{"gene":"NCBP1","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2001,"finding":"CBP80 (NCBP1) is associated with newly synthesized mRNAs undergoing a 'pioneer' round of translation; NMD targets CBP80-bound mRNAs (not yet replaced by eIF4E), and the NMD-susceptible mRNP includes CBP20, PABP2, eIF4G, Upf2, and Upf3 as components. NMD of CBP80-bound mRNA is blocked by cycloheximide or suppressor tRNA, confirming translation-dependence.","method":"Antibody immunopurification of CBP80-bound vs. eIF4E-bound mRNPs; cycloheximide and suppressor tRNA inhibition assays","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal immunopurification with multiple orthogonal functional tests (drug inhibition, suppressor tRNA), foundational study replicated extensively","pmids":["11551508"],"is_preprint":false},{"year":2002,"finding":"CBP80 (NCBP1), but not nuclear eIF4E, is detected in association with intron-containing RNA and the C-terminal domain of RNA polymerase II. The exon junction complex (EJC) components RNPS1, Y14, SRm160, REF/Aly, TAP, Upf3X, and Upf2 are detected on CBP80-bound mRNA in both nuclear and cytoplasmic fractions, but not on eIF4E-bound mRNA, indicating these proteins travel with CBP80-mRNPs after export.","method":"Immunoprecipitation of CBP80-bound vs. eIF4E-bound mRNPs; nuclear/cytoplasmic fractionation; Western blotting","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal IP with fractionation, multiple components tested, independently replicated in subsequent studies","pmids":["12093754"],"is_preprint":false},{"year":1995,"finding":"NCBP1 (CBP80) interacts with three nuclear cap-binding protein interacting proteins (NIP1, NIP2, NIP3) identified by yeast two-hybrid; NCBP1 requires NIP1 (which has an RNP-type RNA binding domain) for binding to the cap structure.","method":"Yeast two-hybrid screen from HeLa cell cDNA library; cap-binding assay","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — yeast two-hybrid plus cap-binding functional assay, single lab, early mechanistic work","pmids":["7478990"],"is_preprint":false},{"year":2005,"finding":"CBP80 (NCBP1) directly interacts with Upf1 and promotes the interaction of Upf1 with Upf2 during NMD, but does not promote Upf1 interaction with Stau1 (which mediates SMD). CBP80 augments the efficiency of NMD but not Staufen1-mediated mRNA decay (SMD).","method":"Co-immunoprecipitation; siRNA knockdown; NMD efficiency assays","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP with functional NMD efficiency assays, discriminated between two decay pathways with multiple orthogonal approaches","pmids":["16186820"],"is_preprint":false},{"year":2005,"finding":"CBP80 (NCBP1) and eIF4G share a common evolutionary origin and similar domain organization (consecutive HEAT domains). A structural model based on the CBP80-CBP20 crystal structure suggests conserved mutual orientation of domains relevant for translation initiation complex assembly.","method":"Computational domain analysis; structural modeling using known CBP80-CBP20 complex structure","journal":"Biochemistry","confidence":"Low","confidence_rationale":"Tier 4 / Weak — primarily computational/structural modeling, limited direct experimental validation in this paper","pmids":["16156639"],"is_preprint":false},{"year":2009,"finding":"CBP80 (NCBP1) directly interacts with CTIF (CBP80/20-dependent translation initiation factor), a new MIF4G domain-containing protein. CTIF is part of the CBP80/20-dependent translation initiation complex, and depletion of CTIF from an in vitro translation system selectively blocks translation of CBP80-bound mRNAs; addition of purified CTIF restores it. CTIF localizes to the perinuclear region, and its down-regulation abrogates NMD.","method":"Co-immunoprecipitation; in vitro translation system depletion/reconstitution; siRNA knockdown; confocal microscopy","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with depletion and add-back, Co-IP, localization, and NMD functional assay; multiple orthogonal methods in one study","pmids":["19648179"],"is_preprint":false},{"year":2010,"finding":"UPF1 binding to CBP80 (NCBP1) promotes NMD at two distinct steps: (1) association of SMG1 and UPF1 with eukaryotic release factors (eRFs) during SURF complex formation at a premature termination codon, and (2) subsequent association of SMG1 and UPF1 with an exon-junction complex. UPF1 binds PTC-containing mRNA more efficiently than PTC-free mRNA in a manner promoted by the UPF1-CBP80 interaction.","method":"Dominant-negative mutant precluding UPF1-CBP80 interaction; co-immunoprecipitation; mRNA binding assays; NMD reporter assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (dominant-negative mutant, Co-IP, functional NMD assay, mRNA binding), mechanistic dissection of two distinct steps","pmids":["20691628"],"is_preprint":false},{"year":2009,"finding":"CBP80 (NCBP1) is present in neuronal dendrites and associates with LSm1-mRNPs assembled in the nucleus; both LSm1 and CBP80 shift into dendritic spines upon stimulation of glutamatergic receptors, suggesting these CBP80-containing mRNPs are translationally activated during local protein synthesis.","method":"Immunofluorescence; subcellular fractionation; glutamatergic receptor stimulation; confocal microscopy","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — localization experiment with functional correlate (receptor stimulation), single lab, localization tied to translational activation context","pmids":["19188494"],"is_preprint":false},{"year":2012,"finding":"CTIF (CBP80/20-dependent translation initiation factor) specifically interacts with eIF3g (a component of the eIF3 ribosome-recruitment complex), bridging CBP80 and eIF3 to enable ribosome recruitment during CBP80/20-dependent translation. Down-regulation of CTIF redistributes CBP80 from polysome to subpolysome fractions without affecting eIF4E distribution. Artificial tethering of CTIF to an intercistronic region drives translation of the downstream cistron in an eIF3-dependent manner.","method":"Co-immunoprecipitation; polysome fractionation; siRNA knockdown; tethering assay; NMD reporter assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods including Co-IP, polysome fractionation, tethering assay, and functional NMD assay in single study","pmids":["22493286"],"is_preprint":false},{"year":2015,"finding":"NCBP1 (CBP80), but not NCBP2 (CBP20), is required for cell viability and poly(A) RNA nuclear export. NCBP1 forms an alternative cap-binding complex with NCBP3 (C17orf85) that binds mRNA, associates with mRNA processing machinery, and contributes to poly(A) RNA export. Loss of NCBP3 is compensated by NCBP2 under steady-state conditions but NCBP3 becomes critical under stress (e.g., virus infection).","method":"Knockdown/knockout viability assays; RNA export assays (FISH); mass spectrometry interactome; Co-immunoprecipitation","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (MS interactome, Co-IP, functional RNA export assay, cell viability), identification of alternative complex with NCBP3","pmids":["26382858"],"is_preprint":false},{"year":2008,"finding":"NMD triggered by EMCV IRES-initiated translation targets CBP80/20-bound mRNA but does not detectably target eIF4E-bound mRNA, establishing that even IRES-initiated translation undergoes a CBP80-associated pioneer round leading to NMD when translation terminates prematurely.","method":"NMD reporter assays with EMCV IRES constructs; immunoprecipitation of CBP80-bound vs. eIF4E-bound mRNA fractions","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional NMD assay with IRES constructs plus fractionation, single lab, mechanistic extension of established CBP80-NMD framework","pmids":["18369367"],"is_preprint":false},{"year":2011,"finding":"In yeast, the CBP80 ortholog Cbc1/Sto1 associates with polysomes and is required for rapid translation reinitiation after osmotic stress. Deletion of CBC1 causes hypersensitivity to cycloheximide and synthetic sickness with limiting eIF4E. Osmostress-responsive mRNAs are transcriptionally induced in cbc1Δ cells but fail to rapidly associate with polysomes. Under osmotic stress, Cbc1 relocalizes from nucleus to cytoplasm.","method":"Polysome fractionation; genetic epistasis (cbc1Δ, eIF4E temperature-sensitive allele); cycloheximide sensitivity assay; live-cell localization","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — polysome fractionation, genetic epistasis, localization experiment, multiple functional readouts in yeast ortholog","pmids":["22072789"],"is_preprint":false},{"year":2011,"finding":"Ago2 competes with CBP80/20 for cap association, thereby inhibiting CBP80/20-dependent translation (CT) and abrogating NMD that is coupled to CT. Tethering of Ago2 (but not of cap-association-deficient Ago2F2V2) to the 3'UTR of PTC-containing mRNA abrogates NMD. Immunoprecipitation with CBP80 antibody confirms that Ago2, but not Ago2F2V2, inhibits binding of CBP80/20 to the cap structure.","method":"Tethering assay; co-immunoprecipitation with CBP80 antibody; NMD reporter assay; Ago2 mutant (F2V2)","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with functional NMD assay and mutant discrimination, single lab","pmids":["21840310"],"is_preprint":false},{"year":2018,"finding":"CBP80 (NCBP1) binds the HIV-1 viral protein Rev and the unspliced full-length mRNA in both nucleus and cytoplasm. CBP80 supports Rev-mediated nuclear export and translation of the unspliced mRNA. Rev interacts with DEAD-box helicase eIF4AI, and the Rev/RRE axis is required for assembly of a CBP80-eIF4AI complex on the unspliced mRNA.","method":"Co-immunoprecipitation; RNA immunoprecipitation; translation and nuclear export assays; RIP","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, RNA-IP, and functional export/translation assays, single lab study","pmids":["30239828"],"is_preprint":false},{"year":2010,"finding":"In yeast, Cbp80 (NCBP1 ortholog) plays distinct roles in splicing: it promotes initial 5' splice site recognition by U1 snRNP and, independently, facilitates U2 snRNP recruitment in a manner dependent on sequences near the 5' splice site. Deletion of Cbp80 suppresses the splicing defect caused by a mutation in the RPL30 binding site that normally disrupts L30-mediated splicing repression.","method":"Genetic epistasis (cbp80 deletion suppressor screen); splicing assays","journal":"RNA (New York, N.Y.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis (suppressor screen) with mechanistic splicing assays, yeast ortholog, single lab","pmids":["20801768"],"is_preprint":false},{"year":2019,"finding":"NCBP1 up-regulates CUL4B expression via interaction with NCBP3, constituting an NCBP1-NCBP3-CUL4B axis that promotes lung cancer cell growth. CUL4B silencing significantly reverses NCBP1-induced tumorigenesis in vitro.","method":"Co-immunoprecipitation; knockdown/overexpression; cell growth and migration assays; CUL4B rescue experiment","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP plus functional rescue experiment, single lab, moderate mechanistic resolution","pmids":["31448526"],"is_preprint":false},{"year":2019,"finding":"In Drosophila, Cbp80 (NCBP1 ortholog) cooperates with Paip2 at active promoters to ensure proper RNA polymerase II CTD Ser5 phosphorylation, linking the cap-binding complex to transcription initiation/early elongation.","method":"Co-immunoprecipitation; ChIP; Pol II CTD phosphorylation assay; ~300 kDa complex characterization","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with ChIP and functional Pol II phosphorylation assay, Drosophila ortholog, single lab","pmids":["31001806"],"is_preprint":false},{"year":2023,"finding":"NCBP1 enhances the m6A catalytic function of METTL3 by maintaining METTL3 mRNA stabilization, leading to increased m6A modification of c-MYC mRNA and enhanced DLBCL cell proliferation via the NCBP1/METTL3/m6A/c-MYC axis.","method":"Co-immunoprecipitation; siRNA knockdown; m6A methylation assay; mRNA stability assay; cell proliferation assay","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP with functional m6A and mRNA stability assays, single lab","pmids":["37244946"],"is_preprint":false},{"year":2024,"finding":"NCBP1 is recruited by IGF2BP3 to inhibit CDK6 mRNA decay; IGF2BP3 recognizes m6A modification at the GGACU motif (nucleotides 110-114) in the 5'UTR of CDK6 mRNA and recruits NCBP1 to enhance CDK6 mRNA stability, thereby inhibiting renal tubular senescence.","method":"Co-immunoprecipitation (IP-MS); m6A site mapping; mRNA stability assay; siRNA knockdown; overexpression rescue","journal":"Translational research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — IP-MS plus functional mRNA stability and rescue experiments, single lab","pmids":["38945255"],"is_preprint":false},{"year":2026,"finding":"NCBP1 propagates nuclear electrophile stress signals through a single cysteine residue (C436). Electrophile modification of NCBP1(C436) impairs association between NCBP1 and SF3A1 (an essential spliceosome component), triggering alternative splicing of >250 genes including S6 kinase, whose alternatively spliced isoform is sufficient to inhibit global protein translation.","method":"Precision localized electrophile generation; genetic code expansion; alternative splicing sequencing; Co-immunoprecipitation (NCBP1-SF3A1 interaction); site-directed mutagenesis (C436); polysome/translation assays","journal":"Nature chemical biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — site-directed mutagenesis at specific cysteine, Co-IP, alternative splicing profiling, and functional translation assay with multiple orthogonal methods in single rigorous study","pmids":["41667655"],"is_preprint":false},{"year":2026,"finding":"Ncbp1 depletion in mouse embryos causes morula arrest with nuclear poly(A) RNA retention and downregulation of lipid metabolic pathways, notably SCD1 (stearoyl-CoA desaturase 1). Exogenous oleic acid supplementation partially rescues blastocyst formation, implicating NCBP1 in SCD1-OA-mediated lipid metabolic homeostasis during morula-to-blastocyst transition via its role in mRNA export.","method":"siRNA knockdown via zygotic microinjection; mRNA rescue (co-injection); poly(A) RNA FISH; RNA sequencing; quantitative proteomics; oleic acid rescue experiment","journal":"Reproduction (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with mRNA rescue, poly(A) FISH, transcriptomics and proteomics, functional rescue, single lab","pmids":["41575276"],"is_preprint":false},{"year":2020,"finding":"CTIF inhibits HIV-1 Gag synthesis by associating with HIV-1 Rev through its N-terminal domain and being recruited onto the full-length RNA RNP complex. CTIF induces cytoplasmic accumulation of Rev, impeding Rev association with CBP80. Rev and CTIF compete for binding to CBP80, establishing a regulatory interplay between the CBC-dependent translation machinery and HIV-1 replication.","method":"Co-immunoprecipitation; subcellular fractionation; siRNA knockdown; translation reporter assays","journal":"RNA biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with functional translation and localization assays, single lab","pmids":["33103564"],"is_preprint":false},{"year":2017,"finding":"In Drosophila, Cbp80 (NCBP1 ortholog) knockdown in the female germline leads to delocalization and reduced protein levels of the piRNA pathway factors Piwi, Aub, and Ago3, and impairs both primary piRNA biogenesis and the ping-pong secondary amplification cycle, without significantly altering piRNA precursor transcript levels or nuage localization.","method":"Germline-specific RNAi knockdown; small RNA sequencing; immunofluorescence for piRNA pathway factors","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — knockdown with sequencing and localization, Drosophila ortholog, single lab","pmids":["28746365"],"is_preprint":false}],"current_model":"NCBP1 (CBP80) is the large subunit of the nuclear cap-binding complex (CBC) that binds the 5'-cap of newly synthesized RNA and orchestrates multiple steps of mRNA biogenesis: it associates with pre-mRNA co-transcriptionally (interacting with RNA Pol II CTD), promotes U1 and U2 snRNP recruitment for splicing, mediates poly(A) mRNA nuclear export (either with NCBP2 or the alternative partner NCBP3), and directs a 'pioneer' round of cytoplasmic translation by recruiting the specific initiation factor CTIF, which bridges NCBP1 to eIF3g for ribosome recruitment; during this pioneer round, NCBP1 scaffolds the NMD machinery by directly binding UPF1 and promoting UPF1-UPF2 interaction, enabling SURF complex formation and EJC engagement at premature termination codons; NCBP1 also receives and propagates nuclear stress signals through a specific cysteine (C436) that, when electrophile-modified, disrupts interaction with spliceosome component SF3A1 to drive alternative splicing and translation inhibition."},"narrative":{"mechanistic_narrative":"NCBP1 (CBP80) is the large subunit of the nuclear cap-binding complex that binds the 5'-cap of newly synthesized mRNA and coordinates downstream steps of mRNA biogenesis, from co-transcriptional loading through nuclear export, splicing, and a pioneer round of translation [PMID:11551508, PMID:12093754]. It associates with intron-containing RNA and the RNA polymerase II C-terminal domain, and CBP80-bound mRNPs carry exon-junction complex components and NMD factors into the cytoplasm, whereas eIF4E-bound mRNPs do not [PMID:12093754]. During the pioneer round, CBP80-bound mRNAs are the substrate for nonsense-mediated decay: NCBP1 directly binds UPF1 and promotes UPF1-UPF2 interaction, driving SURF complex assembly with SMG1 and release factors at premature termination codons and subsequent engagement of the exon-junction complex [PMID:16186820, PMID:20691628]. NCBP1 directs cap-dependent translation of these mRNPs by recruiting the dedicated initiation factor CTIF, which bridges NCBP1 to eIF3g for ribosome recruitment [PMID:19648179, PMID:22493286]. Beyond the canonical CBP80-CBP20 partnership, NCBP1 forms an alternative cap-binding complex with NCBP3 that supports poly(A) RNA nuclear export and is essential for cell viability [PMID:26382858]. NCBP1 also serves as a sensor of nuclear electrophile stress through cysteine C436: modification of this residue disrupts the NCBP1-SF3A1 interaction, triggering widespread alternative splicing and translational repression [PMID:41667655]. In several cancer and disease contexts, NCBP1 has been linked to mRNA stabilization programs, including an NCBP1-NCBP3-CUL4B axis in lung cancer, METTL3/m6A-dependent c-MYC regulation in lymphoma, and IGF2BP3-recruited stabilization of CDK6 mRNA [PMID:31448526, PMID:37244946, PMID:38945255].","teleology":[{"year":1995,"claim":"Established how NCBP1 achieves cap binding, showing it does not act alone but requires partner subunits with RNA-binding capacity.","evidence":"Yeast two-hybrid screen and cap-binding assay identifying NIP1/2/3 interactors","pmids":["7478990"],"confidence":"Medium","gaps":["Identity of NIPs relative to the later-defined CBP20/NCBP2 not resolved here","Functional consequences of the cap binding in vivo not tested"]},{"year":2001,"claim":"Defined NCBP1 as the mark of newly synthesized 'pioneer' mRNPs and showed these, not eIF4E-bound mRNAs, are the substrate for NMD, linking cap identity to mRNA surveillance.","evidence":"Reciprocal immunopurification of CBP80- vs eIF4E-bound mRNPs with cycloheximide and suppressor tRNA inhibition","pmids":["11551508"],"confidence":"High","gaps":["Direct molecular bridge from CBP80 to NMD factors not yet defined","Translation initiation mechanism for CBP80-mRNPs unknown"]},{"year":2002,"claim":"Connected NCBP1 to co-transcriptional loading and cytoplasmic cargo delivery, showing CBP80-mRNPs associate with Pol II CTD and carry EJC/NMD components after export.","evidence":"Immunoprecipitation with nuclear/cytoplasmic fractionation and Western blotting","pmids":["12093754"],"confidence":"High","gaps":["Order of EJC versus CBC loading not resolved","Direct versus indirect CTD association not distinguished"]},{"year":2005,"claim":"Provided the molecular basis for CBP80-dependent NMD specificity by showing NCBP1 directly binds UPF1 and promotes UPF1-UPF2, while not affecting Staufen-mediated decay.","evidence":"Reciprocal Co-IP, siRNA knockdown, and NMD versus SMD efficiency assays","pmids":["16186820"],"confidence":"High","gaps":["Structural detail of NCBP1-UPF1 interface unresolved","How PTC recognition is communicated to CBP80 not shown"]},{"year":2009,"claim":"Identified CTIF as the dedicated initiation factor for CBP80-bound mRNAs, explaining how the pioneer round is translated distinctly from steady-state eIF4E-dependent translation.","evidence":"Co-IP, in vitro translation depletion/reconstitution with purified CTIF, siRNA, and NMD assay","pmids":["19648179"],"confidence":"High","gaps":["Mechanism of ribosome recruitment downstream of CTIF not yet defined"]},{"year":2009,"claim":"Extended NCBP1 pioneer mRNPs to neuronal local translation, showing CBP80/LSm1 mRNPs relocate to dendritic spines upon synaptic stimulation.","evidence":"Immunofluorescence, subcellular fractionation, and glutamatergic stimulation","pmids":["19188494"],"confidence":"Medium","gaps":["Direct demonstration of translational activation of these specific mRNPs not shown","Functional outcome on synaptic protein synthesis untested"]},{"year":2010,"claim":"Dissected two mechanistic steps by which UPF1-NCBP1 binding drives NMD, ordering SURF complex formation and EJC engagement at the PTC.","evidence":"Dominant-negative UPF1-CBP80 disruption mutant, Co-IP, mRNA binding, and NMD reporters","pmids":["20691628"],"confidence":"High","gaps":["Kinetics of SURF-to-EJC transition not resolved","Role of CBP80 conformation untested"]},{"year":2008,"claim":"Showed the CBP80 pioneer round and its coupled NMD apply even to IRES-initiated translation, generalizing the surveillance role across initiation modes.","evidence":"EMCV IRES NMD reporters with CBP80 vs eIF4E mRNP fractionation","pmids":["18369367"],"confidence":"Medium","gaps":["How IRES initiation engages CBP80 mechanistically unclear"]},{"year":2011,"claim":"Identified Ago2 as a competitive regulator of CBP80 cap binding, linking miRNA machinery to suppression of pioneer-round translation and coupled NMD.","evidence":"Tethering assays, CBP80 Co-IP, NMD reporters, and cap-association-deficient Ago2 mutant","pmids":["21840310"],"confidence":"Medium","gaps":["Physiological extent of Ago2-CBC competition not quantified"]},{"year":2011,"claim":"Established a conserved cytoplasmic translation role for the yeast CBP80 ortholog under stress, showing it is required for rapid polysome reassociation of osmostress mRNAs.","evidence":"Polysome fractionation, cbc1delta genetic epistasis with eIF4E, cycloheximide sensitivity, and stress-induced relocalization","pmids":["22072789"],"confidence":"High","gaps":["Direct conservation of this stress translation function in human NCBP1 not tested"]},{"year":2010,"claim":"Defined dual splicing functions of the CBP80 ortholog, promoting both U1 5' splice site recognition and U2 snRNP recruitment.","evidence":"Yeast cbp80 deletion suppressor screen and splicing assays","pmids":["20801768"],"confidence":"Medium","gaps":["Mechanistic basis of U2 recruitment dependence on 5'SS-proximal sequences unresolved","Conservation in human splicing not directly tested here"]},{"year":2012,"claim":"Completed the ribosome-recruitment chain by showing CTIF bridges NCBP1 to eIF3g, mechanistically distinguishing CBP80/20-dependent translation from eIF4E-dependent translation.","evidence":"Co-IP, polysome fractionation, CTIF tethering driving downstream cistron translation, and NMD reporter","pmids":["22493286"],"confidence":"High","gaps":["Structural model of the NCBP1-CTIF-eIF3 assembly not resolved"]},{"year":2015,"claim":"Resolved the essentiality and export functions of NCBP1, showing it alone (not CBP20) is required for viability and poly(A) export and can form an alternative complex with NCBP3.","evidence":"Knockout viability, FISH RNA export assays, mass spectrometry interactome, and Co-IP","pmids":["26382858"],"confidence":"High","gaps":["Division of labor between NCBP2 and NCBP3 partnerships under different conditions not fully mapped"]},{"year":2018,"claim":"Showed NCBP1 is co-opted by HIV-1 Rev to support nuclear export and translation of unspliced viral mRNA via a CBP80-eIF4AI complex.","evidence":"Co-IP, RNA-IP, and export/translation assays with Rev/RRE","pmids":["30239828"],"confidence":"Medium","gaps":["Whether NCBP1 directly binds Rev versus via the mRNP not fully resolved"]},{"year":2020,"claim":"Revealed a regulatory counterpoint in which CTIF competes with Rev for CBP80 binding and inhibits HIV-1 Gag synthesis.","evidence":"Co-IP, fractionation, siRNA, and translation reporters","pmids":["33103564"],"confidence":"Medium","gaps":["In vivo balance of CTIF-Rev competition during infection unquantified"]},{"year":2019,"claim":"Linked NCBP1 to cap-binding-complex roles in transcription, showing the Drosophila ortholog with Paip2 supports Pol II CTD Ser5 phosphorylation at active promoters.","evidence":"Co-IP, ChIP, and Pol II CTD phosphorylation assays in Drosophila","pmids":["31001806"],"confidence":"Medium","gaps":["Conservation of this promoter function in human NCBP1 not established"]},{"year":2017,"claim":"Connected NCBP1 to small-RNA pathways, showing the Drosophila ortholog is required for Piwi/Aub/Ago3 stability and piRNA biogenesis.","evidence":"Germline RNAi, small RNA sequencing, and immunofluorescence","pmids":["28746365"],"confidence":"Medium","gaps":["Direct molecular substrate of CBC in piRNA biogenesis unresolved","Human relevance not tested"]},{"year":2019,"claim":"Implicated NCBP1 in oncogenic mRNA programs via an NCBP1-NCBP3-CUL4B axis promoting lung cancer growth.","evidence":"Co-IP, knockdown/overexpression, and CUL4B rescue in cell growth assays","pmids":["31448526"],"confidence":"Medium","gaps":["Mechanism of CUL4B upregulation by the complex not detailed"]},{"year":2023,"claim":"Extended NCBP1's mRNA-stabilization role to m6A regulation, showing it stabilizes METTL3 mRNA to enhance c-MYC m6A modification in lymphoma.","evidence":"Co-IP, siRNA, m6A and mRNA stability assays, proliferation assays","pmids":["37244946"],"confidence":"Medium","gaps":["Direct versus indirect basis of METTL3 mRNA stabilization unresolved"]},{"year":2024,"claim":"Showed NCBP1 acts as an m6A-reader-recruited stabilizer, where IGF2BP3 recruits it to the CDK6 5'UTR to suppress senescence.","evidence":"IP-MS, m6A site mapping, mRNA stability, and rescue assays","pmids":["38945255"],"confidence":"Medium","gaps":["Generalizability of IGF2BP3-NCBP1 stabilization to other transcripts untested"]},{"year":2026,"claim":"Identified NCBP1 as a nuclear electrophile-stress sensor, where modification of cysteine C436 disrupts NCBP1-SF3A1 binding to reprogram alternative splicing and inhibit translation.","evidence":"Precision electrophile generation, genetic code expansion, C436 mutagenesis, Co-IP, splicing sequencing, and polysome assays","pmids":["41667655"],"confidence":"High","gaps":["Endogenous electrophiles engaging C436 in vivo not enumerated","Link between specific spliced isoforms and translation block beyond S6 kinase not fully mapped"]},{"year":2026,"claim":"Demonstrated a developmental requirement, showing Ncbp1 depletion causes morula arrest with nuclear poly(A) retention and lipid-metabolic deficits rescuable by oleic acid.","evidence":"Zygotic siRNA, poly(A) FISH, RNA-seq, proteomics, and oleic acid rescue in mouse embryos","pmids":["41575276"],"confidence":"Medium","gaps":["Whether the lipid phenotype is solely export-dependent versus additional roles unresolved"]},{"year":null,"claim":"How NCBP1's distinct partnerships (NCBP2 versus NCBP3, CTIF, UPF1, SF3A1, and m6A readers) are selected and switched on individual transcripts under different cellular and stress states remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model of partner selection across export, translation, NMD, and splicing","Structural basis for context-dependent complex assembly unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,1,2,9]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[3,5,6,8]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[19]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,9,11]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,1,11]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,1,3,6,9]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[1,16]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[5,8]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[9,20]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[11,19]}],"complexes":["nuclear cap-binding complex (CBC; NCBP1-NCBP2)","alternative cap-binding complex (NCBP1-NCBP3)","SURF complex","CBP80/20-dependent translation initiation complex"],"partners":["NCBP2","NCBP3","CTIF","UPF1","UPF2","SF3A1","EIF3G"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q09161","full_name":"Nuclear cap-binding protein subunit 1","aliases":["80 kDa nuclear cap-binding protein","CBP80","NCBP 80 kDa subunit"],"length_aa":790,"mass_kda":91.8,"function":"Component of the cap-binding complex (CBC), which binds cotranscriptionally 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 and is 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, NCBP1/CBP80 does not bind directly capped RNAs (m7GpppG-capped RNA) but is required to stabilize the movement of the N-terminal loop of NCBP2/CBP20 and lock the CBC into a high affinity cap-binding state with the cap structure. Associates with NCBP3 to form an alternative cap-binding complex (CBC) which plays a key role in mRNA export and is particularly important in cellular stress situations such as virus infections. The conventional CBC with NCBP2 binds both small nuclear RNA (snRNA) and messenger (mRNA) and is involved in their export from the nucleus whereas the alternative CBC with NCBP3 does not bind snRNA and associates only with mRNA thereby playing a role only in mRNA export. NCBP1/CBP80 is required for cell growth and viability (PubMed:26382858)","subcellular_location":"Nucleus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q09161/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/NCBP1","classification":"Common Essential","n_dependent_lines":1201,"n_total_lines":1208,"dependency_fraction":0.9942052980132451},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"PHAX","stoichiometry":10.0},{"gene":"PRPF4B","stoichiometry":10.0},{"gene":"CPSF6","stoichiometry":0.2},{"gene":"DDX21","stoichiometry":0.2},{"gene":"DDX39B","stoichiometry":0.2},{"gene":"DHX9","stoichiometry":0.2},{"gene":"HNRNPH1","stoichiometry":0.2},{"gene":"KPNA1","stoichiometry":0.2},{"gene":"KPNA2","stoichiometry":0.2},{"gene":"KPNA3","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/NCBP1","total_profiled":1310},"omim":[{"mim_id":"620106","title":"SPASTIC PARAPLEGIA 88, AUTOSOMAL DOMINANT; SPG88","url":"https://www.omim.org/entry/620106"},{"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"},{"mim_id":"613178","title":"CAP-BINDING COMPLEX-DEPENDENT TRANSLATION INITIATION FACTOR; CTIF","url":"https://www.omim.org/entry/613178"},{"mim_id":"612427","title":"RNA-BINDING MOTIF PROTEIN 25; RBM25","url":"https://www.omim.org/entry/612427"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/NCBP1"},"hgnc":{"alias_symbol":["CBP80","Sto1"],"prev_symbol":["NCBP"]},"alphafold":{"accession":"Q09161","domains":[{"cath_id":"1.25.40.180","chopping":"32-260","consensus_level":"high","plddt":97.4011,"start":32,"end":260},{"cath_id":"1.25.40.180","chopping":"312-475","consensus_level":"medium","plddt":98.0629,"start":312,"end":475},{"cath_id":"1.25.40.180","chopping":"642-786","consensus_level":"medium","plddt":92.4149,"start":642,"end":786}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q09161","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q09161-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q09161-F1-predicted_aligned_error_v6.png","plddt_mean":94.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NCBP1","jax_strain_url":"https://www.jax.org/strain/search?query=NCBP1"},"sequence":{"accession":"Q09161","fasta_url":"https://rest.uniprot.org/uniprotkb/Q09161.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q09161/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q09161"}},"corpus_meta":[{"pmid":"11551508","id":"PMC_11551508","title":"Evidence 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synthesized mRNAs undergoing a 'pioneer' round of translation; NMD targets CBP80-bound mRNAs (not yet replaced by eIF4E), and the NMD-susceptible mRNP includes CBP20, PABP2, eIF4G, Upf2, and Upf3 as components. NMD of CBP80-bound mRNA is blocked by cycloheximide or suppressor tRNA, confirming translation-dependence.\",\n      \"method\": \"Antibody immunopurification of CBP80-bound vs. eIF4E-bound mRNPs; cycloheximide and suppressor tRNA inhibition assays\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal immunopurification with multiple orthogonal functional tests (drug inhibition, suppressor tRNA), foundational study replicated extensively\",\n      \"pmids\": [\"11551508\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"CBP80 (NCBP1), but not nuclear eIF4E, is detected in association with intron-containing RNA and the C-terminal domain of RNA polymerase II. The exon junction complex (EJC) components RNPS1, Y14, SRm160, REF/Aly, TAP, Upf3X, and Upf2 are detected on CBP80-bound mRNA in both nuclear and cytoplasmic fractions, but not on eIF4E-bound mRNA, indicating these proteins travel with CBP80-mRNPs after export.\",\n      \"method\": \"Immunoprecipitation of CBP80-bound vs. eIF4E-bound mRNPs; nuclear/cytoplasmic fractionation; Western blotting\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal IP with fractionation, multiple components tested, independently replicated in subsequent studies\",\n      \"pmids\": [\"12093754\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"NCBP1 (CBP80) interacts with three nuclear cap-binding protein interacting proteins (NIP1, NIP2, NIP3) identified by yeast two-hybrid; NCBP1 requires NIP1 (which has an RNP-type RNA binding domain) for binding to the cap structure.\",\n      \"method\": \"Yeast two-hybrid screen from HeLa cell cDNA library; cap-binding assay\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — yeast two-hybrid plus cap-binding functional assay, single lab, early mechanistic work\",\n      \"pmids\": [\"7478990\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"CBP80 (NCBP1) directly interacts with Upf1 and promotes the interaction of Upf1 with Upf2 during NMD, but does not promote Upf1 interaction with Stau1 (which mediates SMD). CBP80 augments the efficiency of NMD but not Staufen1-mediated mRNA decay (SMD).\",\n      \"method\": \"Co-immunoprecipitation; siRNA knockdown; NMD efficiency assays\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP with functional NMD efficiency assays, discriminated between two decay pathways with multiple orthogonal approaches\",\n      \"pmids\": [\"16186820\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"CBP80 (NCBP1) and eIF4G share a common evolutionary origin and similar domain organization (consecutive HEAT domains). A structural model based on the CBP80-CBP20 crystal structure suggests conserved mutual orientation of domains relevant for translation initiation complex assembly.\",\n      \"method\": \"Computational domain analysis; structural modeling using known CBP80-CBP20 complex structure\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — primarily computational/structural modeling, limited direct experimental validation in this paper\",\n      \"pmids\": [\"16156639\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CBP80 (NCBP1) directly interacts with CTIF (CBP80/20-dependent translation initiation factor), a new MIF4G domain-containing protein. CTIF is part of the CBP80/20-dependent translation initiation complex, and depletion of CTIF from an in vitro translation system selectively blocks translation of CBP80-bound mRNAs; addition of purified CTIF restores it. CTIF localizes to the perinuclear region, and its down-regulation abrogates NMD.\",\n      \"method\": \"Co-immunoprecipitation; in vitro translation system depletion/reconstitution; siRNA knockdown; confocal microscopy\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with depletion and add-back, Co-IP, localization, and NMD functional assay; multiple orthogonal methods in one study\",\n      \"pmids\": [\"19648179\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"UPF1 binding to CBP80 (NCBP1) promotes NMD at two distinct steps: (1) association of SMG1 and UPF1 with eukaryotic release factors (eRFs) during SURF complex formation at a premature termination codon, and (2) subsequent association of SMG1 and UPF1 with an exon-junction complex. UPF1 binds PTC-containing mRNA more efficiently than PTC-free mRNA in a manner promoted by the UPF1-CBP80 interaction.\",\n      \"method\": \"Dominant-negative mutant precluding UPF1-CBP80 interaction; co-immunoprecipitation; mRNA binding assays; NMD reporter assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (dominant-negative mutant, Co-IP, functional NMD assay, mRNA binding), mechanistic dissection of two distinct steps\",\n      \"pmids\": [\"20691628\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CBP80 (NCBP1) is present in neuronal dendrites and associates with LSm1-mRNPs assembled in the nucleus; both LSm1 and CBP80 shift into dendritic spines upon stimulation of glutamatergic receptors, suggesting these CBP80-containing mRNPs are translationally activated during local protein synthesis.\",\n      \"method\": \"Immunofluorescence; subcellular fractionation; glutamatergic receptor stimulation; confocal microscopy\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — localization experiment with functional correlate (receptor stimulation), single lab, localization tied to translational activation context\",\n      \"pmids\": [\"19188494\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CTIF (CBP80/20-dependent translation initiation factor) specifically interacts with eIF3g (a component of the eIF3 ribosome-recruitment complex), bridging CBP80 and eIF3 to enable ribosome recruitment during CBP80/20-dependent translation. Down-regulation of CTIF redistributes CBP80 from polysome to subpolysome fractions without affecting eIF4E distribution. Artificial tethering of CTIF to an intercistronic region drives translation of the downstream cistron in an eIF3-dependent manner.\",\n      \"method\": \"Co-immunoprecipitation; polysome fractionation; siRNA knockdown; tethering assay; NMD reporter assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods including Co-IP, polysome fractionation, tethering assay, and functional NMD assay in single study\",\n      \"pmids\": [\"22493286\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"NCBP1 (CBP80), but not NCBP2 (CBP20), is required for cell viability and poly(A) RNA nuclear export. NCBP1 forms an alternative cap-binding complex with NCBP3 (C17orf85) that binds mRNA, associates with mRNA processing machinery, and contributes to poly(A) RNA export. Loss of NCBP3 is compensated by NCBP2 under steady-state conditions but NCBP3 becomes critical under stress (e.g., virus infection).\",\n      \"method\": \"Knockdown/knockout viability assays; RNA export assays (FISH); mass spectrometry interactome; Co-immunoprecipitation\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (MS interactome, Co-IP, functional RNA export assay, cell viability), identification of alternative complex with NCBP3\",\n      \"pmids\": [\"26382858\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"NMD triggered by EMCV IRES-initiated translation targets CBP80/20-bound mRNA but does not detectably target eIF4E-bound mRNA, establishing that even IRES-initiated translation undergoes a CBP80-associated pioneer round leading to NMD when translation terminates prematurely.\",\n      \"method\": \"NMD reporter assays with EMCV IRES constructs; immunoprecipitation of CBP80-bound vs. eIF4E-bound mRNA fractions\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional NMD assay with IRES constructs plus fractionation, single lab, mechanistic extension of established CBP80-NMD framework\",\n      \"pmids\": [\"18369367\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"In yeast, the CBP80 ortholog Cbc1/Sto1 associates with polysomes and is required for rapid translation reinitiation after osmotic stress. Deletion of CBC1 causes hypersensitivity to cycloheximide and synthetic sickness with limiting eIF4E. Osmostress-responsive mRNAs are transcriptionally induced in cbc1Δ cells but fail to rapidly associate with polysomes. Under osmotic stress, Cbc1 relocalizes from nucleus to cytoplasm.\",\n      \"method\": \"Polysome fractionation; genetic epistasis (cbc1Δ, eIF4E temperature-sensitive allele); cycloheximide sensitivity assay; live-cell localization\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — polysome fractionation, genetic epistasis, localization experiment, multiple functional readouts in yeast ortholog\",\n      \"pmids\": [\"22072789\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Ago2 competes with CBP80/20 for cap association, thereby inhibiting CBP80/20-dependent translation (CT) and abrogating NMD that is coupled to CT. Tethering of Ago2 (but not of cap-association-deficient Ago2F2V2) to the 3'UTR of PTC-containing mRNA abrogates NMD. Immunoprecipitation with CBP80 antibody confirms that Ago2, but not Ago2F2V2, inhibits binding of CBP80/20 to the cap structure.\",\n      \"method\": \"Tethering assay; co-immunoprecipitation with CBP80 antibody; NMD reporter assay; Ago2 mutant (F2V2)\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with functional NMD assay and mutant discrimination, single lab\",\n      \"pmids\": [\"21840310\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CBP80 (NCBP1) binds the HIV-1 viral protein Rev and the unspliced full-length mRNA in both nucleus and cytoplasm. CBP80 supports Rev-mediated nuclear export and translation of the unspliced mRNA. Rev interacts with DEAD-box helicase eIF4AI, and the Rev/RRE axis is required for assembly of a CBP80-eIF4AI complex on the unspliced mRNA.\",\n      \"method\": \"Co-immunoprecipitation; RNA immunoprecipitation; translation and nuclear export assays; RIP\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, RNA-IP, and functional export/translation assays, single lab study\",\n      \"pmids\": [\"30239828\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"In yeast, Cbp80 (NCBP1 ortholog) plays distinct roles in splicing: it promotes initial 5' splice site recognition by U1 snRNP and, independently, facilitates U2 snRNP recruitment in a manner dependent on sequences near the 5' splice site. Deletion of Cbp80 suppresses the splicing defect caused by a mutation in the RPL30 binding site that normally disrupts L30-mediated splicing repression.\",\n      \"method\": \"Genetic epistasis (cbp80 deletion suppressor screen); splicing assays\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis (suppressor screen) with mechanistic splicing assays, yeast ortholog, single lab\",\n      \"pmids\": [\"20801768\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"NCBP1 up-regulates CUL4B expression via interaction with NCBP3, constituting an NCBP1-NCBP3-CUL4B axis that promotes lung cancer cell growth. CUL4B silencing significantly reverses NCBP1-induced tumorigenesis in vitro.\",\n      \"method\": \"Co-immunoprecipitation; knockdown/overexpression; cell growth and migration assays; CUL4B rescue experiment\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP plus functional rescue experiment, single lab, moderate mechanistic resolution\",\n      \"pmids\": [\"31448526\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In Drosophila, Cbp80 (NCBP1 ortholog) cooperates with Paip2 at active promoters to ensure proper RNA polymerase II CTD Ser5 phosphorylation, linking the cap-binding complex to transcription initiation/early elongation.\",\n      \"method\": \"Co-immunoprecipitation; ChIP; Pol II CTD phosphorylation assay; ~300 kDa complex characterization\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with ChIP and functional Pol II phosphorylation assay, Drosophila ortholog, single lab\",\n      \"pmids\": [\"31001806\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"NCBP1 enhances the m6A catalytic function of METTL3 by maintaining METTL3 mRNA stabilization, leading to increased m6A modification of c-MYC mRNA and enhanced DLBCL cell proliferation via the NCBP1/METTL3/m6A/c-MYC axis.\",\n      \"method\": \"Co-immunoprecipitation; siRNA knockdown; m6A methylation assay; mRNA stability assay; cell proliferation assay\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP with functional m6A and mRNA stability assays, single lab\",\n      \"pmids\": [\"37244946\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NCBP1 is recruited by IGF2BP3 to inhibit CDK6 mRNA decay; IGF2BP3 recognizes m6A modification at the GGACU motif (nucleotides 110-114) in the 5'UTR of CDK6 mRNA and recruits NCBP1 to enhance CDK6 mRNA stability, thereby inhibiting renal tubular senescence.\",\n      \"method\": \"Co-immunoprecipitation (IP-MS); m6A site mapping; mRNA stability assay; siRNA knockdown; overexpression rescue\",\n      \"journal\": \"Translational research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — IP-MS plus functional mRNA stability and rescue experiments, single lab\",\n      \"pmids\": [\"38945255\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"NCBP1 propagates nuclear electrophile stress signals through a single cysteine residue (C436). Electrophile modification of NCBP1(C436) impairs association between NCBP1 and SF3A1 (an essential spliceosome component), triggering alternative splicing of >250 genes including S6 kinase, whose alternatively spliced isoform is sufficient to inhibit global protein translation.\",\n      \"method\": \"Precision localized electrophile generation; genetic code expansion; alternative splicing sequencing; Co-immunoprecipitation (NCBP1-SF3A1 interaction); site-directed mutagenesis (C436); polysome/translation assays\",\n      \"journal\": \"Nature chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — site-directed mutagenesis at specific cysteine, Co-IP, alternative splicing profiling, and functional translation assay with multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"41667655\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Ncbp1 depletion in mouse embryos causes morula arrest with nuclear poly(A) RNA retention and downregulation of lipid metabolic pathways, notably SCD1 (stearoyl-CoA desaturase 1). Exogenous oleic acid supplementation partially rescues blastocyst formation, implicating NCBP1 in SCD1-OA-mediated lipid metabolic homeostasis during morula-to-blastocyst transition via its role in mRNA export.\",\n      \"method\": \"siRNA knockdown via zygotic microinjection; mRNA rescue (co-injection); poly(A) RNA FISH; RNA sequencing; quantitative proteomics; oleic acid rescue experiment\",\n      \"journal\": \"Reproduction (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with mRNA rescue, poly(A) FISH, transcriptomics and proteomics, functional rescue, single lab\",\n      \"pmids\": [\"41575276\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CTIF inhibits HIV-1 Gag synthesis by associating with HIV-1 Rev through its N-terminal domain and being recruited onto the full-length RNA RNP complex. CTIF induces cytoplasmic accumulation of Rev, impeding Rev association with CBP80. Rev and CTIF compete for binding to CBP80, establishing a regulatory interplay between the CBC-dependent translation machinery and HIV-1 replication.\",\n      \"method\": \"Co-immunoprecipitation; subcellular fractionation; siRNA knockdown; translation reporter assays\",\n      \"journal\": \"RNA biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with functional translation and localization assays, single lab\",\n      \"pmids\": [\"33103564\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In Drosophila, Cbp80 (NCBP1 ortholog) knockdown in the female germline leads to delocalization and reduced protein levels of the piRNA pathway factors Piwi, Aub, and Ago3, and impairs both primary piRNA biogenesis and the ping-pong secondary amplification cycle, without significantly altering piRNA precursor transcript levels or nuage localization.\",\n      \"method\": \"Germline-specific RNAi knockdown; small RNA sequencing; immunofluorescence for piRNA pathway factors\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — knockdown with sequencing and localization, Drosophila ortholog, single lab\",\n      \"pmids\": [\"28746365\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NCBP1 (CBP80) is the large subunit of the nuclear cap-binding complex (CBC) that binds the 5'-cap of newly synthesized RNA and orchestrates multiple steps of mRNA biogenesis: it associates with pre-mRNA co-transcriptionally (interacting with RNA Pol II CTD), promotes U1 and U2 snRNP recruitment for splicing, mediates poly(A) mRNA nuclear export (either with NCBP2 or the alternative partner NCBP3), and directs a 'pioneer' round of cytoplasmic translation by recruiting the specific initiation factor CTIF, which bridges NCBP1 to eIF3g for ribosome recruitment; during this pioneer round, NCBP1 scaffolds the NMD machinery by directly binding UPF1 and promoting UPF1-UPF2 interaction, enabling SURF complex formation and EJC engagement at premature termination codons; NCBP1 also receives and propagates nuclear stress signals through a specific cysteine (C436) that, when electrophile-modified, disrupts interaction with spliceosome component SF3A1 to drive alternative splicing and translation inhibition.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NCBP1 (CBP80) is the large subunit of the nuclear cap-binding complex that binds the 5'-cap of newly synthesized mRNA and coordinates downstream steps of mRNA biogenesis, from co-transcriptional loading through nuclear export, splicing, and a pioneer round of translation [#0, #1]. It associates with intron-containing RNA and the RNA polymerase II C-terminal domain, and CBP80-bound mRNPs carry exon-junction complex components and NMD factors into the cytoplasm, whereas eIF4E-bound mRNPs do not [#1]. During the pioneer round, CBP80-bound mRNAs are the substrate for nonsense-mediated decay: NCBP1 directly binds UPF1 and promotes UPF1-UPF2 interaction, driving SURF complex assembly with SMG1 and release factors at premature termination codons and subsequent engagement of the exon-junction complex [#3, #6]. NCBP1 directs cap-dependent translation of these mRNPs by recruiting the dedicated initiation factor CTIF, which bridges NCBP1 to eIF3g for ribosome recruitment [#5, #8]. Beyond the canonical CBP80-CBP20 partnership, NCBP1 forms an alternative cap-binding complex with NCBP3 that supports poly(A) RNA nuclear export and is essential for cell viability [#9]. NCBP1 also serves as a sensor of nuclear electrophile stress through cysteine C436: modification of this residue disrupts the NCBP1-SF3A1 interaction, triggering widespread alternative splicing and translational repression [#19]. In several cancer and disease contexts, NCBP1 has been linked to mRNA stabilization programs, including an NCBP1-NCBP3-CUL4B axis in lung cancer, METTL3/m6A-dependent c-MYC regulation in lymphoma, and IGF2BP3-recruited stabilization of CDK6 mRNA [#15, #17, #18].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Established how NCBP1 achieves cap binding, showing it does not act alone but requires partner subunits with RNA-binding capacity.\",\n      \"evidence\": \"Yeast two-hybrid screen and cap-binding assay identifying NIP1/2/3 interactors\",\n      \"pmids\": [\"7478990\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Identity of NIPs relative to the later-defined CBP20/NCBP2 not resolved here\", \"Functional consequences of the cap binding in vivo not tested\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Defined NCBP1 as the mark of newly synthesized 'pioneer' mRNPs and showed these, not eIF4E-bound mRNAs, are the substrate for NMD, linking cap identity to mRNA surveillance.\",\n      \"evidence\": \"Reciprocal immunopurification of CBP80- vs eIF4E-bound mRNPs with cycloheximide and suppressor tRNA inhibition\",\n      \"pmids\": [\"11551508\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Direct molecular bridge from CBP80 to NMD factors not yet defined\", \"Translation initiation mechanism for CBP80-mRNPs unknown\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Connected NCBP1 to co-transcriptional loading and cytoplasmic cargo delivery, showing CBP80-mRNPs associate with Pol II CTD and carry EJC/NMD components after export.\",\n      \"evidence\": \"Immunoprecipitation with nuclear/cytoplasmic fractionation and Western blotting\",\n      \"pmids\": [\"12093754\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Order of EJC versus CBC loading not resolved\", \"Direct versus indirect CTD association not distinguished\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Provided the molecular basis for CBP80-dependent NMD specificity by showing NCBP1 directly binds UPF1 and promotes UPF1-UPF2, while not affecting Staufen-mediated decay.\",\n      \"evidence\": \"Reciprocal Co-IP, siRNA knockdown, and NMD versus SMD efficiency assays\",\n      \"pmids\": [\"16186820\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Structural detail of NCBP1-UPF1 interface unresolved\", \"How PTC recognition is communicated to CBP80 not shown\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identified CTIF as the dedicated initiation factor for CBP80-bound mRNAs, explaining how the pioneer round is translated distinctly from steady-state eIF4E-dependent translation.\",\n      \"evidence\": \"Co-IP, in vitro translation depletion/reconstitution with purified CTIF, siRNA, and NMD assay\",\n      \"pmids\": [\"19648179\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Mechanism of ribosome recruitment downstream of CTIF not yet defined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Extended NCBP1 pioneer mRNPs to neuronal local translation, showing CBP80/LSm1 mRNPs relocate to dendritic spines upon synaptic stimulation.\",\n      \"evidence\": \"Immunofluorescence, subcellular fractionation, and glutamatergic stimulation\",\n      \"pmids\": [\"19188494\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Direct demonstration of translational activation of these specific mRNPs not shown\", \"Functional outcome on synaptic protein synthesis untested\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Dissected two mechanistic steps by which UPF1-NCBP1 binding drives NMD, ordering SURF complex formation and EJC engagement at the PTC.\",\n      \"evidence\": \"Dominant-negative UPF1-CBP80 disruption mutant, Co-IP, mRNA binding, and NMD reporters\",\n      \"pmids\": [\"20691628\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Kinetics of SURF-to-EJC transition not resolved\", \"Role of CBP80 conformation untested\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Showed the CBP80 pioneer round and its coupled NMD apply even to IRES-initiated translation, generalizing the surveillance role across initiation modes.\",\n      \"evidence\": \"EMCV IRES NMD reporters with CBP80 vs eIF4E mRNP fractionation\",\n      \"pmids\": [\"18369367\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"How IRES initiation engages CBP80 mechanistically unclear\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identified Ago2 as a competitive regulator of CBP80 cap binding, linking miRNA machinery to suppression of pioneer-round translation and coupled NMD.\",\n      \"evidence\": \"Tethering assays, CBP80 Co-IP, NMD reporters, and cap-association-deficient Ago2 mutant\",\n      \"pmids\": [\"21840310\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Physiological extent of Ago2-CBC competition not quantified\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Established a conserved cytoplasmic translation role for the yeast CBP80 ortholog under stress, showing it is required for rapid polysome reassociation of osmostress mRNAs.\",\n      \"evidence\": \"Polysome fractionation, cbc1delta genetic epistasis with eIF4E, cycloheximide sensitivity, and stress-induced relocalization\",\n      \"pmids\": [\"22072789\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Direct conservation of this stress translation function in human NCBP1 not tested\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined dual splicing functions of the CBP80 ortholog, promoting both U1 5' splice site recognition and U2 snRNP recruitment.\",\n      \"evidence\": \"Yeast cbp80 deletion suppressor screen and splicing assays\",\n      \"pmids\": [\"20801768\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Mechanistic basis of U2 recruitment dependence on 5'SS-proximal sequences unresolved\", \"Conservation in human splicing not directly tested here\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Completed the ribosome-recruitment chain by showing CTIF bridges NCBP1 to eIF3g, mechanistically distinguishing CBP80/20-dependent translation from eIF4E-dependent translation.\",\n      \"evidence\": \"Co-IP, polysome fractionation, CTIF tethering driving downstream cistron translation, and NMD reporter\",\n      \"pmids\": [\"22493286\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Structural model of the NCBP1-CTIF-eIF3 assembly not resolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Resolved the essentiality and export functions of NCBP1, showing it alone (not CBP20) is required for viability and poly(A) export and can form an alternative complex with NCBP3.\",\n      \"evidence\": \"Knockout viability, FISH RNA export assays, mass spectrometry interactome, and Co-IP\",\n      \"pmids\": [\"26382858\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Division of labor between NCBP2 and NCBP3 partnerships under different conditions not fully mapped\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed NCBP1 is co-opted by HIV-1 Rev to support nuclear export and translation of unspliced viral mRNA via a CBP80-eIF4AI complex.\",\n      \"evidence\": \"Co-IP, RNA-IP, and export/translation assays with Rev/RRE\",\n      \"pmids\": [\"30239828\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Whether NCBP1 directly binds Rev versus via the mRNP not fully resolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Revealed a regulatory counterpoint in which CTIF competes with Rev for CBP80 binding and inhibits HIV-1 Gag synthesis.\",\n      \"evidence\": \"Co-IP, fractionation, siRNA, and translation reporters\",\n      \"pmids\": [\"33103564\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"In vivo balance of CTIF-Rev competition during infection unquantified\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Linked NCBP1 to cap-binding-complex roles in transcription, showing the Drosophila ortholog with Paip2 supports Pol II CTD Ser5 phosphorylation at active promoters.\",\n      \"evidence\": \"Co-IP, ChIP, and Pol II CTD phosphorylation assays in Drosophila\",\n      \"pmids\": [\"31001806\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Conservation of this promoter function in human NCBP1 not established\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Connected NCBP1 to small-RNA pathways, showing the Drosophila ortholog is required for Piwi/Aub/Ago3 stability and piRNA biogenesis.\",\n      \"evidence\": \"Germline RNAi, small RNA sequencing, and immunofluorescence\",\n      \"pmids\": [\"28746365\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Direct molecular substrate of CBC in piRNA biogenesis unresolved\", \"Human relevance not tested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Implicated NCBP1 in oncogenic mRNA programs via an NCBP1-NCBP3-CUL4B axis promoting lung cancer growth.\",\n      \"evidence\": \"Co-IP, knockdown/overexpression, and CUL4B rescue in cell growth assays\",\n      \"pmids\": [\"31448526\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Mechanism of CUL4B upregulation by the complex not detailed\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended NCBP1's mRNA-stabilization role to m6A regulation, showing it stabilizes METTL3 mRNA to enhance c-MYC m6A modification in lymphoma.\",\n      \"evidence\": \"Co-IP, siRNA, m6A and mRNA stability assays, proliferation assays\",\n      \"pmids\": [\"37244946\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Direct versus indirect basis of METTL3 mRNA stabilization unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed NCBP1 acts as an m6A-reader-recruited stabilizer, where IGF2BP3 recruits it to the CDK6 5'UTR to suppress senescence.\",\n      \"evidence\": \"IP-MS, m6A site mapping, mRNA stability, and rescue assays\",\n      \"pmids\": [\"38945255\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Generalizability of IGF2BP3-NCBP1 stabilization to other transcripts untested\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identified NCBP1 as a nuclear electrophile-stress sensor, where modification of cysteine C436 disrupts NCBP1-SF3A1 binding to reprogram alternative splicing and inhibit translation.\",\n      \"evidence\": \"Precision electrophile generation, genetic code expansion, C436 mutagenesis, Co-IP, splicing sequencing, and polysome assays\",\n      \"pmids\": [\"41667655\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Endogenous electrophiles engaging C436 in vivo not enumerated\", \"Link between specific spliced isoforms and translation block beyond S6 kinase not fully mapped\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Demonstrated a developmental requirement, showing Ncbp1 depletion causes morula arrest with nuclear poly(A) retention and lipid-metabolic deficits rescuable by oleic acid.\",\n      \"evidence\": \"Zygotic siRNA, poly(A) FISH, RNA-seq, proteomics, and oleic acid rescue in mouse embryos\",\n      \"pmids\": [\"41575276\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Whether the lipid phenotype is solely export-dependent versus additional roles unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How NCBP1's distinct partnerships (NCBP2 versus NCBP3, CTIF, UPF1, SF3A1, and m6A readers) are selected and switched on individual transcripts under different cellular and stress states remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model of partner selection across export, translation, NMD, and splicing\", \"Structural basis for context-dependent complex assembly unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 1, 2, 9]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [3, 5, 6, 8]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [19]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 9, 11]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 1, 11]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": []}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 1, 3, 6, 9]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [1, 16]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [5, 8]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [9, 20]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [11, 19]}\n    ],\n    \"complexes\": [\n      \"nuclear cap-binding complex (CBC; NCBP1-NCBP2)\",\n      \"alternative cap-binding complex (NCBP1-NCBP3)\",\n      \"SURF complex\",\n      \"CBP80/20-dependent translation initiation complex\"\n    ],\n    \"partners\": [\n      \"NCBP2\",\n      \"NCBP3\",\n      \"CTIF\",\n      \"UPF1\",\n      \"UPF2\",\n      \"SF3A1\",\n      \"eIF3g\",\n      \"SF3A1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":7,"faith_total":7,"faith_pct":100.0}}