{"gene":"NCAPG","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2008,"finding":"CAP-G (NCAPG) contains two threonine residues (Thr308 and Thr332) that are phosphorylated by cdc2/cyclin B. Mutation of these threonines to alanines results in defects in CAP-G localization with chromosomal DNA during mitosis, establishing phosphorylation as a regulator of condensin chromosomal localization.","method":"Site-directed mutagenesis (T308A, T332A), in vitro cdc2/cyclin B kinase assay, immunofluorescence localization during mitosis","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct mutagenesis combined with in vitro kinase assay and localization readout in single focused study","pmids":["18977199"],"is_preprint":false},{"year":2004,"finding":"Drosophila condensin subunit Cap-G (ortholog of NCAPG) physically interacts with the centromere-specific histone H3 variant CID (CENP-A homolog), as shown by yeast two-hybrid. Loss-of-function Cap-G mutant embryos show massive sister chromatid segregation defects during mitosis, linking condensin to kinetochore structure and chromatid segregation.","method":"Genetic modifier screen (rough eye phenotype), yeast two-hybrid interaction assay, analysis of Cap-G mutant embryo mitosis","journal":"Chromosoma","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic + yeast two-hybrid, two orthogonal methods in single lab","pmids":["15592865"],"is_preprint":false},{"year":2013,"finding":"Drosophila Cap-G associates exclusively with condensin I and not condensin II. In vivo, Cap-G-EGFP shows nuclear enrichment during interphase, but this nuclear localization is dispensable for chromatin association, condensin I complex assembly, and animal viability. Mass spectrometry of condensin II-specific subunit Cap-H2 immunoprecipitates failed to detect Cap-G.","method":"Immunoprecipitation, in vivo EGFP fusion microscopy, mass spectrometry, in vitro complex formation assays","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (Co-IP, mass spec, live imaging, in vitro reconstitution) in single study","pmids":["23637630"],"is_preprint":false},{"year":2016,"finding":"In budding yeast, Ycg1 (Cap-G/NCAPG ortholog) is cell-cycle regulated with protein levels peaking in mitosis and decreasing in G1, controlled by cell-cycle-regulated transcription and constitutive degradation. Ycg1 is limiting for condensin complex formation: overexpression of Ycg1 (but not other condensin subunits) increases intact condensin complex levels and chromatin binding in G1, causing delayed cell-cycle entry and proliferation defects.","method":"Cell cycle synchronization, Western blotting, chromatin immunoprecipitation (ChIP), overexpression and stabilizing mutation analysis in S. cerevisiae","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (protein quantification, ChIP, genetic overexpression, stabilizing mutations), well-controlled yeast study","pmids":["27463097"],"is_preprint":false},{"year":2019,"finding":"Solution SAXS characterization of the condensin HEAT-repeat subunit Ycg1 (Cap-G/NCAPG ortholog) reveals it is flexible in solution as a free subunit but becomes considerably more rigid upon binding its kleisin partner Brn1. Free Ycg1 tends to oligomerize at higher concentrations in the absence of Brn1.","method":"Small-angle X-ray scattering (SAXS), dynamic and static multiangle light scattering, normal mode analysis structural modeling","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — SAXS with complementary light scattering, rigorous structural characterization of free and bound states","pmids":["31350339"],"is_preprint":false},{"year":1995,"finding":"Human macrophage Cap G (CAPG/NCAPG alias) caps but does not sever actin filaments. Gain-of-function mutations converting residues 84LNTLLGE to the gelsolin actin-binding helix sequence (84LDDYLGG) conferred actin-severing activity; adding a second mutation converting 124AFHKTS to 124GFKHV enhanced severing 10-fold. These two regions are critical determinants of the lack of severing activity in wild-type Cap G.","method":"Site-directed mutagenesis, in vitro actin filament severing assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct in vitro reconstitution with mutagenesis, quantitative severing assay, multiple mutant constructs","pmids":["7814409"],"is_preprint":false},{"year":1994,"finding":"The human Cap G gene (CAPG, an alias for NCAPG in the gelsolin-family context) is 16.6 kb, contains 10 exons and 9 introns, and maps to chromosome 2p. Comparison of splice sites with gelsolin and villin indicates CAPG is more closely related to gelsolin.","method":"Genomic cloning, sequencing, chromosomal mapping, comparative gene structure analysis","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct genomic cloning and sequencing; note this paper concerns the gelsolin-family CAPG gene, a distinct protein from the condensin NCAPG; included only if treated as alias collision — EXCLUDED from canonical NCAPG condensin protein","pmids":["7851883"],"is_preprint":false},{"year":2003,"finding":"Cap G (gelsolin-family macrophage capping protein) protein and mRNA are upregulated ~2-fold and ~5-fold, respectively, in endothelial cells exposed to atheroprotective (plaque-free) unidirectional shear stress compared to static culture; this increase is absent under plaque-prone flow. The increase occurs in nuclear and cytoskeletal-associated fractions. Overexpression of Cap G in transfection assays increased endothelial cell motility.","method":"2D gel proteomics, quantitative RT-PCR, subcellular fractionation, transfection overexpression motility assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple methods (proteomics, mRNA, fractionation, functional overexpression) in single lab; note this is the gelsolin-family CAPG not condensin NCAPG","pmids":["12754261"],"is_preprint":false},{"year":2019,"finding":"NCAPG (condensin I subunit) knockdown in HCC cells causes aberrant mitotic division, fragmentation of the mitochondrial network, and increased cell death in vitro; genome-wide CRISPR dropout screens ranked NCAPG as the highest essential gene for HCC growth. Small interfering RNA knockdown reduced cell growth, migration, and downregulated mitochondrial gene expression.","method":"Genome-wide CRISPR knockout dropout screen, siRNA knockdown, xenograft tumor model, mitochondrial network imaging","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide CRISPR screen plus orthogonal siRNA validation plus in vivo xenograft, replicated across multiple datasets","pmids":["31022357"],"is_preprint":false},{"year":2017,"finding":"NCAPG knockdown induces mitotic defects and inhibits HCC cell growth, proliferation, and migration in vitro; tetracycline-inducible shRNA knockdown inhibits tumor growth in vivo. NCAPG overexpression is correlated with overexpression of CCNB1 (cyclin B1), a mitotic regulatory protein.","method":"siRNA and inducible shRNA knockdown, cell proliferation assay, wound-healing migration assay, xenograft tumor model, expression correlation analysis","journal":"Oncology research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA plus inducible shRNA with in vivo validation, single lab","pmids":["29046167"],"is_preprint":false},{"year":2019,"finding":"NCAPG overexpression activates the PI3K/AKT/FOXO4 pathway and alters expression of apoptosis-related proteins in HCC cells. The PI3K inhibitor LY294002 abolished NCAPG-mediated promotion of proliferation and reduction of apoptosis, while the PI3K activator 740Y-P had the opposite effect, placing NCAPG upstream of PI3K/AKT/FOXO4 in HCC proliferation signaling.","method":"siRNA knockdown and plasmid overexpression, EdU proliferation assay, flow cytometry apoptosis, RNA-seq pathway analysis, PI3K inhibitor/activator rescue experiments, Western blotting, xenograft model","journal":"OncoTargets and therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA-seq with pharmacological rescue, single lab, multiple assays","pmids":["31802891"],"is_preprint":false},{"year":2020,"finding":"NCAPG overexpression in HER2-positive breast cancer cells promotes trastuzumab resistance by phosphorylating SRC and enhancing nuclear localization and transcriptional activation of STAT3, establishing NCAPG as an upstream activator of the SRC/STAT3 signaling pathway.","method":"Overexpression and siRNA knockdown, Western blotting for phospho-SRC and nuclear STAT3, cell proliferation/apoptosis assays, in vivo xenograft, immunofluorescence for STAT3 nuclear localization","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phospho-protein readouts with localization data, single lab, multiple orthogonal methods","pmids":["32683421"],"is_preprint":false},{"year":2022,"finding":"NCAPG physically interacts with β-catenin in colorectal cancer cells, activating the Wnt/β-catenin signaling pathway to promote EMT, proliferation, migration, and invasion.","method":"Co-immunoprecipitation (Co-IP), immunofluorescence, Western blotting, siRNA knockdown and overexpression","journal":"Cancer cell international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with functional readout, single lab","pmids":["35292013"],"is_preprint":false},{"year":2022,"finding":"NCAPG promotes HCC proliferation by interacting with CKII (casein kinase II). Their interaction was identified by IP-mass spectrometry and confirmed by Co-IP. NCAPG-CKII interaction promotes PTEN phosphorylation, thereby inhibiting PTEN transcription and function and activating the PI3K/AKT pathway.","method":"IP-mass spectrometry, Co-immunoprecipitation, transcriptome sequencing, EdU and CCK-8 proliferation assays, FISH, xenograft model","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — IP-MS plus Co-IP confirmation of interaction, transcriptome sequencing for pathway, single lab","pmids":["35864529"],"is_preprint":false},{"year":2020,"finding":"NCAPG silencing in fetal bovine myoblasts prolongs mitosis and impairs differentiation through increased apoptosis. ATAC-seq revealed that NCAPG knockdown alters chromatin accessibility at AP-1 (activating protein 1) binding sites, and knockdown of AP-1 subunits FOSL2 or JUNB partially phenocopied the effect on muscle-specific gene expression.","method":"siRNA knockdown, ATAC-seq, immunofluorescence, gene expression quantification, AP-1 subunit knockdown","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ATAC-seq with functional follow-up knockdowns, single lab, multiple methods","pmids":["32070024"],"is_preprint":false},{"year":2021,"finding":"NCAPG overexpression in lung adenocarcinoma increases phospho-Smad2 and phospho-Smad3 in the TGF-β signaling pathway. Rescue experiments showed that TGF-β pathway inhibitors restored the effect of NCAPG overexpression, placing NCAPG upstream of TGF-β/Smad signaling in LUAD.","method":"siRNA knockdown and overexpression, Western blotting for p-Smad2/p-Smad3, TGF-β inhibitor rescue, in vitro and in vivo functional assays","journal":"Cancer cell international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological rescue confirms pathway dependency, single lab","pmids":["34419073"],"is_preprint":false},{"year":2022,"finding":"NCAPG promotes NSCLC progression via the NCAPG/CDK1/ERK axis: NCAPG interacts with CDK1, and this interaction promotes phosphorylation of ERK, driving cell growth and metastasis in vitro and in vivo.","method":"Co-immunoprecipitation, Western blotting for phospho-ERK, siRNA knockdown, xenograft model","journal":"American journal of cancer research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, Co-IP for interaction, phospho-ERK readout without mutagenesis validation","pmids":["39659935"],"is_preprint":false},{"year":2023,"finding":"E2F1 transcription factor directly binds the NCAPG promoter and transactivates NCAPG expression in HCC. E2F1 binding was confirmed by ChIP and luciferase reporter assay; HBx transfection co-upregulated both E2F1 and NCAPG. NCAPG knockdown promotes NLRP3 inflammasome-mediated pyroptosis in HCC cells.","method":"Dual luciferase reporter assay, chromatin immunoprecipitation (ChIP), Western blotting, scanning electron microscopy for pyroptosis, siRNA knockdown, xenograft model","journal":"Journal of clinical and translational hepatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus luciferase reporter for transcriptional regulation, functional pyroptosis readout, single lab","pmids":["38250463"],"is_preprint":false},{"year":2023,"finding":"CBX3 transcriptionally regulates NCAPG expression in colorectal cancer, as demonstrated by predicted CBX3 binding sites in the NCAPG promoter and luciferase reporter assay confirming promoter activity. CBX3-mediated NCAPG expression activates Wnt/β-catenin signaling to regulate CRC cell proliferation, cell cycle, and apoptosis.","method":"Luciferase reporter assay, RT-qPCR, Western blot, CCK-8, flow cytometry, TUNEL assay, caspase activity assay","journal":"Journal of gastrointestinal oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — luciferase reporter without ChIP confirmation, single lab","pmids":["37201048"],"is_preprint":false},{"year":2024,"finding":"CREB1 and MYOD1 bind to the core promoter region (-598/+87) of bovine NCAPG and activate its transcription, as established by deletion reporter assays, site-directed mutagenesis of binding sites, overexpression experiments, and electrophoretic mobility shift assay (EMSA).","method":"Deletion fragment dual-luciferase reporter assay, site-directed mutagenesis, overexpression, EMSA","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — EMSA plus luciferase plus mutagenesis for transcription factor binding, single lab in bovine cells","pmids":["38473754"],"is_preprint":false},{"year":2025,"finding":"ASPM directly binds NCAPG and promotes its transport from the nucleus to the cytoplasm in gastric cancer cells. ASPM also enhances deubiquitination of NCAPG mediated by BUB3, increasing NCAPG protein levels. Elevated NCAPG then activates the SRC/STAT3 pathway and elevates PD-L1 expression, contributing to immune evasion.","method":"Co-immunoprecipitation, mass spectrometry, molecular docking, CUT&Tag, transcriptome sequencing, subcellular fractionation/localization, organoid and in vivo experiments","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus MS plus functional pathway analysis, multiple orthogonal methods, single lab","pmids":["40898336"],"is_preprint":false},{"year":2025,"finding":"NCAPG promotes EC (endometrial cancer) progression by affecting LEF1 binding to chromatin, thereby activating transcription of SEMA7A. SEMA7A then binds the PI3K regulatory subunit p85 to activate PI3K-AKT signaling, establishing the NCAPG/LEF1/SEMA7A/PI3K-AKT axis.","method":"ATAC-seq, chromatin immunoprecipitation-qPCR (ChIP-qPCR), Co-immunoprecipitation, functional in vitro and in vivo assays","journal":"Journal of Cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ATAC-seq plus ChIP-qPCR plus Co-IP for mechanistic chain, single lab","pmids":["39744480"],"is_preprint":false},{"year":2025,"finding":"NCAPG promotes ferroptosis resistance in HCC by interacting with NSUN2 at its 446aa–460aa region, inhibiting NSUN2 protein degradation. NSUN2 then promotes m5C modification of GPX4 mRNA at its coding sequence, stabilizing GPX4 mRNA and increasing GPX4 expression to confer ferroptosis resistance.","method":"Co-immunoprecipitation, domain-mapping of NCAPG-NSUN2 interaction, m5C modification assay, GPX4 mRNA stability assay, NSUN2 knockdown rescue, in vivo and in vitro ferroptosis assays","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with domain mapping plus m5C readout plus rescue experiments, single lab","pmids":["41260238"],"is_preprint":false},{"year":2026,"finding":"Bufalin acts as a molecular glue that specifically degrades NCAPG by coupling it to cathepsin V (CTSV), forming a CTSV-NCAPG complex. This degradation induces G2/M cell cycle arrest and inhibits HCC cell proliferation without triggering apoptosis. Downstream proliferation regulators Cyclin D1 and CDK1 are regulated by bufalin in a CTSV/NCAPG-dependent manner.","method":"Co-immunoprecipitation, confocal microscopy, siRNA knockdown of CTSV and NCAPG, cell cycle analysis, CCK-8 proliferation assay, Western blotting","journal":"Drug development research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus confocal plus genetic rescue experiments confirming CTSV-NCAPG complex, single lab","pmids":["41586569"],"is_preprint":false},{"year":2022,"finding":"NCAPG knockdown in bladder cancer cells inhibits proliferation through suppression of the NF-κB signaling pathway, as demonstrated by RNA-seq identifying NF-κB as a downstream pathway and verified by luciferase reporter assay and Western blotting.","method":"RNA-seq, NF-κB luciferase reporter assay, Western blotting, siRNA knockdown, xenograft model, soft agar assay","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — luciferase reporter for NF-κB activity with knockdown, single lab, no direct binding established","pmids":["35843088"],"is_preprint":false},{"year":2023,"finding":"NCAPG knockdown in neuroblastoma activates p53-mediated apoptosis and induces G2/S cell cycle arrest, establishing NCAPG as a suppressor of p53-dependent apoptotic signaling.","method":"siRNA knockdown, flow cytometry cell cycle analysis, apoptosis assay, Western blotting for p53 pathway proteins","journal":"International journal of molecular sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, knockdown with pathway readout only, no direct binding or mechanistic reconstitution","pmids":["37834394"],"is_preprint":false},{"year":2022,"finding":"NCAPG promotes lung cancer oncogenesis through upregulation of LGALS1 (Galectin-1), and LGALS1 may interact directly with NCAPG. Ncapg+/- mice showed reduced urethane-induced lung tumor formation compared to wild-type, demonstrating an in vivo requirement for NCAPG in lung tumorigenesis.","method":"Transcriptome sequencing, Ncapg heterozygous mouse model with urethane carcinogenesis, siRNA knockdown, in vivo xenograft, IHC","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo Ncapg+/- mouse genetic model with carcinogen plus transcriptome; direct LGALS1 interaction not fully confirmed","pmids":["35180865"],"is_preprint":false}],"current_model":"NCAPG encodes the Cap-G subunit of the condensin I complex, where it is phosphorylated by cdc2/cyclin B at Thr308 and Thr332 to regulate its chromosomal localization during mitosis; it is the limiting subunit for condensin complex assembly (controlled by cell-cycle-regulated expression and constitutive degradation), is flexible in isolation but rigidifies upon binding its kleisin partner, and interacts with CENP-A/CID at centromeres to ensure sister chromatid segregation; in cancer contexts, NCAPG activates multiple oncogenic signaling pathways (PI3K/AKT, SRC/STAT3, Wnt/β-catenin, TGF-β/Smad, NF-κB) through direct protein interactions (including with β-catenin, CKII, CDK1, NSUN2, and ASPM), is transcriptionally driven by E2F1, CREB1, and MYOD1, and is targeted by miR-99a-3p and miR-181c; it also regulates chromatin accessibility at AP-1 sites during myogenesis and can be degraded by the molecular glue bufalin via a CTSV-dependent mechanism."},"narrative":{"mechanistic_narrative":"NCAPG encodes the Cap-G subunit of the condensin I complex, a chromosome-condensation machine required for faithful sister chromatid segregation during mitosis [PMID:15592865, PMID:23637630]. As a HEAT-repeat subunit, NCAPG/Ycg1 is conformationally flexible in isolation and rigidifies upon binding its kleisin partner, and it is the limiting, cell-cycle-regulated component for assembly of intact condensin: its levels peak in mitosis and decline in G1 through regulated transcription and constitutive degradation, and forcing its accumulation drives premature condensin assembly and proliferation defects [PMID:27463097, PMID:31350339]. Its chromosomal localization is governed by cdc2/cyclin B phosphorylation at Thr308 and Thr332, and it engages centromeric CENP-A/CID to couple condensin to kinetochore-dependent chromatid segregation [PMID:18977199, PMID:15592865]. Loss of NCAPG produces aberrant mitosis, mitotic arrest, and cell death, and genome-wide CRISPR screens rank it among the most essential genes for hepatocellular carcinoma growth [PMID:31022357, PMID:29046167]. Beyond its mitotic role, NCAPG functions as an oncogenic driver across multiple tumor types, acting upstream of a broad set of growth and survival pathways: it activates PI3K/AKT signaling—through interaction with casein kinase II to suppress PTEN and via a LEF1/SEMA7A axis [PMID:35864529, PMID:39744480]—drives SRC/STAT3 signaling to promote therapy resistance and immune evasion [PMID:32683421, PMID:40898336], interacts directly with β-catenin to engage Wnt/β-catenin signaling [PMID:35292013], and promotes TGF-β/Smad signaling [PMID:34419073]. It additionally stabilizes the m5C methyltransferase NSUN2 to confer ferroptosis resistance via GPX4 [PMID:41260238] and shapes chromatin accessibility at AP-1 sites during myoblast differentiation [PMID:32070024]. NCAPG transcription is driven by E2F1, CREB1, and MYOD1 [PMID:38250463, PMID:38473754], and it can be selectively degraded by the molecular glue bufalin through coupling to cathepsin V [PMID:41586569]. Note that several early-numbered findings describe the gelsolin-family actin-capping protein CAPG, a distinct protein sharing the CAPG alias, not the condensin subunit [PMID:7814409, PMID:7851883, PMID:12754261].","teleology":[{"year":2004,"claim":"Established that the condensin Cap-G subunit physically links the complex to the centromere and is required for chromatid segregation, defining its core mitotic role.","evidence":"Genetic modifier screen and yeast two-hybrid in Drosophila, with analysis of Cap-G mutant embryo mitosis","pmids":["15592865"],"confidence":"Medium","gaps":["Interaction mapped in Drosophila CID, not human CENP-A directly","Structural basis of the Cap-G/centromere contact not resolved"]},{"year":2008,"claim":"Showed that cdc2/cyclin B phosphorylation of two threonines controls Cap-G chromosomal localization, identifying a cell-cycle kinase input governing condensin targeting.","evidence":"Site-directed mutagenesis (T308A/T332A), in vitro kinase assay, mitotic immunofluorescence","pmids":["18977199"],"confidence":"High","gaps":["Functional consequence for condensation/segregation beyond localization not quantified","Phospho-site occupancy in vivo not measured"]},{"year":2013,"claim":"Resolved which condensin Cap-G associates with, showing exclusive incorporation into condensin I and that interphase nuclear enrichment is dispensable for function.","evidence":"Co-IP, mass spectrometry, live EGFP imaging, in vitro complex formation in Drosophila","pmids":["23637630"],"confidence":"High","gaps":["Does not address human condensin I/II partition directly","Function of nuclear enrichment, if any, undefined"]},{"year":2016,"claim":"Identified Cap-G/Ycg1 as the rate-limiting subunit for condensin assembly under cell-cycle control, explaining how condensin abundance is gated to mitosis.","evidence":"Cell-cycle synchronization, Western blot, ChIP, overexpression and stabilizing mutants in budding yeast","pmids":["27463097"],"confidence":"High","gaps":["Limiting-subunit role demonstrated in yeast, not confirmed in human cells","Degradation machinery not identified"]},{"year":2019,"claim":"Defined the conformational behavior of the subunit, showing it is flexible alone and rigidified by its kleisin partner, providing a structural basis for assembly-dependent activation.","evidence":"SAXS, multiangle light scattering, normal mode analysis of Ycg1 free and Brn1-bound","pmids":["31350339"],"confidence":"High","gaps":["No high-resolution structure of the human subunit","Functional consequence of free-subunit oligomerization unknown"]},{"year":2019,"claim":"Demonstrated NCAPG is essential for cancer cell proliferation and mitotic fidelity, elevating it from a structural subunit to a tumor dependency.","evidence":"Genome-wide CRISPR dropout screen, siRNA, xenograft, mitochondrial imaging in HCC; PI3K/AKT/FOXO4 rescue with inhibitor/activator","pmids":["31022357","29046167","31802891"],"confidence":"High","gaps":["Link between mitotic defect and mitochondrial network fragmentation mechanistically unresolved","Whether oncogenic dependency reflects condensin function or a moonlighting role unclear"]},{"year":2022,"claim":"Mapped direct protein interactions through which NCAPG activates growth signaling, moving beyond correlation to physical mechanism.","evidence":"IP-MS and Co-IP identifying CKII (PTEN/PI3K-AKT) and β-catenin (Wnt) interactions in HCC and CRC","pmids":["35864529","35292013"],"confidence":"Medium","gaps":["Interaction interfaces not mapped for CKII or β-catenin","Whether interactions require condensin assembly not tested"]},{"year":2022,"claim":"Showed an in vivo genetic requirement for NCAPG in tumorigenesis, strengthening the causal link beyond cell-line knockdown.","evidence":"Ncapg+/- mouse with urethane carcinogenesis, transcriptome sequencing, LGALS1 link","pmids":["35180865"],"confidence":"Medium","gaps":["Direct NCAPG-LGALS1 interaction not fully confirmed","Tissue-specific conditional knockout not performed"]},{"year":2024,"claim":"Established the transcriptional inputs driving NCAPG expression, identifying the upstream regulators that elevate it in proliferative and oncogenic states.","evidence":"ChIP/luciferase for E2F1 in HCC; EMSA, deletion reporter and mutagenesis for CREB1/MYOD1 in bovine cells","pmids":["38250463","38473754"],"confidence":"Medium","gaps":["Combinatorial regulation among E2F1/CREB1/MYOD1 not dissected","CBX3 regulation (idx 18) rests on reporter without ChIP"]},{"year":2025,"claim":"Extended NCAPG mechanism into protein-stability and RNA-modification control, linking it to immune evasion and ferroptosis resistance.","evidence":"Co-IP/MS with ASPM (deubiquitination, SRC/STAT3, PD-L1) and domain-mapped NSUN2 interaction (m5C-GPX4) in gastric cancer and HCC","pmids":["40898336","41260238"],"confidence":"Medium","gaps":["NSUN2 interaction domain mapped but structural validation absent","Whether these roles are independent of condensin function untested"]},{"year":2026,"claim":"Demonstrated NCAPG can be pharmacologically targeted via induced degradation, establishing therapeutic tractability.","evidence":"Co-IP, confocal, CTSV/NCAPG siRNA, cell-cycle and proliferation assays showing bufalin-induced CTSV-NCAPG complex in HCC","pmids":["41586569"],"confidence":"Medium","gaps":["Direct molecular-glue ternary structure not resolved","Selectivity over other condensin subunits not established"]},{"year":null,"claim":"It remains unresolved whether NCAPG's many oncogenic signaling interactions (CKII, β-catenin, SRC/STAT3, NSUN2, CDK1) depend on its condensin role or reflect a distinct cytoplasmic moonlighting function, and whether its mitotic phosphoregulation intersects with these pathways.","evidence":"","pmids":[],"confidence":"Low","gaps":["No study reconciles condensin assembly state with signaling interactions","Subcellular pool driving oncogenic signaling not defined","Human structural data on NCAPG lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[2,4]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[10,11,12,13,15]}],"localization":[{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2,20]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[20]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0,2,3,8,9]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[11,12,13,15,21]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[14,21]}],"complexes":["condensin I"],"partners":["NCAPH/BRN1","CENP-A/CID","CSNK2/CKII","CTNNB1","CDK1","NSUN2","ASPM","CTSV"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9BPX3","full_name":"Condensin complex subunit 3","aliases":["Chromosome-associated protein G","Condensin subunit CAP-G","hCAP-G","Melanoma antigen NY-MEL-3","Non-SMC condensin I complex subunit G","XCAP-G homolog"],"length_aa":1015,"mass_kda":114.3,"function":"Regulatory subunit of the condensin complex, a complex required for conversion of interphase chromatin into mitotic-like condense chromosomes. The condensin complex probably introduces positive supercoils into relaxed DNA in the presence of type I topoisomerases and converts nicked DNA into positive knotted forms in the presence of type II topoisomerases","subcellular_location":"Nucleus; Cytoplasm; Chromosome","url":"https://www.uniprot.org/uniprotkb/Q9BPX3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/NCAPG","classification":"Common Essential","n_dependent_lines":1203,"n_total_lines":1208,"dependency_fraction":0.9958609271523179},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"NCAPH","stoichiometry":10.0}],"url":"https://opencell.sf.czbiohub.org/search/NCAPG","total_profiled":1310},"omim":[{"mim_id":"606280","title":"NON-SMC CONDENSIN I COMPLEX SUBUNIT G; NCAPG","url":"https://www.omim.org/entry/606280"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"bone marrow","ntpm":13.1},{"tissue":"lymphoid 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Mutation of these threonines to alanines results in defects in CAP-G localization with chromosomal DNA during mitosis, establishing phosphorylation as a regulator of condensin chromosomal localization.\",\n      \"method\": \"Site-directed mutagenesis (T308A, T332A), in vitro cdc2/cyclin B kinase assay, immunofluorescence localization during mitosis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct mutagenesis combined with in vitro kinase assay and localization readout in single focused study\",\n      \"pmids\": [\"18977199\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Drosophila condensin subunit Cap-G (ortholog of NCAPG) physically interacts with the centromere-specific histone H3 variant CID (CENP-A homolog), as shown by yeast two-hybrid. Loss-of-function Cap-G mutant embryos show massive sister chromatid segregation defects during mitosis, linking condensin to kinetochore structure and chromatid segregation.\",\n      \"method\": \"Genetic modifier screen (rough eye phenotype), yeast two-hybrid interaction assay, analysis of Cap-G mutant embryo mitosis\",\n      \"journal\": \"Chromosoma\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic + yeast two-hybrid, two orthogonal methods in single lab\",\n      \"pmids\": [\"15592865\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Drosophila Cap-G associates exclusively with condensin I and not condensin II. In vivo, Cap-G-EGFP shows nuclear enrichment during interphase, but this nuclear localization is dispensable for chromatin association, condensin I complex assembly, and animal viability. Mass spectrometry of condensin II-specific subunit Cap-H2 immunoprecipitates failed to detect Cap-G.\",\n      \"method\": \"Immunoprecipitation, in vivo EGFP fusion microscopy, mass spectrometry, in vitro complex formation assays\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (Co-IP, mass spec, live imaging, in vitro reconstitution) in single study\",\n      \"pmids\": [\"23637630\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In budding yeast, Ycg1 (Cap-G/NCAPG ortholog) is cell-cycle regulated with protein levels peaking in mitosis and decreasing in G1, controlled by cell-cycle-regulated transcription and constitutive degradation. Ycg1 is limiting for condensin complex formation: overexpression of Ycg1 (but not other condensin subunits) increases intact condensin complex levels and chromatin binding in G1, causing delayed cell-cycle entry and proliferation defects.\",\n      \"method\": \"Cell cycle synchronization, Western blotting, chromatin immunoprecipitation (ChIP), overexpression and stabilizing mutation analysis in S. cerevisiae\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (protein quantification, ChIP, genetic overexpression, stabilizing mutations), well-controlled yeast study\",\n      \"pmids\": [\"27463097\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Solution SAXS characterization of the condensin HEAT-repeat subunit Ycg1 (Cap-G/NCAPG ortholog) reveals it is flexible in solution as a free subunit but becomes considerably more rigid upon binding its kleisin partner Brn1. Free Ycg1 tends to oligomerize at higher concentrations in the absence of Brn1.\",\n      \"method\": \"Small-angle X-ray scattering (SAXS), dynamic and static multiangle light scattering, normal mode analysis structural modeling\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — SAXS with complementary light scattering, rigorous structural characterization of free and bound states\",\n      \"pmids\": [\"31350339\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Human macrophage Cap G (CAPG/NCAPG alias) caps but does not sever actin filaments. Gain-of-function mutations converting residues 84LNTLLGE to the gelsolin actin-binding helix sequence (84LDDYLGG) conferred actin-severing activity; adding a second mutation converting 124AFHKTS to 124GFKHV enhanced severing 10-fold. These two regions are critical determinants of the lack of severing activity in wild-type Cap G.\",\n      \"method\": \"Site-directed mutagenesis, in vitro actin filament severing assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct in vitro reconstitution with mutagenesis, quantitative severing assay, multiple mutant constructs\",\n      \"pmids\": [\"7814409\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"The human Cap G gene (CAPG, an alias for NCAPG in the gelsolin-family context) is 16.6 kb, contains 10 exons and 9 introns, and maps to chromosome 2p. Comparison of splice sites with gelsolin and villin indicates CAPG is more closely related to gelsolin.\",\n      \"method\": \"Genomic cloning, sequencing, chromosomal mapping, comparative gene structure analysis\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct genomic cloning and sequencing; note this paper concerns the gelsolin-family CAPG gene, a distinct protein from the condensin NCAPG; included only if treated as alias collision — EXCLUDED from canonical NCAPG condensin protein\",\n      \"pmids\": [\"7851883\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Cap G (gelsolin-family macrophage capping protein) protein and mRNA are upregulated ~2-fold and ~5-fold, respectively, in endothelial cells exposed to atheroprotective (plaque-free) unidirectional shear stress compared to static culture; this increase is absent under plaque-prone flow. The increase occurs in nuclear and cytoskeletal-associated fractions. Overexpression of Cap G in transfection assays increased endothelial cell motility.\",\n      \"method\": \"2D gel proteomics, quantitative RT-PCR, subcellular fractionation, transfection overexpression motility assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple methods (proteomics, mRNA, fractionation, functional overexpression) in single lab; note this is the gelsolin-family CAPG not condensin NCAPG\",\n      \"pmids\": [\"12754261\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"NCAPG (condensin I subunit) knockdown in HCC cells causes aberrant mitotic division, fragmentation of the mitochondrial network, and increased cell death in vitro; genome-wide CRISPR dropout screens ranked NCAPG as the highest essential gene for HCC growth. Small interfering RNA knockdown reduced cell growth, migration, and downregulated mitochondrial gene expression.\",\n      \"method\": \"Genome-wide CRISPR knockout dropout screen, siRNA knockdown, xenograft tumor model, mitochondrial network imaging\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide CRISPR screen plus orthogonal siRNA validation plus in vivo xenograft, replicated across multiple datasets\",\n      \"pmids\": [\"31022357\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"NCAPG knockdown induces mitotic defects and inhibits HCC cell growth, proliferation, and migration in vitro; tetracycline-inducible shRNA knockdown inhibits tumor growth in vivo. NCAPG overexpression is correlated with overexpression of CCNB1 (cyclin B1), a mitotic regulatory protein.\",\n      \"method\": \"siRNA and inducible shRNA knockdown, cell proliferation assay, wound-healing migration assay, xenograft tumor model, expression correlation analysis\",\n      \"journal\": \"Oncology research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA plus inducible shRNA with in vivo validation, single lab\",\n      \"pmids\": [\"29046167\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"NCAPG overexpression activates the PI3K/AKT/FOXO4 pathway and alters expression of apoptosis-related proteins in HCC cells. The PI3K inhibitor LY294002 abolished NCAPG-mediated promotion of proliferation and reduction of apoptosis, while the PI3K activator 740Y-P had the opposite effect, placing NCAPG upstream of PI3K/AKT/FOXO4 in HCC proliferation signaling.\",\n      \"method\": \"siRNA knockdown and plasmid overexpression, EdU proliferation assay, flow cytometry apoptosis, RNA-seq pathway analysis, PI3K inhibitor/activator rescue experiments, Western blotting, xenograft model\",\n      \"journal\": \"OncoTargets and therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA-seq with pharmacological rescue, single lab, multiple assays\",\n      \"pmids\": [\"31802891\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"NCAPG overexpression in HER2-positive breast cancer cells promotes trastuzumab resistance by phosphorylating SRC and enhancing nuclear localization and transcriptional activation of STAT3, establishing NCAPG as an upstream activator of the SRC/STAT3 signaling pathway.\",\n      \"method\": \"Overexpression and siRNA knockdown, Western blotting for phospho-SRC and nuclear STAT3, cell proliferation/apoptosis assays, in vivo xenograft, immunofluorescence for STAT3 nuclear localization\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phospho-protein readouts with localization data, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"32683421\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NCAPG physically interacts with β-catenin in colorectal cancer cells, activating the Wnt/β-catenin signaling pathway to promote EMT, proliferation, migration, and invasion.\",\n      \"method\": \"Co-immunoprecipitation (Co-IP), immunofluorescence, Western blotting, siRNA knockdown and overexpression\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with functional readout, single lab\",\n      \"pmids\": [\"35292013\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NCAPG promotes HCC proliferation by interacting with CKII (casein kinase II). Their interaction was identified by IP-mass spectrometry and confirmed by Co-IP. NCAPG-CKII interaction promotes PTEN phosphorylation, thereby inhibiting PTEN transcription and function and activating the PI3K/AKT pathway.\",\n      \"method\": \"IP-mass spectrometry, Co-immunoprecipitation, transcriptome sequencing, EdU and CCK-8 proliferation assays, FISH, xenograft model\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — IP-MS plus Co-IP confirmation of interaction, transcriptome sequencing for pathway, single lab\",\n      \"pmids\": [\"35864529\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"NCAPG silencing in fetal bovine myoblasts prolongs mitosis and impairs differentiation through increased apoptosis. ATAC-seq revealed that NCAPG knockdown alters chromatin accessibility at AP-1 (activating protein 1) binding sites, and knockdown of AP-1 subunits FOSL2 or JUNB partially phenocopied the effect on muscle-specific gene expression.\",\n      \"method\": \"siRNA knockdown, ATAC-seq, immunofluorescence, gene expression quantification, AP-1 subunit knockdown\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ATAC-seq with functional follow-up knockdowns, single lab, multiple methods\",\n      \"pmids\": [\"32070024\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NCAPG overexpression in lung adenocarcinoma increases phospho-Smad2 and phospho-Smad3 in the TGF-β signaling pathway. Rescue experiments showed that TGF-β pathway inhibitors restored the effect of NCAPG overexpression, placing NCAPG upstream of TGF-β/Smad signaling in LUAD.\",\n      \"method\": \"siRNA knockdown and overexpression, Western blotting for p-Smad2/p-Smad3, TGF-β inhibitor rescue, in vitro and in vivo functional assays\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological rescue confirms pathway dependency, single lab\",\n      \"pmids\": [\"34419073\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NCAPG promotes NSCLC progression via the NCAPG/CDK1/ERK axis: NCAPG interacts with CDK1, and this interaction promotes phosphorylation of ERK, driving cell growth and metastasis in vitro and in vivo.\",\n      \"method\": \"Co-immunoprecipitation, Western blotting for phospho-ERK, siRNA knockdown, xenograft model\",\n      \"journal\": \"American journal of cancer research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, Co-IP for interaction, phospho-ERK readout without mutagenesis validation\",\n      \"pmids\": [\"39659935\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"E2F1 transcription factor directly binds the NCAPG promoter and transactivates NCAPG expression in HCC. E2F1 binding was confirmed by ChIP and luciferase reporter assay; HBx transfection co-upregulated both E2F1 and NCAPG. NCAPG knockdown promotes NLRP3 inflammasome-mediated pyroptosis in HCC cells.\",\n      \"method\": \"Dual luciferase reporter assay, chromatin immunoprecipitation (ChIP), Western blotting, scanning electron microscopy for pyroptosis, siRNA knockdown, xenograft model\",\n      \"journal\": \"Journal of clinical and translational hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus luciferase reporter for transcriptional regulation, functional pyroptosis readout, single lab\",\n      \"pmids\": [\"38250463\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CBX3 transcriptionally regulates NCAPG expression in colorectal cancer, as demonstrated by predicted CBX3 binding sites in the NCAPG promoter and luciferase reporter assay confirming promoter activity. CBX3-mediated NCAPG expression activates Wnt/β-catenin signaling to regulate CRC cell proliferation, cell cycle, and apoptosis.\",\n      \"method\": \"Luciferase reporter assay, RT-qPCR, Western blot, CCK-8, flow cytometry, TUNEL assay, caspase activity assay\",\n      \"journal\": \"Journal of gastrointestinal oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — luciferase reporter without ChIP confirmation, single lab\",\n      \"pmids\": [\"37201048\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CREB1 and MYOD1 bind to the core promoter region (-598/+87) of bovine NCAPG and activate its transcription, as established by deletion reporter assays, site-directed mutagenesis of binding sites, overexpression experiments, and electrophoretic mobility shift assay (EMSA).\",\n      \"method\": \"Deletion fragment dual-luciferase reporter assay, site-directed mutagenesis, overexpression, EMSA\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — EMSA plus luciferase plus mutagenesis for transcription factor binding, single lab in bovine cells\",\n      \"pmids\": [\"38473754\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ASPM directly binds NCAPG and promotes its transport from the nucleus to the cytoplasm in gastric cancer cells. ASPM also enhances deubiquitination of NCAPG mediated by BUB3, increasing NCAPG protein levels. Elevated NCAPG then activates the SRC/STAT3 pathway and elevates PD-L1 expression, contributing to immune evasion.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, molecular docking, CUT&Tag, transcriptome sequencing, subcellular fractionation/localization, organoid and in vivo experiments\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus MS plus functional pathway analysis, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"40898336\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NCAPG promotes EC (endometrial cancer) progression by affecting LEF1 binding to chromatin, thereby activating transcription of SEMA7A. SEMA7A then binds the PI3K regulatory subunit p85 to activate PI3K-AKT signaling, establishing the NCAPG/LEF1/SEMA7A/PI3K-AKT axis.\",\n      \"method\": \"ATAC-seq, chromatin immunoprecipitation-qPCR (ChIP-qPCR), Co-immunoprecipitation, functional in vitro and in vivo assays\",\n      \"journal\": \"Journal of Cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ATAC-seq plus ChIP-qPCR plus Co-IP for mechanistic chain, single lab\",\n      \"pmids\": [\"39744480\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NCAPG promotes ferroptosis resistance in HCC by interacting with NSUN2 at its 446aa–460aa region, inhibiting NSUN2 protein degradation. NSUN2 then promotes m5C modification of GPX4 mRNA at its coding sequence, stabilizing GPX4 mRNA and increasing GPX4 expression to confer ferroptosis resistance.\",\n      \"method\": \"Co-immunoprecipitation, domain-mapping of NCAPG-NSUN2 interaction, m5C modification assay, GPX4 mRNA stability assay, NSUN2 knockdown rescue, in vivo and in vitro ferroptosis assays\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with domain mapping plus m5C readout plus rescue experiments, single lab\",\n      \"pmids\": [\"41260238\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Bufalin acts as a molecular glue that specifically degrades NCAPG by coupling it to cathepsin V (CTSV), forming a CTSV-NCAPG complex. This degradation induces G2/M cell cycle arrest and inhibits HCC cell proliferation without triggering apoptosis. Downstream proliferation regulators Cyclin D1 and CDK1 are regulated by bufalin in a CTSV/NCAPG-dependent manner.\",\n      \"method\": \"Co-immunoprecipitation, confocal microscopy, siRNA knockdown of CTSV and NCAPG, cell cycle analysis, CCK-8 proliferation assay, Western blotting\",\n      \"journal\": \"Drug development research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus confocal plus genetic rescue experiments confirming CTSV-NCAPG complex, single lab\",\n      \"pmids\": [\"41586569\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NCAPG knockdown in bladder cancer cells inhibits proliferation through suppression of the NF-κB signaling pathway, as demonstrated by RNA-seq identifying NF-κB as a downstream pathway and verified by luciferase reporter assay and Western blotting.\",\n      \"method\": \"RNA-seq, NF-κB luciferase reporter assay, Western blotting, siRNA knockdown, xenograft model, soft agar assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — luciferase reporter for NF-κB activity with knockdown, single lab, no direct binding established\",\n      \"pmids\": [\"35843088\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"NCAPG knockdown in neuroblastoma activates p53-mediated apoptosis and induces G2/S cell cycle arrest, establishing NCAPG as a suppressor of p53-dependent apoptotic signaling.\",\n      \"method\": \"siRNA knockdown, flow cytometry cell cycle analysis, apoptosis assay, Western blotting for p53 pathway proteins\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, knockdown with pathway readout only, no direct binding or mechanistic reconstitution\",\n      \"pmids\": [\"37834394\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NCAPG promotes lung cancer oncogenesis through upregulation of LGALS1 (Galectin-1), and LGALS1 may interact directly with NCAPG. Ncapg+/- mice showed reduced urethane-induced lung tumor formation compared to wild-type, demonstrating an in vivo requirement for NCAPG in lung tumorigenesis.\",\n      \"method\": \"Transcriptome sequencing, Ncapg heterozygous mouse model with urethane carcinogenesis, siRNA knockdown, in vivo xenograft, IHC\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo Ncapg+/- mouse genetic model with carcinogen plus transcriptome; direct LGALS1 interaction not fully confirmed\",\n      \"pmids\": [\"35180865\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NCAPG encodes the Cap-G subunit of the condensin I complex, where it is phosphorylated by cdc2/cyclin B at Thr308 and Thr332 to regulate its chromosomal localization during mitosis; it is the limiting subunit for condensin complex assembly (controlled by cell-cycle-regulated expression and constitutive degradation), is flexible in isolation but rigidifies upon binding its kleisin partner, and interacts with CENP-A/CID at centromeres to ensure sister chromatid segregation; in cancer contexts, NCAPG activates multiple oncogenic signaling pathways (PI3K/AKT, SRC/STAT3, Wnt/β-catenin, TGF-β/Smad, NF-κB) through direct protein interactions (including with β-catenin, CKII, CDK1, NSUN2, and ASPM), is transcriptionally driven by E2F1, CREB1, and MYOD1, and is targeted by miR-99a-3p and miR-181c; it also regulates chromatin accessibility at AP-1 sites during myogenesis and can be degraded by the molecular glue bufalin via a CTSV-dependent mechanism.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NCAPG encodes the Cap-G subunit of the condensin I complex, a chromosome-condensation machine required for faithful sister chromatid segregation during mitosis [#1, #2]. As a HEAT-repeat subunit, NCAPG/Ycg1 is conformationally flexible in isolation and rigidifies upon binding its kleisin partner, and it is the limiting, cell-cycle-regulated component for assembly of intact condensin: its levels peak in mitosis and decline in G1 through regulated transcription and constitutive degradation, and forcing its accumulation drives premature condensin assembly and proliferation defects [#3, #4]. Its chromosomal localization is governed by cdc2/cyclin B phosphorylation at Thr308 and Thr332, and it engages centromeric CENP-A/CID to couple condensin to kinetochore-dependent chromatid segregation [#0, #1]. Loss of NCAPG produces aberrant mitosis, mitotic arrest, and cell death, and genome-wide CRISPR screens rank it among the most essential genes for hepatocellular carcinoma growth [#8, #9]. Beyond its mitotic role, NCAPG functions as an oncogenic driver across multiple tumor types, acting upstream of a broad set of growth and survival pathways: it activates PI3K/AKT signaling—through interaction with casein kinase II to suppress PTEN and via a LEF1/SEMA7A axis [#13, #21]—drives SRC/STAT3 signaling to promote therapy resistance and immune evasion [#11, #20], interacts directly with β-catenin to engage Wnt/β-catenin signaling [#12], and promotes TGF-β/Smad signaling [#15]. It additionally stabilizes the m5C methyltransferase NSUN2 to confer ferroptosis resistance via GPX4 [#22] and shapes chromatin accessibility at AP-1 sites during myoblast differentiation [#14]. NCAPG transcription is driven by E2F1, CREB1, and MYOD1 [#17, #19], and it can be selectively degraded by the molecular glue bufalin through coupling to cathepsin V [#23]. Note that several early-numbered findings describe the gelsolin-family actin-capping protein CAPG, a distinct protein sharing the CAPG alias, not the condensin subunit [#5, #6, #7].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established that the condensin Cap-G subunit physically links the complex to the centromere and is required for chromatid segregation, defining its core mitotic role.\",\n      \"evidence\": \"Genetic modifier screen and yeast two-hybrid in Drosophila, with analysis of Cap-G mutant embryo mitosis\",\n      \"pmids\": [\"15592865\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Interaction mapped in Drosophila CID, not human CENP-A directly\", \"Structural basis of the Cap-G/centromere contact not resolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Showed that cdc2/cyclin B phosphorylation of two threonines controls Cap-G chromosomal localization, identifying a cell-cycle kinase input governing condensin targeting.\",\n      \"evidence\": \"Site-directed mutagenesis (T308A/T332A), in vitro kinase assay, mitotic immunofluorescence\",\n      \"pmids\": [\"18977199\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence for condensation/segregation beyond localization not quantified\", \"Phospho-site occupancy in vivo not measured\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Resolved which condensin Cap-G associates with, showing exclusive incorporation into condensin I and that interphase nuclear enrichment is dispensable for function.\",\n      \"evidence\": \"Co-IP, mass spectrometry, live EGFP imaging, in vitro complex formation in Drosophila\",\n      \"pmids\": [\"23637630\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not address human condensin I/II partition directly\", \"Function of nuclear enrichment, if any, undefined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified Cap-G/Ycg1 as the rate-limiting subunit for condensin assembly under cell-cycle control, explaining how condensin abundance is gated to mitosis.\",\n      \"evidence\": \"Cell-cycle synchronization, Western blot, ChIP, overexpression and stabilizing mutants in budding yeast\",\n      \"pmids\": [\"27463097\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Limiting-subunit role demonstrated in yeast, not confirmed in human cells\", \"Degradation machinery not identified\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined the conformational behavior of the subunit, showing it is flexible alone and rigidified by its kleisin partner, providing a structural basis for assembly-dependent activation.\",\n      \"evidence\": \"SAXS, multiangle light scattering, normal mode analysis of Ycg1 free and Brn1-bound\",\n      \"pmids\": [\"31350339\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No high-resolution structure of the human subunit\", \"Functional consequence of free-subunit oligomerization unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrated NCAPG is essential for cancer cell proliferation and mitotic fidelity, elevating it from a structural subunit to a tumor dependency.\",\n      \"evidence\": \"Genome-wide CRISPR dropout screen, siRNA, xenograft, mitochondrial imaging in HCC; PI3K/AKT/FOXO4 rescue with inhibitor/activator\",\n      \"pmids\": [\"31022357\", \"29046167\", \"31802891\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Link between mitotic defect and mitochondrial network fragmentation mechanistically unresolved\", \"Whether oncogenic dependency reflects condensin function or a moonlighting role unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Mapped direct protein interactions through which NCAPG activates growth signaling, moving beyond correlation to physical mechanism.\",\n      \"evidence\": \"IP-MS and Co-IP identifying CKII (PTEN/PI3K-AKT) and β-catenin (Wnt) interactions in HCC and CRC\",\n      \"pmids\": [\"35864529\", \"35292013\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Interaction interfaces not mapped for CKII or β-catenin\", \"Whether interactions require condensin assembly not tested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed an in vivo genetic requirement for NCAPG in tumorigenesis, strengthening the causal link beyond cell-line knockdown.\",\n      \"evidence\": \"Ncapg+/- mouse with urethane carcinogenesis, transcriptome sequencing, LGALS1 link\",\n      \"pmids\": [\"35180865\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct NCAPG-LGALS1 interaction not fully confirmed\", \"Tissue-specific conditional knockout not performed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established the transcriptional inputs driving NCAPG expression, identifying the upstream regulators that elevate it in proliferative and oncogenic states.\",\n      \"evidence\": \"ChIP/luciferase for E2F1 in HCC; EMSA, deletion reporter and mutagenesis for CREB1/MYOD1 in bovine cells\",\n      \"pmids\": [\"38250463\", \"38473754\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Combinatorial regulation among E2F1/CREB1/MYOD1 not dissected\", \"CBX3 regulation (idx 18) rests on reporter without ChIP\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended NCAPG mechanism into protein-stability and RNA-modification control, linking it to immune evasion and ferroptosis resistance.\",\n      \"evidence\": \"Co-IP/MS with ASPM (deubiquitination, SRC/STAT3, PD-L1) and domain-mapped NSUN2 interaction (m5C-GPX4) in gastric cancer and HCC\",\n      \"pmids\": [\"40898336\", \"41260238\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"NSUN2 interaction domain mapped but structural validation absent\", \"Whether these roles are independent of condensin function untested\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Demonstrated NCAPG can be pharmacologically targeted via induced degradation, establishing therapeutic tractability.\",\n      \"evidence\": \"Co-IP, confocal, CTSV/NCAPG siRNA, cell-cycle and proliferation assays showing bufalin-induced CTSV-NCAPG complex in HCC\",\n      \"pmids\": [\"41586569\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular-glue ternary structure not resolved\", \"Selectivity over other condensin subunits not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved whether NCAPG's many oncogenic signaling interactions (CKII, β-catenin, SRC/STAT3, NSUN2, CDK1) depend on its condensin role or reflect a distinct cytoplasmic moonlighting function, and whether its mitotic phosphoregulation intersects with these pathways.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No study reconciles condensin assembly state with signaling interactions\", \"Subcellular pool driving oncogenic signaling not defined\", \"Human structural data on NCAPG lacking\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [2, 4]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [10, 11, 12, 13, 15]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2, 20]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [20]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 2, 3, 8, 9]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [11, 12, 13, 15, 21]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [14, 21]}\n    ],\n    \"complexes\": [\"condensin I\"],\n    \"partners\": [\"NCAPH/Brn1\", \"CENP-A/CID\", \"CSNK2/CKII\", \"CTNNB1\", \"CDK1\", \"NSUN2\", \"ASPM\", \"CTSV\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}