Affinage

NCAPH

Condensin complex subunit 2 · UniProt Q15003

Length
741 aa
Mass
82.6 kDa
Annotated
2026-04-29
31 papers in source corpus 13 papers cited in narrative 13 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NCAPH (CAP-H) is the kleisin subunit of the condensin I complex, essential for mitotic chromosome condensation, sister chromatid resolution, and maintenance of centromeric heterochromatin integrity. NCAPH bridges the SMC2/SMC4 ATPase heads and is required for non-SMC subunit association with chromatin; its activity is regulated by Cdk1 phosphorylation of a conserved central kleisin residue that relieves auto-inhibition, by caspase-3 cleavage that triggers mitotic cell death during prolonged arrest, and by TRIM21-mediated K11 ubiquitination that targets it for proteasomal degradation (PMID:16199875, PMID:21151026, PMID:39103348). Beyond chromosome architecture, NCAPH physically interacts with the Holliday junction resolvase GEN1 to stabilize it on chromatin at G2/M and resolve ultra-fine DNA bridges arising from inter-strand crosslinks (PMID:36380731). In cancer contexts, NCAPH activates PI3K/AKT/mTOR, MEK/ERK, and Hippo-YAP1 signaling, binds and stabilizes PD-L1 to promote immune evasion, and directly occupies the E2F1 promoter to drive cell-cycle gene expression (PMID:33311486, PMID:34974790, PMID:40999529, PMID:41386505, PMID:39991770).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2001 Medium

    Establishing where and when NCAPH engages chromosomes: NCAPH localizes to mitotic chromosomes in a non-uniform, symmetric pattern along sister chromatids and resides in nucleoli during interphase, with chromosome loading occurring after histone H3 phosphorylation, defining the temporal order of condensation events.

    Evidence Cell-cycle fractionation and immunofluorescence of hCAP-H in human cells

    PMID:11694586

    Open questions at the time
    • Mechanism recruiting NCAPH to chromosomes after H3 phosphorylation was not determined
    • Functional significance of nucleolar interphase localization was not tested
  2. 2005 High

    Demonstrating that NCAPH is the critical bridge enabling condensin I function: depletion of the kleisin subunit prevents non-SMC subunit chromatin association while SMC2/4 still bind, establishing that NCAPH is required for sister chromatid resolution and centromeric heterochromatin structural integrity under spindle forces.

    Evidence RNAi depletion in Drosophila S2 cells with immunofluorescence, live imaging, and chromatin fractionation

    PMID:16199875

    Open questions at the time
    • Whether residual SMC binding without kleisin performs any function was not addressed
    • Direct physical basis of centromere fragility upon NCAPH loss was not resolved
  3. 2010 High

    Revealing that caspase-3 cleavage of NCAPH is the molecular switch for mitotic cell death: during prolonged mitotic arrest, activated caspase-3 cleaves NCAPH, causing condensin I loss from chromosomes and chromosome disintegration; a caspase-resistant NCAPH mutant rescues viability, establishing NCAPH integrity as the decision point between death and mitotic slippage.

    Evidence In vitro caspase-3 cleavage assay, expression of caspase-resistant CAP-H mutant with cell-fate readouts in human cells

    PMID:21151026

    Open questions at the time
    • Precise cleavage site(s) in NCAPH were identified but structural consequences on the condensin I ring were not modeled
    • Whether other condensin subunits are also caspase targets was not fully explored
  4. 2020 Medium

    Connecting NCAPH to oncogenic signaling: NCAPH operates downstream of MYBL2 to drive lung cancer proliferation, and in cervical cancer HPV E7/E2F1 activates NCAPH transcription while NCAPH feeds back to stimulate PI3K/AKT/SGK signaling and alter AP-1 heterodimer composition, establishing NCAPH as a nexus between mitotic regulators and proliferative signaling.

    Evidence ChIP for MYBL2 at NCAPH TSS with epistasis rescue; promoter-binding and AP-1 composition assays with PI3K/AKT pathway readouts in cervical cancer xenografts

    PMID:32200471 PMID:33311486

    Open questions at the time
    • Mechanism by which NCAPH, a chromosome structural protein, activates cytoplasmic kinase cascades is unknown
    • Whether AP-1 switching is a direct or indirect effect of NCAPH was not resolved
  5. 2022 Medium

    Extending NCAPH function to DNA repair: NCAPH physically interacts with the Holliday junction resolvase GEN1 via its N-terminus and stabilizes GEN1 on chromatin at G2/M, enabling resolution of inter-strand crosslink-induced ultra-fine DNA bridges; this placed NCAPH in a DNA repair role beyond simple chromosome compaction.

    Evidence Reciprocal co-immunoprecipitation with domain mapping, chromatin fractionation, and UFB/segregation readouts after siRNA knockdown

    PMID:36380731

    Open questions at the time
    • Whether GEN1 stabilization requires intact condensin I complex or only NCAPH is unclear
    • In vitro reconstitution of the NCAPH–GEN1 interaction on DNA substrates has not been performed
  6. 2022 Medium

    Placing NCAPH upstream of MEK/ERK in bladder cancer: NCAPH overexpression activates MEK/ERK signaling and this is blocked by MEK1/2 inhibitor U0126, establishing pathway epistasis.

    Evidence Gain/loss-of-function with pharmacological MEK inhibition and xenograft validation

    PMID:34974790

    Open questions at the time
    • Direct molecular link between NCAPH and MEK activation is not identified
    • Whether MEK/ERK activation is cell-type specific was not tested
  7. 2023 Medium

    Linking NCAPH to metabolic reprogramming and drug resistance: FOXM1 directly activates NCAPH transcription, and NCAPH promotes glycolysis, stemness, and 5-FU resistance in colon adenocarcinoma, reversible by glycolysis inhibition.

    Evidence ChIP and dual-luciferase for FOXM1-NCAPH promoter binding; glycolysis metabolic assays and sphere formation

    PMID:37260271

    Open questions at the time
    • Glycolytic enzymes directly regulated by NCAPH were not identified
    • Whether NCAPH's metabolic role is independent of condensin I remains unknown
  8. 2024 High

    Defining the degradation pathway for NCAPH: TRIM21 ubiquitinates NCAPH at K11 via its RING domain, targeting it for proteasomal degradation; this destabilization promotes autophagosome formation and suppresses AKT/mTOR signaling, providing the first site-specific ubiquitination mechanism controlling NCAPH protein levels.

    Evidence Mass spectrometry identification of ubiquitination site, domain-mutant co-IP, K11R mutation validation, autophagy and proliferation assays

    PMID:39103348

    Open questions at the time
    • Ubiquitin chain type (K48 vs K63) was not fully characterized
    • Whether TRIM21-mediated degradation is cell-cycle regulated was not tested
  9. 2025 Medium

    Uncovering non-canonical roles in immune evasion and transcriptional regulation: NCAPH stabilizes PD-L1 by competing with HIP1R to prevent its degradation, and independently binds the E2F1 promoter to drive PI3K/AKT/mTOR-dependent cell-cycle progression; NCAPH also interacts with YAP1 to promote its nuclear translocation and cancer stemness via the Hippo pathway.

    Evidence Co-IP/competitive binding for PD-L1/HIP1R, ChIP at E2F1 promoter, co-IP/co-localization for YAP1 with inhibitor rescue, across multiple cancer models

    PMID:39991770 PMID:40999529 PMID:41386505

    Open questions at the time
    • How a chromatin-associated structural protein engages cytoplasmic PD-L1 remains mechanistically unclear
    • Whether NCAPH's transcriptional activity at E2F1 occurs as part of condensin I or independently is unknown
    • Single-lab findings for each interaction await independent replication

Open questions

Synthesis pass · forward-looking unresolved questions
  • The fundamental mechanism by which NCAPH's chromosome-structural role connects to its reported signaling, transcriptional, and immune-modulatory activities in cancer remains unresolved; it is unknown whether these functions require intact condensin I or reflect moonlighting by free NCAPH, and structural details of how Cdk1 phosphorylation of the kleisin central region relieves auto-inhibition await high-resolution characterization.
  • No structural model of NCAPH within human condensin I at atomic resolution
  • Condensin-dependent vs condensin-independent functions of NCAPH have not been systematically separated
  • Cell-cycle-dependent regulation of NCAPH's non-canonical partners (GEN1, YAP1, PD-L1) is uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 3 GO:0140110 transcription regulator activity 1
Localization
GO:0005694 chromosome 4 GO:0005634 nucleus 3 GO:0005730 nucleolus 1
Pathway
R-HSA-1640170 Cell Cycle 4 R-HSA-162582 Signal Transduction 3 R-HSA-5357801 Programmed Cell Death 1 R-HSA-73894 DNA Repair 1
Partners
CD274E2F1GEN1SMC2SMC4TRIM21YAP1
Complex memberships
condensin I

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 Drosophila CAP-H (Barren), the condensin I kleisin subunit, is required for sister chromatid resolution and for maintaining the structural integrity of centromeric/pericentromeric heterochromatin during mitosis; in its absence, condensin I non-SMC subunits fail to associate with chromatin while the SMC core (DmSMC4/2) still binds, and centromeric heterochromatin cannot withstand mitotic spindle forces, leading to irreversible distortion. RNAi depletion in Drosophila S2 cells, immunofluorescence, live imaging, co-immunoprecipitation/chromatin fractionation Molecular and cellular biology High 16199875
2001 Human CAP-H (hCAP-H) protein localizes to mitotic chromosomes in a non-uniform but symmetrical distribution along sister chromatids, and during interphase hCAP-H, hCAP-C, and hCAP-E localize to nucleoli, suggesting condensin I associates with rDNA; chromosome association occurs after histone H3 phosphorylation, indicating H3 phosphorylation precedes condensin-mediated condensation. Cell-cycle fractionation, immunofluorescence, live-cell and fixed imaging of hCAP-H subcellular distribution Molecular biology of the cell Medium 11694586
2010 During prolonged mitotic arrest, activated caspase-3 cleaves CAP-H (condensin I subunit), causing loss of condensin I from chromosomes and compromising chromosome integrity; expression of a caspase-resistant CAP-H prevents mitotic death and allows cells to re-enter interphase, demonstrating that caspase-3-mediated CAP-H cleavage is a key determinant of mitotic cell death. Caspase-3 activity assay, in vitro cleavage, expression of caspase-resistant CAP-H mutant, chromosome integrity and cell-fate readouts Cell death and differentiation High 21151026
2022 NCAPH physically interacts with the Holliday junction resolvase GEN1 via the N-terminus of NCAPH; this interaction is enhanced by DNA inter-strand crosslink (ICL)-inducing agents, and NCAPH stabilizes GEN1 within chromatin at G2/M phase, enabling resolution of ICL-induced ultra-fine DNA bridges and proper chromosome segregation. Co-immunoprecipitation, chromatin fractionation, siRNA knockdown with UFB and chromosome segregation readouts, domain-mapping pulldown Molecules and cells Medium 36380731
2020 The transcription factor MYBL2 directly binds the transcription start site (TSS) of NCAPH and upregulates its expression; NCAPH functions downstream of MYBL2 to promote lung cancer cell proliferation and migration, as NCAPH overexpression partially rescues the effects of MYBL2 knockdown. ChIP assay, siRNA/overexpression, epistasis rescue experiment, cell proliferation and migration assays Molecular and cellular biochemistry Medium 32200471
2020 HPV E7 upregulates NCAPH transcription via E2F1 binding to the NCAPH promoter; NCAPH in turn promotes E7 transcription by shifting the AP-1 heterodimer composition from c-Fos/c-Jun to Fra-1/c-Jun, forming a positive feedback loop; NCAPH overexpression activates the PI3K/AKT/SGK signaling pathway in cervical cancer cells. siRNA knockdown, promoter-binding assays, AP-1 component analysis, PI3K/AKT/SGK pathway western blotting, xenograft models Cell death & disease Medium 33311486
2024 TRIM21 interacts with NCAPH through its PRY/SPRY and CC domains and ubiquitinates NCAPH at the K11 lysine residue via its RING domain, targeting NCAPH for proteasomal degradation; TRIM21-mediated NCAPH destabilization promotes autophagosome formation and reduces cervical cancer cell proliferation via inhibition of the downstream AKT/mTOR pathway. Mass spectrometry, co-immunoprecipitation, structural domain mutation analysis, ubiquitination assay, autophagy and proliferation readouts Cell death & disease High 39103348
2022 NCAPH activates the MEK/ERK signaling pathway in bladder cancer cells to promote proliferation and inhibit apoptosis; MEK1/2 inhibitor U0126 blocks the pro-proliferative effect of NCAPH overexpression, placing NCAPH upstream of MEK/ERK. Gain- and loss-of-function experiments, MEK/ERK pathway western blotting, pharmacological inhibition (U0126), xenograft model Cell cycle (Georgetown, Tex.) Medium 34974790
2025 NCAPH binds PD-L1 and stabilizes it by competing with HIP1R (Huntingtin-interacting protein 1-related), thereby inhibiting PD-L1 protein degradation and contributing to immune evasion in head and neck squamous cell carcinoma; a disrupting peptide (NPIDP) and topotecan (which promotes NCAPH proteasomal degradation) both reduce this effect in vitro and in vivo. Co-immunoprecipitation, competitive binding assay, peptide disruption, topotecan treatment, in vitro and xenograft tumor models Cancer letters Medium 41386505
2025 NCAPH interacts with YAP1 (confirmed by co-immunoprecipitation and immunofluorescence co-localization) and promotes LATS1 and YAP1 expression, YAP1 dephosphorylation, and YAP1 nuclear translocation, thereby enhancing breast cancer stem cell traits; YAP1 inhibitor Verteporfin reverses NCAPH-driven effects. Co-immunoprecipitation, immunofluorescence co-localization, transcriptomic sequencing/GSEA, YAP1 inhibitor rescue experiment, in vitro and in vivo models Stem cell research & therapy Medium 40999529
2025 NCAPH regulates E2F1 transcription by binding to the proximal promoter of E2F1 (shown by ChIP), which subsequently stimulates the PI3K/AKT/mTOR pathway and activates downstream targets for cell cycle progression in prostate cancer cells. ChIP assay, flow cytometry, pathway western blotting, siRNA knockdown, xenograft model International journal of medical sciences Medium 39991770
2023 FOXM1 directly binds the NCAPH promoter (confirmed by ChIP and dual-luciferase assays) and transcriptionally activates NCAPH; NCAPH downstream regulates glycolysis, cancer cell stemness, and 5-FU resistance in colon adenocarcinoma, with glycolysis pathway inhibition reversing NCAPH overexpression effects. ChIP assay, dual-luciferase reporter assay, glycolysis metabolic assay, cell sphere formation, CCK-8 resistance assay Anti-cancer drugs Medium 37260271
2025 Reconstitution of mitotic chromatid assembly in vitro with recombinant condensin I (including CAP-H/NCAPH) reveals that the terminal intrinsically disordered regions (tIDRs) of non-SMC subunits suppress condensin I activity; Cdk1 phosphorylation relieves this self-suppression, and full activation requires phosphorylation of a conserved residue in the central region of the CAP-H kleisin subunit. PP2A-B55 dephosphorylates condensin I to induce its dissociation from reconstituted chromatids, driving disassembly. In vitro reconstitution of chromatid assembly/disassembly with recombinant proteins, cyclin B-Cdk1 and PP2A-B55 phosphorylation assays, mutagenesis of tIDRs and kleisin central region, Xenopus egg extract validation bioRxivpreprint High bio_10.1101_2025.09.08.674995

Source papers

Stage 0 corpus · 31 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 The condensin I subunit Barren/CAP-H is essential for the structural integrity of centromeric heterochromatin during mitosis. Molecular and cellular biology 89 16199875
2017 NCAPH plays important roles in human colon cancer. Cell death & disease 67 28300828
2001 Cell cycle-dependent expression and nucleolar localization of hCAP-H. Molecular biology of the cell 41 11694586
2020 Overexpression of MYBL2 promotes proliferation and migration of non-small-cell lung cancer via upregulating NCAPH. Molecular and cellular biochemistry 39 32200471
2020 HPV E7-mediated NCAPH ectopic expression regulates the carcinogenesis of cervical carcinoma via PI3K/AKT/SGK pathway. Cell death & disease 37 33311486
2019 Non-SMC Condensin I Complex Subunit H (NCAPH) Is Associated with Lymphangiogenesis and Drug Resistance in Oral Squamous Cell Carcinoma. Journal of clinical medicine 25 31892156
2010 Caspase-3-mediated degradation of condensin Cap-H regulates mitotic cell death. Cell death and differentiation 23 21151026
2020 NCAPH Is Required for Proliferation, Migration and Invasion of Non-small-cell Lung Cancer Cells. Anticancer research 21 32487618
2022 NCAPH promotes cell proliferation and inhibits cell apoptosis of bladder cancer cells through MEK/ERK signaling pathway. Cell cycle (Georgetown, Tex.) 20 34974790
2019 Micro-ribonucleic acid expression signature of metastatic castration-resistant prostate cancer: Regulation of NCAPH by antitumor miR-199a/b-3p. International journal of urology : official journal of the Japanese Urological Association 20 30818424
2024 NCAPH, ubiquitinated by TRIM21, promotes cell proliferation by inhibiting autophagy of cervical cancer through AKT/mTOR dependent signaling. Cell death & disease 16 39103348
2021 NCAPH regulates gastric cancer progression through DNA damage response. Neoplasma 15 34962823
2020 NCAPH is upregulated in endometrial cancer and associated with poor clinicopathologic characteristics. Annals of human genetics 15 32628282
2021 Expression and Clinical Significance of the NCAPH, AGGF1, and FOXC2 Proteins in Serous Ovarian Cancer. Cancer management and research 12 34584452
2022 NCAPH promotes proliferation as well as motility of breast cancer cells by activating the PI3K/AKT pathway. Physiology international 10 36067021
2023 FOXM1/NCAPH activates glycolysis to promote colon adenocarcinoma stemness and 5-FU resistance. Anti-cancer drugs 9 37260271
2020 NCAPH is negatively associated with Mcl‑1 in non‑small cell lung cancer. Molecular medicine reports 9 32945371
2024 NCAPH drives breast cancer progression and identifies a gene signature that predicts luminal a tumour recurrence. Clinical and translational medicine 6 38344872
2024 The role of NCAPH in cancer treatment. Cellular signalling 6 38901722
2022 NCAPH Stabilizes GEN1 in Chromatin to Resolve Ultra-Fine DNA Bridges and Maintain Chromosome Stability. Molecules and cells 6 36380731
2022 An integrative pan-cancer analysis reveals the carcinogenic effects of NCAPH in human cancer. Mathematical biosciences and engineering : MBE 6 36650758
2024 MiR-1976/NCAPH/P65 axis inhibits the malignant phenotypes of lung adenocarcinoma. Scientific reports 4 38755247
2024 ZCCHC3 and Efp coordinately contribute to the pathophysiology of triple-negative breast cancer by modulating NCAPH. Biochemical and biophysical research communications 4 39276521
2024 circEIF3I Promotes Colorectal Cancer Metastasis by Regulating the miR-328-3p/NCAPH Axis. Molecular carcinogenesis 3 39620395
2025 NCAPH Promotes the Proliferation of Prostate Cancer Cells Via Modulating the E2F1 Mediated PI3K/AKT/mTOR Axis. International journal of medical sciences 2 39991770
2025 NCAPH promotes glucose metabolism reprogramming and cell stemness in ovarian cancer cells through the MEK/ERK/PD-L1 pathway. Journal of ovarian research 2 40259316
2026 NCAPH as an onco-structural hub linking chromatin architecture to metabolic reprogramming, immune evasion, and therapy resistance. Critical reviews in oncology/hematology 0 41825578
2025 MiR-1976 affects lung squamous cell carcinoma development by targeting NCAPH. Journal of applied genetics 0 40699282
2025 NCAPH-YAP1 interaction promotes breast cancer stemness and tumor progression. Stem cell research & therapy 0 40999529
2025 NCAPH promotes immune evasion via inhibiting PD-L1 protein degradation in head and neck squamous cell carcinoma. Cancer letters 0 41386505
2023 NCAPH Drives Breast Cancer Progression and Identifies a Gene Signature that Predicts Luminal A Tumor Recurrence. Research square 0 37886490