{"gene":"NCBP2","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2001,"finding":"CBP20 (NCBP2) is a component of the NMD-susceptible mRNP complex that also contains CBP80, PABP2, eIF4G, Upf2, and Upf3, and is present on mRNAs undergoing a 'pioneer' round of translation before CBP80-CBP20 are replaced by eIF4E.","method":"Immunopurification of RNP with antibody to CBP80 or eIF4E, followed by identification of co-purifying components; NMD blocked by cycloheximide or suppressor tRNA","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal immunopurification with multiple co-purifying factors identified, functional validation by translation inhibitors, foundational study widely replicated","pmids":["11551508"],"is_preprint":false},{"year":1996,"finding":"Yeast Mud13p/Cbc2 (ortholog of CBP20/NCBP2) is a component of the splicing commitment complex and is required for early steps of spliceosome assembly, functioning as the small cap-binding subunit of the nuclear cap-binding complex (CBC).","method":"Genetic screen for synthetic lethality with U1 snRNA mutations; characterization of splicing in delta-MUD13 yeast strains and extracts; biochemical identification of Mud13p as yeast CBC small subunit","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis combined with biochemical characterization of commitment complex composition and splicing assays in yeast extracts","pmids":["8682299"],"is_preprint":false},{"year":2012,"finding":"Yeast Cbc2 (CBP20/NCBP2 ortholog) binds the m7G cap via specific residues in its cap-binding pocket (Y24, F91, D120, D122, R129, R133), and cap recognition by Cbc2 is essential for meiosis through splicing of MER3 pre-mRNA; an intronless MER3 cDNA fully rescues the sporulation defect of cbc2-NΔ42.","method":"Alanine scanning and N-terminal deletion mutagenesis; genetic interaction screens (synthetic lethality with spliceosome assembly factors); RNA analysis of pre-mRNA splicing in meiosis; rescue with intronless MER3 cDNA","journal":"RNA (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1 / Strong — active-site mutagenesis combined with genetic epistasis, specific pathway rescue experiment, and direct RNA splicing analysis","pmids":["23002122"],"is_preprint":false},{"year":2010,"finding":"Full-length CBP20 (NCBP2) binds CBP80 and the m7G cap via its RNA recognition motif (RRM); an alternatively spliced isoform CBP20S lacking most of the RRM fails to bind CBP80 or the m7G cap but retains mRNA binding and localizes to active transcription sites and nucleolar caps upon transcription inhibition.","method":"Characterization of alternative splice variant; cap-binding and CBP80-binding assays; live-cell imaging and localization upon transcription inhibition","journal":"Nucleus (Austin, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding assays and live imaging with functional localization data, single lab study","pmids":["21326824"],"is_preprint":false},{"year":2020,"finding":"NCBP2 (via its Drosophila ortholog Cbp20 and Xenopus ortholog ncbp2) genetically interacts with other 3q29 deletion region genes to enhance apoptosis, disrupt cellular organization, and impair brain morphology; these defects are rescued by overexpression of apoptosis inhibitors Diap1 and xiap, placing NCBP2 upstream of apoptotic pathways during neurodevelopment.","method":"Tissue-specific RNAi knockdown in Drosophila melanogaster and Xenopus laevis; quantitative phenotypic assays for apoptosis and brain morphology; pairwise knockdown epistasis screen; rescue by apoptosis inhibitor overexpression","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with rescue experiment in two independent model organisms, single lab","pmids":["32053595"],"is_preprint":false},{"year":2023,"finding":"NCBP2 promotes pancreatic ductal adenocarcinoma progression by enhancing translation of c-JUN, which activates MEK/ERK signaling; NCBP2 knockdown inhibits PDAC cell proliferation and NCBP2 overexpression promotes growth in vitro and in vivo.","method":"Stable NCBP2 knockdown and overexpression cell lines; in vitro proliferation assays; in vivo xenograft models; western blot for c-JUN and MEK/ERK pathway components","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function and gain-of-function with defined molecular pathway, in vitro and in vivo, single lab","pmids":["38001714"],"is_preprint":false},{"year":2026,"finding":"NCBP2 stabilizes LIPG mRNA via direct binding to the m7G motif in the 5'-cap structure of LIPG mRNA, increasing LIPG expression and promoting lipid droplet accumulation in colorectal cancer cells, driving CRC proliferation, migration, and invasion.","method":"NCBP2 overexpression and knockdown in CRC cell lines and in vivo models; direct RNA-protein binding assay to m7G cap structure; measurement of LIPG mRNA stability and lipid droplet accumulation; in vivo tumor models","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding to m7G cap demonstrated, functional downstream effects measured, single lab","pmids":["41872454"],"is_preprint":false},{"year":2026,"finding":"NCBP2 regulates alternative splicing of KIF23 to promote cervical cancer progression; NCBP2 also regulates mitophagy via the KIF23-PGAM5 axis; FBXW8 ubiquitinates and degrades NCBP2, inhibiting overactivation of mitophagy.","method":"CCK-8, EdU, Transwell assays; RT-qPCR and western blot; bioinformatics screening; alternative splicing analysis of KIF23; ubiquitination assay for FBXW8-mediated NCBP2 degradation","journal":"Applied biochemistry and biotechnology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, primarily expression-level readouts with limited mechanistic validation of splicing and ubiquitination claims in abstracts","pmids":["41874817"],"is_preprint":false},{"year":2025,"finding":"NCBP2 knockdown leads to reduced cancer cell viability, apoptosis induction, and G1-S cell cycle arrest; RNA sequencing confirmed downregulation of cell-cycle-related pathways upon CBP20 depletion in cancer cells.","method":"NCBP2 knockdown; cell viability assays; cell cycle analysis; RNA sequencing","journal":"Experimental & molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined cellular phenotype and transcriptomic pathway readout, single lab","pmids":["40887503"],"is_preprint":false}],"current_model":"NCBP2 (CBP20) is the small subunit of the nuclear cap-binding complex (CBC) that directly contacts the m7G cap of RNA Pol II transcripts via its RRM domain; in complex with CBP80, it facilitates early spliceosome assembly (commitment complex formation), the pioneer round of mRNA translation (enabling NMD surveillance), and pre-mRNA splicing of specific transcripts (e.g., MER3 during meiosis); as an m7G cap reader it also stabilizes target mRNAs such as LIPG, activates downstream translation (c-JUN/MEK/ERK), regulates alternative splicing (KIF23), and its loss triggers apoptosis and cell cycle arrest, with FBXW8 identified as a ubiquitin E3 ligase that degrades NCBP2."},"narrative":{"mechanistic_narrative":"NCBP2 (CBP20) is the small, cap-binding subunit of the nuclear cap-binding complex (CBC), where it directly contacts the m7G cap of RNA Pol II transcripts through its RNA recognition motif (RRM) while heterodimerizing with the large subunit CBP80 [PMID:21326824]. Conserved cap-recognition residues in the cap-binding pocket are essential for function: in yeast, cap binding by the ortholog Cbc2 is required for splicing of MER3 pre-mRNA and thereby for meiosis, as an intronless MER3 cDNA rescues the cap-binding-defective mutant [PMID:23002122]. As the CBC small subunit, NCBP2/Cbc2 acts at the earliest steps of spliceosome assembly, forming part of the splicing commitment complex [PMID:8682299], and persists on newly exported transcripts as part of an mRNP that includes CBP80, PABP2, eIF4G, Upf2, and Upf3 to direct the pioneer round of translation that licenses nonsense-mediated decay before CBC is replaced by eIF4E [PMID:11551508]. An alternatively spliced isoform (CBP20S) lacking most of the RRM cannot bind CBP80 or the cap yet retains general mRNA binding and accumulates at transcription sites and nucleolar caps [PMID:21326824]. Through its cap-reader activity NCBP2 influences specific transcripts and downstream programs: it stabilizes LIPG mRNA via direct m7G-cap binding to drive lipid-droplet accumulation in colorectal cancer [PMID:41872454] and enhances translation of c-JUN to activate MEK/ERK signaling in pancreatic cancer [PMID:38001714], and its depletion reduces viability, induces apoptosis, and causes G1-S cell cycle arrest [PMID:40887503]. NCBP2 also acts upstream of apoptotic pathways during neurodevelopment, interacting with other 3q29-deletion genes to modulate apoptosis and brain morphology in a manner rescued by apoptosis inhibitors [PMID:32053595].","teleology":[{"year":1996,"claim":"Established that the CBP20 ortholog is a functional CBC subunit acting at the entry point of spliceosome assembly, defining the complex's role in pre-mRNA splicing rather than merely cap protection.","evidence":"Synthetic-lethal genetic screen with U1 snRNA mutations and splicing assays in delta-MUD13 yeast extracts","pmids":["8682299"],"confidence":"High","gaps":["Did not define the cap-binding residues or RRM contribution","Commitment-complex role demonstrated in yeast, not human cells"]},{"year":2001,"claim":"Showed CBP20 persists on exported mRNA in a defined mRNP and marks the pioneer round of translation that enables NMD, distinguishing CBC-bound from eIF4E-bound translation.","evidence":"Reciprocal immunopurification of CBP80/eIF4E mRNPs with co-purifying NMD factors; translation inhibitors to block NMD in human cells","pmids":["11551508"],"confidence":"High","gaps":["Did not isolate the specific contribution of NCBP2 versus CBP80","Mechanism of CBC-to-eIF4E exchange not resolved"]},{"year":2010,"claim":"Mapped cap and CBP80 binding to the RRM and revealed an RRM-deficient isoform, separating cap-reading from general mRNA association and localization.","evidence":"Splice-variant characterization, cap- and CBP80-binding assays, and live-cell imaging upon transcription inhibition","pmids":["21326824"],"confidence":"Medium","gaps":["Functional role of the CBP20S isoform not established","Single-lab study without structural confirmation"]},{"year":2012,"claim":"Identified the specific cap-binding-pocket residues and linked cap recognition to a defined biological output (meiotic splicing of MER3), proving cap reading is functionally essential.","evidence":"Alanine-scanning mutagenesis, genetic epistasis, and intronless-MER3 cDNA rescue in yeast","pmids":["23002122"],"confidence":"High","gaps":["Demonstrated for a single transcript in yeast meiosis","Generality of intron-specific dependence in humans unaddressed"]},{"year":2020,"claim":"Placed NCBP2 upstream of apoptotic pathways in neurodevelopment and within the 3q29 deletion gene network, linking cap-binding machinery to organismal phenotypes.","evidence":"Tissue-specific RNAi and pairwise epistasis in Drosophila and Xenopus with apoptosis-inhibitor rescue","pmids":["32053595"],"confidence":"Medium","gaps":["Molecular mechanism connecting NCBP2 cap-binding to apoptosis not defined","Relevance to human 3q29 phenotypes inferred from orthologs"]},{"year":2023,"claim":"Connected NCBP2 cap-reader activity to oncogenic signaling by showing it enhances c-JUN translation to activate MEK/ERK in pancreatic cancer.","evidence":"Knockdown/overexpression cell lines, xenografts, and pathway western blots","pmids":["38001714"],"confidence":"Medium","gaps":["Direct cap-dependence of c-JUN translation not biochemically isolated","Single-lab, one tumor type"]},{"year":2025,"claim":"Quantified the consequence of NCBP2 loss as a cell-cycle and survival defect, framing it as a candidate dependency in cancer cells.","evidence":"Knockdown, viability/cell-cycle assays, and RNA sequencing in cancer cells","pmids":["40887503"],"confidence":"Medium","gaps":["Causal transcripts driving G1-S arrest not identified","Specificity versus general CBC disruption unresolved"]},{"year":2026,"claim":"Demonstrated transcript-selective regulation by NCBP2 — direct m7G-cap binding stabilizing LIPG mRNA to drive lipid metabolism and tumor progression.","evidence":"Knockdown/overexpression in CRC, direct RNA-protein binding to m7G cap, mRNA stability and lipid-droplet measurements, in vivo models","pmids":["41872454"],"confidence":"Medium","gaps":["How NCBP2 confers selectivity for LIPG over other capped mRNAs is unclear","Single-lab study"]},{"year":2026,"claim":"Proposed NCBP2-controlled alternative splicing of KIF23 and a KIF23-PGAM5 mitophagy axis, with FBXW8 as an E3 ligase degrading NCBP2.","evidence":"Proliferation/migration assays, alternative-splicing analysis, and a FBXW8 ubiquitination assay (single lab)","pmids":["41874817"],"confidence":"Low","gaps":["Splicing and ubiquitination claims have limited mechanistic validation","FBXW8-NCBP2 interaction not independently confirmed","Mitophagy link is correlative"]},{"year":null,"claim":"How NCBP2 achieves transcript selectivity for stabilization, splicing, and translational control while serving as a general cap reader, and how its turnover is regulated, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model explaining selective target recognition","Regulatory inputs controlling CBC versus eIF4E exchange in humans undefined","FBXW8-mediated degradation needs independent confirmation"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,2,3,6]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[3]},{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,1,2]}],"complexes":["nuclear cap-binding complex (CBC)"],"partners":["NCBP1","PABPN1","EIF4G1","UPF2","UPF3","FBXW8"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P52298","full_name":"Nuclear cap-binding protein subunit 2","aliases":["20 kDa nuclear cap-binding protein","Cell proliferation-inducing gene 55 protein","NCBP 20 kDa subunit","CBP20","NCBP-interacting protein 1","NIP1"],"length_aa":156,"mass_kda":18.0,"function":"Component of the cap-binding complex (CBC), which binds co-transcriptionally to the 5' cap of pre-mRNAs and is involved in various processes such as pre-mRNA splicing, translation regulation, nonsense-mediated mRNA decay, RNA-mediated gene silencing (RNAi) by microRNAs (miRNAs) and mRNA export. The CBC complex is involved in mRNA export from the nucleus via its interaction with ALYREF/THOC4/ALY, leading to the recruitment of the mRNA export machinery to the 5' end of mRNA and to mRNA export in a 5' to 3' direction through the nuclear pore. The CBC complex is also involved in mediating U snRNA and intronless mRNAs export from the nucleus. The CBC complex is essential for a pioneer round of mRNA translation, before steady state translation when the CBC complex is replaced by cytoplasmic cap-binding protein eIF4E. The pioneer round of mRNA translation mediated by the CBC complex plays a central role in nonsense-mediated mRNA decay (NMD), NMD only taking place in mRNAs bound to the CBC complex, but not on eIF4E-bound mRNAs. The CBC complex enhances NMD in mRNAs containing at least one exon-junction complex (EJC) via its interaction with UPF1, promoting the interaction between UPF1 and UPF2. The CBC complex is also involved in 'failsafe' NMD, which is independent of the EJC complex, while it does not participate in Staufen-mediated mRNA decay (SMD). During cell proliferation, the CBC complex is also involved in microRNAs (miRNAs) biogenesis via its interaction with SRRT/ARS2, thereby being required for miRNA-mediated RNA interference. The CBC complex also acts as a negative regulator of PARN, thereby acting as an inhibitor of mRNA deadenylation. In the CBC complex, NCBP2/CBP20 recognizes and binds capped RNAs (m7GpppG-capped RNA) but requires NCBP1/CBP80 to stabilize the movement of its N-terminal loop and lock the CBC into a high affinity cap-binding state with the cap structure. The conventional cap-binding complex with NCBP2 binds both small nuclear RNA (snRNA) and messenger (mRNA) and is involved in their export from the nucleus (PubMed:26382858)","subcellular_location":"Nucleus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/P52298/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/NCBP2","classification":"Common Essential","n_dependent_lines":1205,"n_total_lines":1208,"dependency_fraction":0.9975165562913907},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"RBM42","stoichiometry":4.0},{"gene":"CPSF6","stoichiometry":0.2},{"gene":"DDX21","stoichiometry":0.2},{"gene":"RBM39","stoichiometry":0.2},{"gene":"RBM8A","stoichiometry":0.2},{"gene":"SF3A1","stoichiometry":0.2},{"gene":"SNRPA","stoichiometry":0.2},{"gene":"SNRPB","stoichiometry":0.2},{"gene":"SNRPC","stoichiometry":0.2},{"gene":"SNRPF","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/NCBP2","total_profiled":1310},"omim":[{"mim_id":"621467","title":"NCBP2 ANTISENSE RNA 2 (HEAD TO HEAD); NCBP2AS2","url":"https://www.omim.org/entry/621467"},{"mim_id":"620106","title":"SPASTIC PARAPLEGIA 88, AUTOSOMAL DOMINANT; SPG88","url":"https://www.omim.org/entry/620106"},{"mim_id":"616970","title":"MARVEL DOMAIN-CONTAINING PROTEIN 1; MARVELD1","url":"https://www.omim.org/entry/616970"},{"mim_id":"616624","title":"NUCLEAR CAP-BINDING PROTEIN 3; NCBP3","url":"https://www.omim.org/entry/616624"},{"mim_id":"614469","title":"SERRATE RNA EFFECTOR MOLECULE; SRRT","url":"https://www.omim.org/entry/614469"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Basal body","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/NCBP2"},"hgnc":{"alias_symbol":["NIP1","CBP20","Cbc2"],"prev_symbol":[]},"alphafold":{"accession":"P52298","domains":[{"cath_id":"3.30.70.330","chopping":"18-148","consensus_level":"high","plddt":97.0128,"start":18,"end":148}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P52298","model_url":"https://alphafold.ebi.ac.uk/files/AF-P52298-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P52298-F1-predicted_aligned_error_v6.png","plddt_mean":93.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NCBP2","jax_strain_url":"https://www.jax.org/strain/search?query=NCBP2"},"sequence":{"accession":"P52298","fasta_url":"https://rest.uniprot.org/uniprotkb/P52298.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P52298/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P52298"}},"corpus_meta":[{"pmid":"11551508","id":"PMC_11551508","title":"Evidence for a pioneer round of mRNA translation: mRNAs subject to nonsense-mediated decay in mammalian cells are bound by CBP80 and CBP20.","date":"2001","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/11551508","citation_count":491,"is_preprint":false},{"pmid":"30019807","id":"PMC_30019807","title":"Simultaneous CRISPR/Cas9-mediated editing of cassava eIF4E isoforms nCBP-1 and nCBP-2 reduces cassava brown streak disease symptom severity and incidence.","date":"2018","source":"Plant biotechnology journal","url":"https://pubmed.ncbi.nlm.nih.gov/30019807","citation_count":176,"is_preprint":false},{"pmid":"18829588","id":"PMC_18829588","title":"Two cap-binding proteins CBP20 and CBP80 are involved in processing primary MicroRNAs.","date":"2008","source":"Plant & cell physiology","url":"https://pubmed.ncbi.nlm.nih.gov/18829588","citation_count":138,"is_preprint":false},{"pmid":"8682299","id":"PMC_8682299","title":"The yeast splicing factor Mud13p is a commitment complex component and corresponds to CBP20, the small subunit of the nuclear cap-binding complex.","date":"1996","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/8682299","citation_count":130,"is_preprint":false},{"pmid":"30723174","id":"PMC_30723174","title":"Hypoxic cancer-associated fibroblasts increase NCBP2-AS2/HIAR to promote endothelial sprouting through enhanced VEGF signaling.","date":"2019","source":"Science signaling","url":"https://pubmed.ncbi.nlm.nih.gov/30723174","citation_count":99,"is_preprint":false},{"pmid":"32053595","id":"PMC_32053595","title":"NCBP2 modulates neurodevelopmental defects of the 3q29 deletion in Drosophila and Xenopus laevis models.","date":"2020","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/32053595","citation_count":38,"is_preprint":false},{"pmid":"27870849","id":"PMC_27870849","title":"Phosphorylation of CBP20 Links MicroRNA to Root Growth in the Ethylene Response.","date":"2016","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/27870849","citation_count":32,"is_preprint":false},{"pmid":"23002122","id":"PMC_23002122","title":"Genetic interactions of hypomorphic mutations in the m7G cap-binding pocket of yeast nuclear cap binding complex: an essential role for Cbc2 in meiosis via splicing of MER3 pre-mRNA.","date":"2012","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/23002122","citation_count":26,"is_preprint":false},{"pmid":"37067401","id":"PMC_37067401","title":"m7G-related genes-NCBP2 and EIF4E3 determine immune contexture in head and neck squamous cell carcinoma by regulating CCL4/CCL5 expression.","date":"2023","source":"Molecular carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/37067401","citation_count":21,"is_preprint":false},{"pmid":"21326824","id":"PMC_21326824","title":"Binding properties and dynamic localization of an alternative isoform of the cap-binding complex subunit CBP20.","date":"2010","source":"Nucleus (Austin, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/21326824","citation_count":18,"is_preprint":false},{"pmid":"38001714","id":"PMC_38001714","title":"The m7G Reader NCBP2 Promotes Pancreatic Cancer Progression by Upregulating MAPK/ERK Signaling.","date":"2023","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/38001714","citation_count":16,"is_preprint":false},{"pmid":"33180718","id":"PMC_33180718","title":"Cuticular waxes-A shield of barley mutant in CBP20 (Cap-Binding Protein 20) gene when struggling with drought stress.","date":"2020","source":"Plant science : an international journal of experimental plant biology","url":"https://pubmed.ncbi.nlm.nih.gov/33180718","citation_count":12,"is_preprint":false},{"pmid":"37483091","id":"PMC_37483091","title":"Anisomycin inhibits the activity of human ovarian cancer stem cells via regulating antisense RNA NCBP2-AS2/MEK/ERK/STAT3 signaling.","date":"2023","source":"The journal of gene medicine","url":"https://pubmed.ncbi.nlm.nih.gov/37483091","citation_count":4,"is_preprint":false},{"pmid":"38964031","id":"PMC_38964031","title":"Comprehensive investigation in oncogenic functions and immunological roles of NCBP2 and its validation in prostate cancer.","date":"2024","source":"Translational oncology","url":"https://pubmed.ncbi.nlm.nih.gov/38964031","citation_count":3,"is_preprint":false},{"pmid":"39975220","id":"PMC_39975220","title":"NCBP2-AS2 is a mitochondrial microprotein, regulates energy metabolism and neurogenesis, and is downregulated in Alzheimer's disease.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/39975220","citation_count":3,"is_preprint":false},{"pmid":"40887503","id":"PMC_40887503","title":"Comprehensive profiling of RNA modification-related genes identifies RNA m7G binding protein CBP20 as a therapeutic target for tumor growth inhibition.","date":"2025","source":"Experimental & molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/40887503","citation_count":2,"is_preprint":false},{"pmid":"7584487","id":"PMC_7584487","title":"The production and preclinical characterization of a chimeric anti-breast-cancer antibody, cBC2.","date":"1994","source":"Therapeutic immunology","url":"https://pubmed.ncbi.nlm.nih.gov/7584487","citation_count":2,"is_preprint":false},{"pmid":"41065851","id":"PMC_41065851","title":"A2M-AS1, DBH-AS1, and NCBP2-AS2 in breast cancer: expression patterns, CA125-3 association, and a DBH-AS1-NCBP2-AS2 axis.","date":"2025","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/41065851","citation_count":0,"is_preprint":false},{"pmid":"41872454","id":"PMC_41872454","title":"NCBP2 drives colorectal cancer growth and metastasis through LIPG-mediated lipid droplet accumulation.","date":"2026","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/41872454","citation_count":0,"is_preprint":false},{"pmid":"41874817","id":"PMC_41874817","title":"NCBP2 Regulates PGAM5-Mediated Mitophagy Via KIF23 Alternative Splicing To Promote Cervical Cancer ProgressionRun Title: NCBP2 Promotes Cervical Cancer Via Mitophagy.","date":"2026","source":"Applied biochemistry and biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/41874817","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.01.25.634884","title":"NCBP2-AS2 is a mitochondrial microprotein, regulates energy metabolism and neurogenesis, and is downregulated in Alzheimer’s disease","date":"2025-01-27","source":"bioRxiv","url":"https://doi.org/10.1101/2025.01.25.634884","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":12847,"output_tokens":2394,"usd":0.037226,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9488,"output_tokens":3182,"usd":0.063495,"stage2_stop_reason":"end_turn"},"total_usd":0.100721,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"CBP20 (NCBP2) is a component of the NMD-susceptible mRNP complex that also contains CBP80, PABP2, eIF4G, Upf2, and Upf3, and is present on mRNAs undergoing a 'pioneer' round of translation before CBP80-CBP20 are replaced by eIF4E.\",\n      \"method\": \"Immunopurification of RNP with antibody to CBP80 or eIF4E, followed by identification of co-purifying components; NMD blocked by cycloheximide or suppressor tRNA\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal immunopurification with multiple co-purifying factors identified, functional validation by translation inhibitors, foundational study widely replicated\",\n      \"pmids\": [\"11551508\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Yeast Mud13p/Cbc2 (ortholog of CBP20/NCBP2) is a component of the splicing commitment complex and is required for early steps of spliceosome assembly, functioning as the small cap-binding subunit of the nuclear cap-binding complex (CBC).\",\n      \"method\": \"Genetic screen for synthetic lethality with U1 snRNA mutations; characterization of splicing in delta-MUD13 yeast strains and extracts; biochemical identification of Mud13p as yeast CBC small subunit\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis combined with biochemical characterization of commitment complex composition and splicing assays in yeast extracts\",\n      \"pmids\": [\"8682299\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Yeast Cbc2 (CBP20/NCBP2 ortholog) binds the m7G cap via specific residues in its cap-binding pocket (Y24, F91, D120, D122, R129, R133), and cap recognition by Cbc2 is essential for meiosis through splicing of MER3 pre-mRNA; an intronless MER3 cDNA fully rescues the sporulation defect of cbc2-NΔ42.\",\n      \"method\": \"Alanine scanning and N-terminal deletion mutagenesis; genetic interaction screens (synthetic lethality with spliceosome assembly factors); RNA analysis of pre-mRNA splicing in meiosis; rescue with intronless MER3 cDNA\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — active-site mutagenesis combined with genetic epistasis, specific pathway rescue experiment, and direct RNA splicing analysis\",\n      \"pmids\": [\"23002122\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Full-length CBP20 (NCBP2) binds CBP80 and the m7G cap via its RNA recognition motif (RRM); an alternatively spliced isoform CBP20S lacking most of the RRM fails to bind CBP80 or the m7G cap but retains mRNA binding and localizes to active transcription sites and nucleolar caps upon transcription inhibition.\",\n      \"method\": \"Characterization of alternative splice variant; cap-binding and CBP80-binding assays; live-cell imaging and localization upon transcription inhibition\",\n      \"journal\": \"Nucleus (Austin, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding assays and live imaging with functional localization data, single lab study\",\n      \"pmids\": [\"21326824\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"NCBP2 (via its Drosophila ortholog Cbp20 and Xenopus ortholog ncbp2) genetically interacts with other 3q29 deletion region genes to enhance apoptosis, disrupt cellular organization, and impair brain morphology; these defects are rescued by overexpression of apoptosis inhibitors Diap1 and xiap, placing NCBP2 upstream of apoptotic pathways during neurodevelopment.\",\n      \"method\": \"Tissue-specific RNAi knockdown in Drosophila melanogaster and Xenopus laevis; quantitative phenotypic assays for apoptosis and brain morphology; pairwise knockdown epistasis screen; rescue by apoptosis inhibitor overexpression\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with rescue experiment in two independent model organisms, single lab\",\n      \"pmids\": [\"32053595\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"NCBP2 promotes pancreatic ductal adenocarcinoma progression by enhancing translation of c-JUN, which activates MEK/ERK signaling; NCBP2 knockdown inhibits PDAC cell proliferation and NCBP2 overexpression promotes growth in vitro and in vivo.\",\n      \"method\": \"Stable NCBP2 knockdown and overexpression cell lines; in vitro proliferation assays; in vivo xenograft models; western blot for c-JUN and MEK/ERK pathway components\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function and gain-of-function with defined molecular pathway, in vitro and in vivo, single lab\",\n      \"pmids\": [\"38001714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"NCBP2 stabilizes LIPG mRNA via direct binding to the m7G motif in the 5'-cap structure of LIPG mRNA, increasing LIPG expression and promoting lipid droplet accumulation in colorectal cancer cells, driving CRC proliferation, migration, and invasion.\",\n      \"method\": \"NCBP2 overexpression and knockdown in CRC cell lines and in vivo models; direct RNA-protein binding assay to m7G cap structure; measurement of LIPG mRNA stability and lipid droplet accumulation; in vivo tumor models\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding to m7G cap demonstrated, functional downstream effects measured, single lab\",\n      \"pmids\": [\"41872454\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"NCBP2 regulates alternative splicing of KIF23 to promote cervical cancer progression; NCBP2 also regulates mitophagy via the KIF23-PGAM5 axis; FBXW8 ubiquitinates and degrades NCBP2, inhibiting overactivation of mitophagy.\",\n      \"method\": \"CCK-8, EdU, Transwell assays; RT-qPCR and western blot; bioinformatics screening; alternative splicing analysis of KIF23; ubiquitination assay for FBXW8-mediated NCBP2 degradation\",\n      \"journal\": \"Applied biochemistry and biotechnology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, primarily expression-level readouts with limited mechanistic validation of splicing and ubiquitination claims in abstracts\",\n      \"pmids\": [\"41874817\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NCBP2 knockdown leads to reduced cancer cell viability, apoptosis induction, and G1-S cell cycle arrest; RNA sequencing confirmed downregulation of cell-cycle-related pathways upon CBP20 depletion in cancer cells.\",\n      \"method\": \"NCBP2 knockdown; cell viability assays; cell cycle analysis; RNA sequencing\",\n      \"journal\": \"Experimental & molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined cellular phenotype and transcriptomic pathway readout, single lab\",\n      \"pmids\": [\"40887503\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NCBP2 (CBP20) is the small subunit of the nuclear cap-binding complex (CBC) that directly contacts the m7G cap of RNA Pol II transcripts via its RRM domain; in complex with CBP80, it facilitates early spliceosome assembly (commitment complex formation), the pioneer round of mRNA translation (enabling NMD surveillance), and pre-mRNA splicing of specific transcripts (e.g., MER3 during meiosis); as an m7G cap reader it also stabilizes target mRNAs such as LIPG, activates downstream translation (c-JUN/MEK/ERK), regulates alternative splicing (KIF23), and its loss triggers apoptosis and cell cycle arrest, with FBXW8 identified as a ubiquitin E3 ligase that degrades NCBP2.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NCBP2 (CBP20) is the small, cap-binding subunit of the nuclear cap-binding complex (CBC), where it directly contacts the m7G cap of RNA Pol II transcripts through its RNA recognition motif (RRM) while heterodimerizing with the large subunit CBP80 [#3]. Conserved cap-recognition residues in the cap-binding pocket are essential for function: in yeast, cap binding by the ortholog Cbc2 is required for splicing of MER3 pre-mRNA and thereby for meiosis, as an intronless MER3 cDNA rescues the cap-binding-defective mutant [#2]. As the CBC small subunit, NCBP2/Cbc2 acts at the earliest steps of spliceosome assembly, forming part of the splicing commitment complex [#1], and persists on newly exported transcripts as part of an mRNP that includes CBP80, PABP2, eIF4G, Upf2, and Upf3 to direct the pioneer round of translation that licenses nonsense-mediated decay before CBC is replaced by eIF4E [#0]. An alternatively spliced isoform (CBP20S) lacking most of the RRM cannot bind CBP80 or the cap yet retains general mRNA binding and accumulates at transcription sites and nucleolar caps [#3]. Through its cap-reader activity NCBP2 influences specific transcripts and downstream programs: it stabilizes LIPG mRNA via direct m7G-cap binding to drive lipid-droplet accumulation in colorectal cancer [#6] and enhances translation of c-JUN to activate MEK/ERK signaling in pancreatic cancer [#5], and its depletion reduces viability, induces apoptosis, and causes G1-S cell cycle arrest [#8]. NCBP2 also acts upstream of apoptotic pathways during neurodevelopment, interacting with other 3q29-deletion genes to modulate apoptosis and brain morphology in a manner rescued by apoptosis inhibitors [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Established that the CBP20 ortholog is a functional CBC subunit acting at the entry point of spliceosome assembly, defining the complex's role in pre-mRNA splicing rather than merely cap protection.\",\n      \"evidence\": \"Synthetic-lethal genetic screen with U1 snRNA mutations and splicing assays in delta-MUD13 yeast extracts\",\n      \"pmids\": [\"8682299\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the cap-binding residues or RRM contribution\", \"Commitment-complex role demonstrated in yeast, not human cells\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Showed CBP20 persists on exported mRNA in a defined mRNP and marks the pioneer round of translation that enables NMD, distinguishing CBC-bound from eIF4E-bound translation.\",\n      \"evidence\": \"Reciprocal immunopurification of CBP80/eIF4E mRNPs with co-purifying NMD factors; translation inhibitors to block NMD in human cells\",\n      \"pmids\": [\"11551508\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not isolate the specific contribution of NCBP2 versus CBP80\", \"Mechanism of CBC-to-eIF4E exchange not resolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Mapped cap and CBP80 binding to the RRM and revealed an RRM-deficient isoform, separating cap-reading from general mRNA association and localization.\",\n      \"evidence\": \"Splice-variant characterization, cap- and CBP80-binding assays, and live-cell imaging upon transcription inhibition\",\n      \"pmids\": [\"21326824\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional role of the CBP20S isoform not established\", \"Single-lab study without structural confirmation\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified the specific cap-binding-pocket residues and linked cap recognition to a defined biological output (meiotic splicing of MER3), proving cap reading is functionally essential.\",\n      \"evidence\": \"Alanine-scanning mutagenesis, genetic epistasis, and intronless-MER3 cDNA rescue in yeast\",\n      \"pmids\": [\"23002122\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Demonstrated for a single transcript in yeast meiosis\", \"Generality of intron-specific dependence in humans unaddressed\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Placed NCBP2 upstream of apoptotic pathways in neurodevelopment and within the 3q29 deletion gene network, linking cap-binding machinery to organismal phenotypes.\",\n      \"evidence\": \"Tissue-specific RNAi and pairwise epistasis in Drosophila and Xenopus with apoptosis-inhibitor rescue\",\n      \"pmids\": [\"32053595\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism connecting NCBP2 cap-binding to apoptosis not defined\", \"Relevance to human 3q29 phenotypes inferred from orthologs\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Connected NCBP2 cap-reader activity to oncogenic signaling by showing it enhances c-JUN translation to activate MEK/ERK in pancreatic cancer.\",\n      \"evidence\": \"Knockdown/overexpression cell lines, xenografts, and pathway western blots\",\n      \"pmids\": [\"38001714\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct cap-dependence of c-JUN translation not biochemically isolated\", \"Single-lab, one tumor type\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Quantified the consequence of NCBP2 loss as a cell-cycle and survival defect, framing it as a candidate dependency in cancer cells.\",\n      \"evidence\": \"Knockdown, viability/cell-cycle assays, and RNA sequencing in cancer cells\",\n      \"pmids\": [\"40887503\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal transcripts driving G1-S arrest not identified\", \"Specificity versus general CBC disruption unresolved\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Demonstrated transcript-selective regulation by NCBP2 — direct m7G-cap binding stabilizing LIPG mRNA to drive lipid metabolism and tumor progression.\",\n      \"evidence\": \"Knockdown/overexpression in CRC, direct RNA-protein binding to m7G cap, mRNA stability and lipid-droplet measurements, in vivo models\",\n      \"pmids\": [\"41872454\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How NCBP2 confers selectivity for LIPG over other capped mRNAs is unclear\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Proposed NCBP2-controlled alternative splicing of KIF23 and a KIF23-PGAM5 mitophagy axis, with FBXW8 as an E3 ligase degrading NCBP2.\",\n      \"evidence\": \"Proliferation/migration assays, alternative-splicing analysis, and a FBXW8 ubiquitination assay (single lab)\",\n      \"pmids\": [\"41874817\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Splicing and ubiquitination claims have limited mechanistic validation\", \"FBXW8-NCBP2 interaction not independently confirmed\", \"Mitophagy link is correlative\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How NCBP2 achieves transcript selectivity for stabilization, splicing, and translational control while serving as a general cap reader, and how its turnover is regulated, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model explaining selective target recognition\", \"Regulatory inputs controlling CBC versus eIF4E exchange in humans undefined\", \"FBXW8-mediated degradation needs independent confirmation\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 2, 3, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"R-HSA-72163\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"complexes\": [\"nuclear cap-binding complex (CBC)\"],\n    \"partners\": [\"NCBP1\", \"PABPN1\", \"EIF4G1\", \"UPF2\", \"UPF3\", \"FBXW8\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}