia/ICL DNA repair.","evidence":"Two concurrent studies using genome-wide CRISPR screens, Co-IP with FANCA pre-mRNA and U2AF heterodimer, domain-deletion mutants, RNA-seq, and HDR/ICL DNA repair assays","pmids":["38964321","39025073"],"confidence":"High","gaps":["How CCAR1 recognizes specific poison-exon transcripts genome-wide not defined","Relationship between CCAR1's splicing and coactivator activities mechanistically unintegrated"]},{"year":null,"claim":"It remains unresolved how CCAR1's chromatin coactivator, spliceosome-associated, and cytoplasmic/apoptotic activities are partitioned and coordinated within a single cell, and whether one domain organization governs all of them.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structure of full-length CCAR1 or its domain interfaces in the corpus","No unified model linking transcription, splicing, and apoptosis functions","β-catenin restriction in ESCs rests on indirect localization without direct binding (Low confidence)"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,8,9,10,13,16]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[18,20]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,8,18]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,3,8,16]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2,19]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,8,9,10,16]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[18,20]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[20]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[3,14,15]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[15,17]}],"complexes":["Mediator complex (CCAR1–MED1)","KDM4B–CCAR1–MED1 complex","U2AF heterodimer association"],"partners":["MED1","GATA2","GATA1","KDM4B","H2AX","NEMO/IKBKG","U2AF","DCLK1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8IX12","full_name":"Cell division cycle and apoptosis regulator protein 1","aliases":["Cell cycle and apoptosis regulatory protein 1","CARP-1","Death inducer with SAP domain"],"length_aa":1150,"mass_kda":132.8,"function":"Associates with components of the Mediator and p160 coactivator complexes that play a role as intermediaries transducing regulatory signals from upstream transcriptional activator proteins to basal transcription machinery at the core promoter. Recruited to endogenous nuclear receptor target genes in response to the appropriate hormone. Also functions as a p53 coactivator. May thus play an important role in transcriptional regulation (By similarity). May be involved in apoptosis signaling in the presence of the reinoid CD437. Apoptosis induction involves sequestration of 14-3-3 protein(s) and mediated altered expression of multiple cell cycle regulatory genes including MYC, CCNB1 and CDKN1A. Plays a role in cell cycle progression and/or cell proliferation (PubMed:12816952). In association with CALCOCO1 enhances GATA1- and MED1-mediated transcriptional activation from the gamma-globin promoter during erythroid differentiation of K562 erythroleukemia cells (PubMed:24245781). Can act as a both a coactivator and corepressor of AR-mediated transcription. Contributes to chromatin looping and AR transcription complex assembly by stabilizing AR-GATA2 association on chromatin and facilitating MED1 and RNA polymerase II recruitment to AR-binding sites. May play an important role in the growth and tumorigenesis of prostate cancer cells (PubMed:23887938)","subcellular_location":"Cytoplasm, perinuclear region","url":"https://www.uniprot.org/uniprotkb/Q8IX12/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/CCAR1","classification":"Common Essential","n_dependent_lines":960,"n_total_lines":1208,"dependency_fraction":0.7947019867549668},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000060339","cell_line_id":"CID000799","localizations":[{"compartment":"nuclear_punctae","grade":3},{"compartment":"nucleoplasm","grade":3}],"interactors":[{"gene":"RBM17","stoichiometry":4.0},{"gene":"U2AF2","stoichiometry":4.0},{"gene":"ARFIP2","stoichiometry":0.2},{"gene":"BUD23","stoichiometry":0.2},{"gene":"MVB12A","stoichiometry":0.2},{"gene":"MARCKSL1","stoichiometry":0.2},{"gene":"CLU","stoichiometry":0.2},{"gene":"SNRPE","stoichiometry":0.2},{"gene":"COMMD1","stoichiometry":0.2},{"gene":"COMMD6","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000799","total_profiled":1310},"omim":[{"mim_id":"612569","title":"CELL DIVISION CYCLE AND APOPTOSIS REGULATOR 1; CCAR1","url":"https://www.omim.org/entry/612569"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Golgi apparatus","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CCAR1"},"hgnc":{"alias_symbol":["CARP1","CARP-1","uc.285+","FLJ10590"],"prev_symbol":[]},"alphafold":{"accession":"Q8IX12","domains":[{"cath_id":"2.40.50.140","chopping":"148-208","consensus_level":"high","plddt":92.4056,"start":148,"end":208},{"cath_id":"3.90.79.10","chopping":"376-581_729-779","consensus_level":"high","plddt":91.5677,"start":376,"end":779},{"cath_id":"1.20.5","chopping":"1047-1124","consensus_level":"medium","plddt":92.4465,"start":1047,"end":1124}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IX12","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IX12-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IX12-F1-predicted_aligned_error_v6.png","plddt_mean":69.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CCAR1","jax_strain_url":"https://www.jax.org/strain/search?query=CCAR1"},"sequence":{"accession":"Q8IX12","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8IX12.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8IX12/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IX12"}},"corpus_meta":[{"pmid":"31281495","id":"PMC_31281495","title":"Circular RNAs negatively regulate cancer stem cells by physically binding FMRP against CCAR1 complex in hepatocellular carcinoma.","date":"2019","source":"Theranostics","url":"https://pubmed.ncbi.nlm.nih.gov/31281495","citation_count":211,"is_preprint":false},{"pmid":"18722177","id":"PMC_18722177","title":"CCAR1, a key regulator of mediator complex recruitment to nuclear receptor transcription complexes.","date":"2008","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/18722177","citation_count":122,"is_preprint":false},{"pmid":"19073175","id":"PMC_19073175","title":"Microtubule-dependent association of AKAP350A and CCAR1 with RNA stress granules.","date":"2008","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/19073175","citation_count":65,"is_preprint":false},{"pmid":"27002217","id":"PMC_27002217","title":"CCAR1 5' UTR as a natural miRancer of miR-1254 overrides tamoxifen resistance.","date":"2016","source":"Cell research","url":"https://pubmed.ncbi.nlm.nih.gov/27002217","citation_count":64,"is_preprint":false},{"pmid":"35040440","id":"PMC_35040440","title":"Immune responses to CCAR1 and other dermatomyositis autoantigens are associated with attenuated cancer emergence.","date":"2022","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/35040440","citation_count":51,"is_preprint":false},{"pmid":"21903591","id":"PMC_21903591","title":"Antagonists of anaphase-promoting complex (APC)-2-cell cycle and apoptosis regulatory protein (CARP)-1 interaction are novel regulators of cell growth and apoptosis.","date":"2011","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21903591","citation_count":42,"is_preprint":false},{"pmid":"25894788","id":"PMC_25894788","title":"CARP-1/CCAR1: a biphasic regulator of cancer cell growth and apoptosis.","date":"2015","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/25894788","citation_count":38,"is_preprint":false},{"pmid":"25033755","id":"PMC_25033755","title":"Pierisins and CARP-1: ADP-ribosylation of DNA by ARTCs in butterflies and shellfish.","date":"2015","source":"Current topics in microbiology and immunology","url":"https://pubmed.ncbi.nlm.nih.gov/25033755","citation_count":38,"is_preprint":false},{"pmid":"24811171","id":"PMC_24811171","title":"Coregulator cell cycle and apoptosis regulator 1 (CCAR1) positively regulates adipocyte differentiation through the glucocorticoid signaling pathway.","date":"2014","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24811171","citation_count":33,"is_preprint":false},{"pmid":"33230478","id":"PMC_33230478","title":"Circular RNA circRIMS1 Acts as a Sponge of miR-433-3p to Promote Bladder Cancer Progression by Regulating CCAR1 Expression.","date":"2020","source":"Molecular therapy. Nucleic acids","url":"https://pubmed.ncbi.nlm.nih.gov/33230478","citation_count":33,"is_preprint":false},{"pmid":"16945908","id":"PMC_16945908","title":"Purification and molecular cloning of a DNA ADP-ribosylating protein, CARP-1, from the edible clam Meretrix lamarckii.","date":"2006","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/16945908","citation_count":33,"is_preprint":false},{"pmid":"23975424","id":"PMC_23975424","title":"Par-4/THAP1 complex and Notch3 competitively regulated pre-mRNA splicing of CCAR1 and affected inversely the survival of T-cell acute lymphoblastic leukemia cells.","date":"2013","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/23975424","citation_count":31,"is_preprint":false},{"pmid":"35522902","id":"PMC_35522902","title":"Targeting DCLK1 overcomes 5-fluorouracil resistance in colorectal cancer through inhibiting CCAR1/β-catenin pathway-mediated cancer stemness.","date":"2022","source":"Clinical and translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/35522902","citation_count":29,"is_preprint":false},{"pmid":"20852740","id":"PMC_20852740","title":"The LIM Protein Zyxin Binds CARP-1 and Promotes Apoptosis.","date":"2010","source":"Genes & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/20852740","citation_count":29,"is_preprint":false},{"pmid":"37563361","id":"PMC_37563361","title":"m6A-modified circABCC4 promotes stemness and metastasis of prostate cancer by recruiting IGF2BP2 to increase stability of CCAR1.","date":"2023","source":"Cancer gene therapy","url":"https://pubmed.ncbi.nlm.nih.gov/37563361","citation_count":28,"is_preprint":false},{"pmid":"36762496","id":"PMC_36762496","title":"Association of Anti-CCAR1 Autoantibodies With Decreased Cancer Risk Relative to the General Population in Patients With Anti-Transcriptional Intermediary Factor 1γ-Positive Dermatomyositis.","date":"2023","source":"Arthritis & rheumatology (Hoboken, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/36762496","citation_count":28,"is_preprint":false},{"pmid":"34031372","id":"PMC_34031372","title":"The KDM4B-CCAR1-MED1 axis is a critical regulator of osteoclast differentiation and bone homeostasis.","date":"2021","source":"Bone research","url":"https://pubmed.ncbi.nlm.nih.gov/34031372","citation_count":28,"is_preprint":false},{"pmid":"28230774","id":"PMC_28230774","title":"Inhibition of CCAR1, a Coactivator of β-Catenin, Suppresses the Proliferation and Migration of Gastric Cancer Cells.","date":"2017","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/28230774","citation_count":26,"is_preprint":false},{"pmid":"33403784","id":"PMC_33403784","title":"CCAR1 and CCAR2 as gene chameleons with antagonistic duality: Preclinical, human translational, and mechanistic basis.","date":"2020","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/33403784","citation_count":25,"is_preprint":false},{"pmid":"23887938","id":"PMC_23887938","title":"CCAR1 promotes chromatin loading of androgen receptor (AR) transcription complex by stabilizing the association between AR and GATA2.","date":"2013","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/23887938","citation_count":25,"is_preprint":false},{"pmid":"25610865","id":"PMC_25610865","title":"DBC1/CCAR2 and CCAR1 Are Largely Disordered Proteins that Have Evolved from One Common Ancestor.","date":"2014","source":"BioMed research international","url":"https://pubmed.ncbi.nlm.nih.gov/25610865","citation_count":24,"is_preprint":false},{"pmid":"29285223","id":"PMC_29285223","title":"A CARP-1 functional mimetic loaded vitamin E-TPGS micellar nano-formulation for inhibition of renal cell carcinoma.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/29285223","citation_count":20,"is_preprint":false},{"pmid":"20594350","id":"PMC_20594350","title":"A novel mechanism of cell growth regulation by Cell Cycle and Apoptosis Regulatory Protein (CARP)-1.","date":"2010","source":"Journal of molecular signaling","url":"https://pubmed.ncbi.nlm.nih.gov/20594350","citation_count":20,"is_preprint":false},{"pmid":"26485930","id":"PMC_26485930","title":"Identification and Testing of Novel CARP-1 Functional Mimetic Compounds as Inhibitors of Non-Small Cell Lung and Triple Negative Breast Cancers.","date":"2015","source":"Journal of biomedical nanotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/26485930","citation_count":20,"is_preprint":false},{"pmid":"17071197","id":"PMC_17071197","title":"Pressure stimulates breast cancer cell adhesion independently of cell cycle and apoptosis regulatory protein (CARP)-1 regulation of focal adhesion kinase.","date":"2006","source":"American journal of surgery","url":"https://pubmed.ncbi.nlm.nih.gov/17071197","citation_count":20,"is_preprint":false},{"pmid":"23826121","id":"PMC_23826121","title":"CARP-1 functional mimetics: a novel class of small molecule inhibitors of medulloblastoma cell growth.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23826121","citation_count":18,"is_preprint":false},{"pmid":"24598827","id":"PMC_24598827","title":"CARP-1 functional mimetics are a novel class of small molecule inhibitors of malignant pleural mesothelioma cells.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24598827","citation_count":17,"is_preprint":false},{"pmid":"32422326","id":"PMC_32422326","title":"MiR-122-5p increases radiosensitivity and aggravates radiation-induced rectal injury through CCAR1.","date":"2020","source":"Toxicology and applied pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/32422326","citation_count":16,"is_preprint":false},{"pmid":"22905258","id":"PMC_22905258","title":"Necdin enhances myoblasts survival by facilitating the degradation of the mediator of apoptosis CCAR1/CARP1.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22905258","citation_count":15,"is_preprint":false},{"pmid":"24245781","id":"PMC_24245781","title":"CCAR1/CoCoA pair-mediated recruitment of the Mediator defines a novel pathway for GATA1 function.","date":"2013","source":"Genes to cells : devoted to molecular & cellular mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/24245781","citation_count":12,"is_preprint":false},{"pmid":"30769864","id":"PMC_30769864","title":"A H2AX⁻CARP-1 Interaction Regulates Apoptosis Signaling Following DNA Damage.","date":"2019","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/30769864","citation_count":12,"is_preprint":false},{"pmid":"25033461","id":"PMC_25033461","title":"Mechanisms of neuroblastoma cell growth inhibition by CARP-1 functional mimetics.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25033461","citation_count":12,"is_preprint":false},{"pmid":"34475041","id":"PMC_34475041","title":"Telmisartan Facilitates the Anticancer Effects of CARP-1 Functional Mimetic and Sorafenib in Rociletinib Resistant Non-small Cell Lung Cancer.","date":"2021","source":"Anticancer research","url":"https://pubmed.ncbi.nlm.nih.gov/34475041","citation_count":12,"is_preprint":false},{"pmid":"30038713","id":"PMC_30038713","title":"A CARP-1 functional mimetic compound is synergistic with BRAF-targeting in non-small cell lung cancers.","date":"2018","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/30038713","citation_count":12,"is_preprint":false},{"pmid":"22266316","id":"PMC_22266316","title":"CCAR1 is required for Ngn3-mediated endocrine differentiation.","date":"2012","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/22266316","citation_count":11,"is_preprint":false},{"pmid":"27687593","id":"PMC_27687593","title":"CARP-1 functional mimetics are novel inhibitors of drug-resistant triple negative breast cancers.","date":"2016","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/27687593","citation_count":11,"is_preprint":false},{"pmid":"23764399","id":"PMC_23764399","title":"Cell cycle and apoptosis regulatory protein (CARP)-1 is expressed in osteoblasts and regulated by PTH.","date":"2013","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/23764399","citation_count":10,"is_preprint":false},{"pmid":"38964321","id":"PMC_38964321","title":"CCAR1 promotes DNA repair via alternative splicing.","date":"2024","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/38964321","citation_count":9,"is_preprint":false},{"pmid":"33220423","id":"PMC_33220423","title":"Role of nano-lipid formulation of CARP-1 mimetic, CFM-4.17 to improve systemic exposure and response in osimertinib resistant non-small cell lung cancer.","date":"2020","source":"European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V","url":"https://pubmed.ncbi.nlm.nih.gov/33220423","citation_count":9,"is_preprint":false},{"pmid":"30003683","id":"PMC_30003683","title":"CCAR-1 is a negative regulator of the heat-shock response in Caenorhabditis elegans.","date":"2018","source":"Aging cell","url":"https://pubmed.ncbi.nlm.nih.gov/30003683","citation_count":9,"is_preprint":false},{"pmid":"32945522","id":"PMC_32945522","title":"RP11‑284F21.9 promotes lung carcinoma proliferation and invasion via the regulation of miR‑627‑3p/CCAR1.","date":"2020","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/32945522","citation_count":8,"is_preprint":false},{"pmid":"35745729","id":"PMC_35745729","title":"Combined Transcriptomic and Proteomic Profiling to Unravel Osimertinib, CARP-1 Functional Mimetic (CFM 4.17) Formulation and Telmisartan Combo Treatment in NSCLC Tumor Xenografts.","date":"2022","source":"Pharmaceutics","url":"https://pubmed.ncbi.nlm.nih.gov/35745729","citation_count":7,"is_preprint":false},{"pmid":"32024692","id":"PMC_32024692","title":"Antagonizing binding of cell cycle and apoptosis regulatory protein 1 (CARP-1) to the NEMO/IKKγ protein enhances the anticancer effect of chemotherapy.","date":"2020","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/32024692","citation_count":6,"is_preprint":false},{"pmid":"30397001","id":"PMC_30397001","title":"Cell Cycle and Apoptosis Regulator 1, CCAR1, Regulates Enhancer-Dependent Nuclear Receptor CAR Transactivation.","date":"2018","source":"Molecular pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/30397001","citation_count":4,"is_preprint":false},{"pmid":"20809119","id":"PMC_20809119","title":"Cell cycle and apoptosis regulatory protein (CARP)-1 is a novel, adriamycin-inducible, diffuse large B-cell lymphoma (DLBL) growth suppressor.","date":"2010","source":"Cancer chemotherapy and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/20809119","citation_count":4,"is_preprint":false},{"pmid":"39025073","id":"PMC_39025073","title":"The splicing factor CCAR1 regulates the Fanconi anemia/BRCA pathway.","date":"2024","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/39025073","citation_count":3,"is_preprint":false},{"pmid":"32693681","id":"PMC_32693681","title":"Novel aspects of Cell Division Cycle and Apoptosis Regulator 1 (CCAR1) protein in Morus notabilis: an in silico approach.","date":"2020","source":"Plant signaling & behavior","url":"https://pubmed.ncbi.nlm.nih.gov/32693681","citation_count":2,"is_preprint":false},{"pmid":"38126797","id":"PMC_38126797","title":"CCAR-1 works together with the U2AF large subunit UAF-1 to regulate alternative splicing.","date":"2023","source":"RNA biology","url":"https://pubmed.ncbi.nlm.nih.gov/38126797","citation_count":1,"is_preprint":false},{"pmid":"39514366","id":"PMC_39514366","title":"Anti-Sp4 and anti-CCAR1 autoantibodies in UK vs US patients with adult and juvenile-onset anti-TIF1γ-positive myositis.","date":"2025","source":"Rheumatology (Oxford, England)","url":"https://pubmed.ncbi.nlm.nih.gov/39514366","citation_count":0,"is_preprint":false},{"pmid":"39059366","id":"PMC_39059366","title":"Splicing regulation of DNA repair via CCAR1.","date":"2024","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/39059366","citation_count":0,"is_preprint":false},{"pmid":"40604397","id":"PMC_40604397","title":"circFTO binding with IGF2BP2 regulates trophoblast cells proliferation, migration, and invasion while mediating m6A modification of CCAR1 mRNA in spontaneous abortion.","date":"2025","source":"BMC molecular and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/40604397","citation_count":0,"is_preprint":false},{"pmid":"40130381","id":"PMC_40130381","title":"circTUBD1-hnRNPK Regulates the Proliferation and Migration of LSCC by Targeting CCAR1.","date":"2025","source":"Cancer medicine","url":"https://pubmed.ncbi.nlm.nih.gov/40130381","citation_count":0,"is_preprint":false},{"pmid":"40978202","id":"PMC_40978202","title":"Ccar1 prevents β-catenin nuclear translocation to sustain ground-state pluripotency in mouse ESCs under R2i.","date":"2025","source":"Biochemistry and biophysics reports","url":"https://pubmed.ncbi.nlm.nih.gov/40978202","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":31542,"output_tokens":5637,"usd":0.089591,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":14182,"output_tokens":4889,"usd":0.096568,"stage2_stop_reason":"end_turn"},"total_usd":0.186159,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2008,\n      \"finding\": \"CCAR1 is required for Mediator complex recruitment to nuclear receptor (NR) target gene promoters; CCAR1 associates with components of both the Mediator and p160 coactivator complexes, is recruited to endogenous NR target genes in response to hormone, and its depletion blocks hormone-induced recruitment of Mediator subunits and RNA polymerase II to target promoters.\",\n      \"method\": \"Co-immunoprecipitation, chromatin immunoprecipitation (ChIP), siRNA knockdown with gene expression and cell growth readouts\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, ChIP at endogenous loci, and KD with multiple orthogonal readouts in a single focused study\",\n      \"pmids\": [\"18722177\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CCAR1 also functions as a p53 coactivator, suggesting a broader role in transcriptional regulation beyond nuclear receptors.\",\n      \"method\": \"Functional reporter assays and co-immunoprecipitation\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, functional reporter assay with limited mechanistic detail in the abstract\",\n      \"pmids\": [\"18722177\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CCAR1 localizes to cytosolic RNA stress granules in an arsenite-dependent manner together with AKAP350A and caprin-1; this co-localization requires intact microtubules (disrupted by nocodazole). Reduction of CCAR1 expression alters the size and number of G3BP-containing stress granules.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence/live-cell imaging, nocodazole microtubule disruption, siRNA knockdown\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP identifying interacting partners, direct localization by imaging, functional KD with morphological phenotype, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"19073175\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CCAR1 (CARP-1) is a nuclear protein that binds the LIM domain region of zyxin; this interaction is required for zyxin's pro-apoptotic activity upon UV-C irradiation. Zyxin lacking the CCAR1-binding region shows reduced proapoptotic activity.\",\n      \"method\": \"Affinity pulldown, microsequence analysis, co-immunoprecipitation, domain-deletion mutants, UV-C apoptosis assay\",\n      \"journal\": \"Genes & cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pulldown with protein ID, domain-deletion functional test, single lab\",\n      \"pmids\": [\"20852740\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CCAR1 (CARP-1) physically binds APC/C subunit APC-2 as well as APC/C co-activators Cdc20 and Cdh1, as identified by yeast two-hybrid screening. The CARP-1/APC-2 interaction has a Kd of ~480 nM measured by fluorescence polarization assay. Small molecule antagonists of this interaction (CFMs) induce G2/M arrest and apoptosis in a CARP-1-dependent manner.\",\n      \"method\": \"Yeast two-hybrid, fluorescence polarization assay (Kd measurement), epitope mapping, small-molecule antagonist with KD rescue\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — yeast two-hybrid, in vitro binding assay with Kd, domain mapping, and functional rescue by KD; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"21903591\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Necdin interacts with CCAR1 (identified by two-hybrid screening) and promotes CCAR1 ubiquitination and proteasomal degradation, thereby counteracting CCAR1-mediated apoptosis to support myoblast survival.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, ubiquitination assay, proteasome inhibitor experiments, siRNA knockdown\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid plus Co-IP plus ubiquitination assay, single lab\",\n      \"pmids\": [\"22905258\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CCAR1 physically interacts with the transcription factor Ngn3 and is essential for Ngn3-dependent activation of the NeuroD promoter and Ngn3-induced endocrine transdifferentiation of pancreatic ductal cells.\",\n      \"method\": \"Pulldown assay, co-immunoprecipitation, gene reporter assay, siRNA knockdown of endogenous CCAR1\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP/pulldown plus functional reporter plus KD phenotype, single lab\",\n      \"pmids\": [\"22266316\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Par-4 and THAP1 form a protein complex via their carboxyl termini; THAP1 binds the CCAR1 promoter through its zinc-dependent DNA-binding domain; the Par-4/THAP1 complex activates CCAR1 gene expression and antagonizes Notch3-induced alternative splicing of CCAR1 pre-mRNA (which shifts it toward a shorter, survival-promoting isoform via splicing factors SRp40/SRp55).\",\n      \"method\": \"Co-immunoprecipitation, promoter reporter assays, ChIP, siRNA, alternative splicing analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for complex, ChIP for promoter occupancy, splicing assay; single lab with multiple methods\",\n      \"pmids\": [\"23975424\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CCAR1 acts as a coactivator for the androgen receptor (AR) by stabilizing the interaction between AR and pioneer factor GATA2; CCAR1 directly interacts with both AR and GATA2, facilitating their occupancy at AR-binding enhancers, long-range enhancer–promoter looping, and recruitment of MED1 and RNA polymerase II.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, siRNA knockdown, chromatin conformation capture (3C), in vivo xenograft\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, ChIP at endogenous loci, 3C looping, KD with gene expression and in vivo phenotype; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"23887938\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CCAR1 and CoCoA form a complex with GATA1 and MED1(1-602); reconstituted in vitro complex of recombinant GATA1, CCAR1, CoCoA, and MED1(1-602) was demonstrated, and CCAR1/CoCoA synergistically enhanced GATA1-mediated transcription from the γ-globin promoter.\",\n      \"method\": \"In vitro complex reconstitution with recombinant proteins, co-immunoprecipitation, reporter gene assay, ChIP in K562 cells\",\n      \"journal\": \"Genes to cells\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with recombinant proteins plus ChIP plus reporter assays; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"24245781\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CCAR1 is recruited by glucocorticoid receptor (GR) to PPARγ gene glucocorticoid response elements, is required for GR occupancy and chromatin remodeling at specific PPARγ GBRs, and depletion of CCAR1 markedly suppresses adipogenic differentiation with reduced PPARγ, C/EBPα, and C/EBPδ induction.\",\n      \"method\": \"ChIP, siRNA knockdown, adipocyte differentiation assay, Western blotting\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP at endogenous loci, KD with defined cellular differentiation phenotype, multiple target genes; single lab but multiple orthogonal methods with rigorous controls\",\n      \"pmids\": [\"24811171\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CCAR1 (CARP-1) overexpression inhibits FAK (focal adhesion kinase) Y397 autophosphorylation in breast cancer cells, establishing CCAR1 as a negative regulator of FAK activity.\",\n      \"method\": \"Western blot of pFAK-397 in stable CCAR1-overexpressing cells\",\n      \"journal\": \"American journal of surgery\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single method (western blot), single lab, no mechanistic follow-up\",\n      \"pmids\": [\"17071197\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CCAR1 binds TAZ through amino acids 651–759 of CCAR1; threonine-667 phosphorylation is required for this interaction and for H89-induced apoptosis; CCAR1 overexpression suppresses c-myc transcription.\",\n      \"method\": \"Co-immunoprecipitation, domain-deletion and point-mutant (T667A) analysis, luciferase reporter assay, siRNA\",\n      \"journal\": \"Journal of molecular signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, point mutagenesis, reporter assay; single lab\",\n      \"pmids\": [\"20594350\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CCAR1 functions as an enhancer-dependent coactivator for the constitutive androstane receptor (CAR), specifically at the gtPBREM enhancer of UGT1A1 but not the PBREM enhancer of CYP2B6; CCAR1 is recruited to the gtPBREM by CAR and cooperates with p160 SRC coactivators.\",\n      \"method\": \"Co-immunoprecipitation with FLAG-CAR, reporter gene assays, siRNA knockdown, ChIP\",\n      \"journal\": \"Molecular pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ChIP, reporter assay, KD; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"30397001\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CCAR1 (CARP-1) directly binds H2AX; the interaction requires CCAR1 amino acids 636–650 and H2AX residues 1–35. Surface plasmon resonance measured a Kd of 127 nM for CARP-1(636–650)/H2AX(1–35) peptide binding. CCAR1–H2AX interaction is required for γH2AX accumulation and apoptosis signaling following Adriamycin or CFM-4.16 treatment; deletion of the H2AX-binding epitope abolishes apoptosis.\",\n      \"method\": \"Co-immunoprecipitation, domain-deletion and mutagenesis, surface plasmon resonance (in vitro Kd), siRNA knockdown, EGFP-tagged peptide competition\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro SPR binding (Kd), domain mapping by mutagenesis, Co-IP, functional KD; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"30769864\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CCAR1 (CARP-1) directly binds the NF-κB essential modulator NEMO/IKKγ and regulates the chemotherapy (adriamycin)-activated canonical NF-κB pathway; blockade of NEMO–CCAR1 binding selectively diminishes adriamycin-induced p65 phosphorylation but not TNFα- or IL-1β-induced NF-κB activation.\",\n      \"method\": \"Direct binding assay, co-immunoprecipitation, high-throughput small-molecule screen, siRNA, in vivo xenograft\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding, Co-IP, pharmacological blockade with selective readouts, in vivo validation; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"32024692\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KDM4B physically interacts with CCAR1 and MED1 in a trimeric complex; the KDM4B–CCAR1–MED1 complex localizes to promoters of osteoclast-related genes upon RANKL stimulation, induces H3K9 demethylation (euchromatinization) at those promoters, and enables NF-κB p65 recruitment via direct KDM4B–p65 interaction to drive osteoclastogenesis.\",\n      \"method\": \"Co-immunoprecipitation, genome-wide ChIP-sequencing, conditional KO mouse model (osteopetrotic phenotype), biochemical analysis\",\n      \"journal\": \"Bone research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP for complex, ChIP-seq for genome-wide occupancy, KO mouse with defined bone phenotype; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"34031372\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"DCLK1 kinase interacts with CCAR1 via its C-terminal domain and phosphorylates CCAR1 at Ser343, which is required for CCAR1 protein stabilization; DCLK1-stabilized CCAR1 positively regulates β-catenin signaling and maintains cancer stemness.\",\n      \"method\": \"Co-immunoprecipitation, in vitro/cellular phosphorylation assay with site-specific mutagenesis (Ser343), siRNA knockdown, in vivo xenograft\",\n      \"journal\": \"Clinical and translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — Co-IP, phosphorylation site mutagenesis, KD with functional rescue, in vivo validation; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"35522902\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CCAR1 is required for correct splicing of FANCA pre-mRNA: loss of CCAR1 causes inclusion of a poison exon in FANCA transcript, reducing FANCA protein expression without reducing FANCA mRNA levels. The EF-hand domain of CCAR1 interacts with the U2AF heterodimer of the spliceosome and is required for poison exon excision. Transcriptome-wide analysis shows CCAR1 regulates widespread alternative splicing across many genes.\",\n      \"method\": \"CRISPR inhibition and Cas9-editing genome-wide screen (~18,000 knockdowns), co-immunoprecipitation (CCAR1 with FANCA pre-mRNA and U2AF heterodimer), RNA-seq/transcriptomic analysis, domain-deletion mutants\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — genome-wide functional screen, Co-IP with spliceosome components, domain mutagenesis, transcriptome-wide splicing analysis; replicated independently by two concurrent papers (PMIDs 38964321 and 39025073)\",\n      \"pmids\": [\"38964321\", \"39025073\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PTH treatment of osteoblasts causes nuclear-to-cytoplasmic translocation of CCAR1 protein and down-regulates its expression via PKA- and PKC-dependent, ERK-independent but p38-dependent signaling.\",\n      \"method\": \"Immunofluorescence staining, Western blot, kinase inhibitors (H-89, GF109203X, SB203580, U0126), primary osteoblast culture\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization by immunofluorescence linked to signaling pathway dissection; single lab, multiple pharmacological inhibitors\",\n      \"pmids\": [\"23764399\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CCAR1 co-immunoprecipitates with FANCA pre-mRNA and its EF-hand domain is required for interaction with the U2AF heterodimer of the spliceosome; CCAR1 loss results in FANCA poison exon retention and impairs both HDR and interstrand crosslink/Fanconi anemia pathway repair.\",\n      \"method\": \"Co-immunoprecipitation with pre-mRNA and spliceosome components, domain-deletion analysis, RNA-seq, DNA repair assays (HDR, ICL)\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two independent studies with Co-IP, domain mapping, RNA-seq, and functional DNA repair assays\",\n      \"pmids\": [\"39025073\", \"38964321\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CFM-4 and related CARP-1 functional mimetics bind CCAR1, stimulate CCAR1 expression, and elevate CCAR1-DEDD2 interaction; apoptosis signaling by CFMs involves activation of stress-activated kinases p38 and JNK1/2, caspase cleavage, and loss of cyclin B1, and is abrogated by CCAR1 depletion.\",\n      \"method\": \"Co-immunoprecipitation (CCAR1–DEDD2), siRNA knockdown rescue, Western blotting, in vivo xenograft\",\n      \"journal\": \"Journal of biomedical nanotechnology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP of novel partner, KD rescue of pharmacological phenotype, in vivo validation; single lab\",\n      \"pmids\": [\"26485930\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In mouse ESCs under R2i conditions, Ccar1 knockdown promotes nuclear translocation of β-catenin and upregulates Wnt target genes, indicating that Ccar1 restricts β-catenin nuclear entry to maintain ground-state pluripotency.\",\n      \"method\": \"siRNA knockdown, immunofluorescence for β-catenin localization, qRT-PCR for Wnt target genes\",\n      \"journal\": \"Biochemistry and biophysics reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, indirect localization readout, no direct binding demonstrated (paper notes further interaction assays are needed)\",\n      \"pmids\": [\"40978202\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CCAR1 is a multifunctional perinuclear/nuclear phosphoprotein that acts as a transcriptional coactivator bridging nuclear receptors (ER, AR, GR, CAR), p53, GATA1, and Ngn3 to the Mediator complex; it regulates alternative splicing genome-wide by interacting with the U2AF spliceosome heterodimer via its EF-hand domain—most critically preventing poison-exon inclusion in FANCA mRNA to support Fanconi anemia/BRCA DNA repair; it also modulates apoptosis through direct interactions with H2AX, NEMO/IKKγ, zyxin, TAZ, and APC/C subunit APC-2, and its protein stability is regulated by DCLK1 phosphorylation (Ser343) and necdin-mediated ubiquitin–proteasome degradation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CCAR1 is a multifunctional nuclear protein that operates as a transcriptional coactivator bridging sequence-specific factors to the Mediator complex and as a regulator of pre-mRNA splicing and apoptotic signaling [#0, #18]. As a coactivator it is required for hormone-dependent recruitment of Mediator subunits and RNA polymerase II to nuclear receptor target promoters, associating with both Mediator and p160 coactivator complexes [#0]; this activity extends across diverse DNA-binding factors, including the androgen receptor (where CCAR1 stabilizes the AR\\u2013GATA2 interaction and enables enhancer\\u2013promoter looping and MED1/RNA Pol II recruitment) [#8], the glucocorticoid receptor at PPAR\\u03b3 response elements during adipogenesis [#10], the constitutive androstane receptor at the UGT1A1 gtPBREM enhancer [#13], GATA1 (in a reconstituted complex with CoCoA and MED1 driving \\u03b3-globin transcription) [#9], and Ngn3 during endocrine transdifferentiation [#6]. CCAR1 also forms a trimeric complex with KDM4B and MED1 that demethylates H3K9 at osteoclast gene promoters to license NF-\\u03baB p65 recruitment during osteoclastogenesis [#16]. Independently of transcription, CCAR1 controls genome-wide alternative splicing: its EF-hand domain binds the U2AF spliceosome heterodimer to excise a poison exon from FANCA pre-mRNA, sustaining FANCA protein and thereby supporting homology-directed and Fanconi anemia/interstrand-crosslink DNA repair [#18, #20]. In apoptotic signaling CCAR1 binds H2AX to drive \\u03b3H2AX accumulation [#14], engages NEMO/IKK\\u03b3 to selectively regulate chemotherapy-activated canonical NF-\\u03baB signaling [#15], binds zyxin to enable UV-C-induced apoptosis [#3], and interacts with APC/C subunit APC-2 [#4]. CCAR1 protein levels and activity are set post-translationally by DCLK1-mediated Ser343 phosphorylation, which stabilizes CCAR1 and promotes \\u03b2-catenin signaling and cancer stemness [#17], and by necdin-driven ubiquitin\\u2013proteasome degradation [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Established CCAR1's core molecular role by showing it is the link required to recruit Mediator and RNA Pol II to hormone-activated nuclear receptor promoters, defining it as a bona fide coactivator rather than a generic associated factor.\",\n      \"evidence\": \"Reciprocal Co-IP, ChIP at endogenous NR target genes, and siRNA knockdown with expression/growth readouts; the same study also showed p53 coactivation by reporter assay\",\n      \"pmids\": [\"18722177\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define which CCAR1 domain contacts Mediator versus the p160 complex\", \"p53 coactivation rested on reporter assays without endogenous-locus confirmation\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Revealed an unexpected cytoplasmic role by localizing CCAR1 to arsenite-induced stress granules, indicating functions beyond chromatin.\",\n      \"evidence\": \"Co-IP with AKAP350A/caprin-1, immunofluorescence/live imaging with nocodazole microtubule disruption, and siRNA altering G3BP granule size/number\",\n      \"pmids\": [\"19073175\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of CCAR1 in granules for mRNA fate unresolved\", \"Relationship between granule localization and nuclear coactivator role unknown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Connected CCAR1 to pro-apoptotic and signaling control by mapping interactions with zyxin and TAZ and a phospho-dependent (T667) binding requirement.\",\n      \"evidence\": \"Affinity pulldown/microsequencing and domain-deletion UV-C apoptosis assays for zyxin; Co-IP, T667A mutagenesis and reporter assays for TAZ; western blot of pFAK-Y397 in overexpressing cells\",\n      \"pmids\": [\"20852740\", \"20594350\", \"17071197\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"FAK regulation shown by single-method western blot only (Low confidence)\", \"Kinase responsible for T667 phosphorylation not identified\", \"How these interactions integrate with the nuclear coactivator function unclear\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Provided quantitative biochemistry tying CCAR1 to cell-cycle machinery by demonstrating direct APC-2 binding and druggability of the interface.\",\n      \"evidence\": \"Yeast two-hybrid, fluorescence polarization (Kd ~480 nM), epitope mapping, and CFM small-molecule antagonists inducing CARP-1-dependent G2/M arrest and apoptosis\",\n      \"pmids\": [\"21903591\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CCAR1 modulates APC/C ubiquitin ligase activity directly not shown\", \"Functional role of Cdc20/Cdh1 binding not dissected\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined how CCAR1 abundance is controlled and broadened its transcription-factor partner repertoire to Ngn3.\",\n      \"evidence\": \"Yeast two-hybrid, Co-IP, ubiquitination and proteasome-inhibitor assays for necdin-driven degradation; pulldown, Co-IP, reporter and KD assays for Ngn3-dependent NeuroD activation and transdifferentiation\",\n      \"pmids\": [\"22905258\", \"22266316\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligase mediating necdin-dependent CCAR1 ubiquitination not identified\", \"Whether Ngn3 coactivation uses the same Mediator-bridging mechanism as nuclear receptors untested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Mechanistically detailed CCAR1's coactivator action at the chromatin level for AR and GATA1, including enhancer looping and in vitro complex reconstitution.\",\n      \"evidence\": \"Co-IP, ChIP, 3C looping, KD and xenograft for AR/GATA2/MED1; recombinant reconstitution of GATA1\\u2013CCAR1\\u2013CoCoA\\u2013MED1(1-602) plus ChIP/reporter in K562 cells; separately, Par-4/THAP1 control of CCAR1 transcription and isoform choice, and PTH-driven nuclear-to-cytoplasmic CCAR1 translocation\",\n      \"pmids\": [\"23887938\", \"24245781\", \"23975424\", \"23764399\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and structure of the GATA1\\u2013CCAR1\\u2013CoCoA\\u2013MED1 assembly unresolved\", \"Functional difference between CCAR1 splice isoforms not characterized at protein level\", \"Signal triggering PTH-induced relocalization downstream of p38 unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Extended CCAR1 coactivation to GR-driven adipogenesis, linking it to chromatin remodeling at specific glucocorticoid response elements.\",\n      \"evidence\": \"ChIP, siRNA, adipocyte differentiation assays and western blotting at PPAR\\u03b3 GBRs\",\n      \"pmids\": [\"24811171\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Chromatin-remodeling complex recruited by CCAR1 not identified\", \"Basis for GBR selectivity unexplained\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Resolved a direct apoptotic effector mechanism by mapping a high-affinity CCAR1\\u2013H2AX interface required for \\u03b3H2AX accumulation.\",\n      \"evidence\": \"Co-IP, domain/peptide mapping, surface plasmon resonance (Kd 127 nM), siRNA, and EGFP-peptide competition in chemotherapy/CFM apoptosis assays\",\n      \"pmids\": [\"30769864\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CCAR1 promotes H2AX phosphorylation directly or via recruiting a kinase unknown\", \"Nuclear-coactivator versus DNA-damage roles not reconciled\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed stimulus-selective control of NF-\\u03baB by CCAR1 through direct NEMO binding, restricting its effect to chemotherapy-activated signaling.\",\n      \"evidence\": \"Direct binding and Co-IP, HTS small-molecule blockade with selective p65-phosphorylation readouts, siRNA, and xenograft\",\n      \"pmids\": [\"32024692\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why TNF\\u03b1/IL-1\\u03b2-driven NF-\\u03baB is spared mechanistically unexplained\", \"Structural basis of NEMO\\u2013CCAR1 contact not determined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Placed CCAR1 in a chromatin-modifying coactivator complex with KDM4B and MED1 that couples histone demethylation to NF-\\u03baB recruitment in osteoclastogenesis.\",\n      \"evidence\": \"Co-IP, genome-wide ChIP-seq, and conditional KO mouse with osteopetrotic phenotype\",\n      \"pmids\": [\"34031372\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CCAR1 contributes catalytic versus scaffolding function in the complex unclear\", \"Direct CCAR1\\u2013p65 contact not established\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified an upstream kinase, DCLK1, whose Ser343 phosphorylation stabilizes CCAR1 and links it to \\u03b2-catenin-driven cancer stemness.\",\n      \"evidence\": \"Co-IP, phosphorylation assay with Ser343 mutagenesis, siRNA rescue, and xenograft\",\n      \"pmids\": [\"35522902\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which Ser343 phosphorylation prevents degradation unclear\", \"Direct versus indirect CCAR1 effect on \\u03b2-catenin not resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established a wholly distinct, RNA-level function: CCAR1 is a splicing regulator whose EF-hand domain engages U2AF to excise a FANCA poison exon, mechanistically linking CCAR1 to Fanconi anemia/ICL DNA repair.\",\n      \"evidence\": \"Two concurrent studies using genome-wide CRISPR screens, Co-IP with FANCA pre-mRNA and U2AF heterodimer, domain-deletion mutants, RNA-seq, and HDR/ICL DNA repair assays\",\n      \"pmids\": [\"38964321\", \"39025073\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CCAR1 recognizes specific poison-exon transcripts genome-wide not defined\", \"Relationship between CCAR1's splicing and coactivator activities mechanistically unintegrated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how CCAR1's chromatin coactivator, spliceosome-associated, and cytoplasmic/apoptotic activities are partitioned and coordinated within a single cell, and whether one domain organization governs all of them.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structure of full-length CCAR1 or its domain interfaces in the corpus\", \"No unified model linking transcription, splicing, and apoptosis functions\", \"\\u03b2-catenin restriction in ESCs rests on indirect localization without direct binding (Low confidence)\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 8, 9, 10, 13, 16]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [18, 20]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 8, 18]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 3, 8, 16]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2, 19]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 8, 9, 10, 16]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [18, 20]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [20]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [3, 14, 15]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [15, 17]}\n    ],\n    \"complexes\": [\"Mediator complex (CCAR1\\u2013MED1)\", \"KDM4B\\u2013CCAR1\\u2013MED1 complex\", \"U2AF heterodimer association\"],\n    \"partners\": [\"MED1\", \"GATA2\", \"GATA1\", \"KDM4B\", \"H2AX\", \"NEMO/IKBKG\", \"U2AF\", \"DCLK1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}