Affinage

CDC26

Anaphase-promoting complex subunit CDC26 · UniProt Q8NHZ8

Length
85 aa
Mass
9.8 kDa
Annotated
2026-06-09
26 papers in source corpus 15 papers cited in narrative 15 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CDC26 (APC12/ANAPC12) is a small, conserved subunit of the anaphase-promoting complex/cyclosome (APC/C), the cell cycle-regulated ubiquitin-protein ligase required for entry into anaphase and proteolysis of B-type cyclins (PMID:8895471, PMID:9348530, PMID:10922056). Within the complex it acts as a structural stabilizer of the core TPR subunit APC6 (Cdc16/Cut9): one helix from each protein forms an intermolecular TPR mimic that is required for proper APC/C assembly, and burial of CDC26's acetylated N-terminal methionine within the APC6 TPR superhelix shields an N-degron that would otherwise target CDC26 for degradation (PMID:19668213, PMID:20924356). Loss of CDC26 prevents APC/C-mediated ubiquitination of substrates including mitotic cyclins, Securin, and Polo-like kinase 1, blocking cyclin proteolysis and producing mitotic or meiotic metaphase arrest across yeast, zebrafish, C. elegans, plant, and mammalian systems (PMID:9348530, PMID:25723520, PMID:17141209, PMID:17374146, PMID:30737513, PMID:39542389). CDC26 activity is regulated by LATS1/2, which directly phosphorylate it at Thr7 to weaken the APC6 interaction and reshape APC/C assembly (PMID:25723520). In human oocytes, a homozygous APC12/CDC26 p.R8H mutation disrupts the APC12-APC6 interaction and impairs Securin ubiquitination, causing meiotic metaphase I arrest and female infertility (PMID:39542389). Beyond its APC/C role, CDC26 promotes ferroptosis in pancreatic cancer cells by facilitating ubiquitin-mediated degradation of the ferroptosis inhibitor SLC7A11 (PMID:41249642).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1992 Medium

    Established CDC26 as a genetically defined locus whose product is required for cell growth specifically at elevated temperature, the first functional handle on the gene.

    Evidence Gene disruption, cloning, sequencing, and complementation in S. cerevisiae

    PMID:1736102

    Open questions at the time
    • No molecular function or biochemical role identified
    • Temperature-dependent essentiality mechanism unexplained
  2. 1996 High

    Placed CDC26 inside the APC/cyclosome by identifying it as a subunit of the purified ubiquitin-ligase particle, defining its molecular context.

    Evidence Biochemical purification and subunit identification of the yeast APC complex

    PMID:8895471

    Open questions at the time
    • Stoichiometry and structural role within the complex not defined
    • Substrate specificity contribution unknown
  3. 1997 High

    Confirmed CDC26 as an integral APC component and linked its loss to a failure of mitotic cyclin proteolysis, connecting the subunit to ubiquitin-dependent cell cycle control.

    Evidence Temperature-sensitive mutant analysis, in vivo co-IP with Doc1/Cdc16/Cdc23/Cdc27, and sucrose gradient sedimentation in budding yeast

    PMID:9348530

    Open questions at the time
    • Direct contribution to catalysis vs assembly not separated
    • Which subunit CDC26 contacts not resolved
  4. 1997 Medium

    Showed CDC26 functions in APC/C assembly by demonstrating its fission yeast orthologue restores 20S complex assembly in a cut9 (APC6) mutant, foreshadowing the CDC26-APC6 relationship.

    Evidence Genetic suppression and sucrose gradient analysis of Hcn1 rescue of cut9 in S. pombe

    PMID:9264466

    Open questions at the time
    • Molecular basis of assembly stabilization unknown
    • Single-lab genetic readout
  5. 1999 Medium

    Defined CDC26's checkpoint context, showing it is required for Bub2-dependent but not Mad2-dependent mitotic arrest bypass, separating its pathway from the spindle assembly checkpoint branch.

    Evidence Genetic epistasis with double mutants and DNA re-replication assays in budding yeast

    PMID:10352016

    Open questions at the time
    • Mechanistic link between CDC26/APC and Bub2 not defined
    • Restricted to budding yeast
  6. 2000 Medium

    Demonstrated conservation of CDC26 as an APC subunit in humans, extending its function from yeast to vertebrates.

    Evidence Mass spectrometric identification of subunits from purified human APC

    PMID:10922056

    Open questions at the time
    • Human-specific functional role not tested
    • Regulation in human cells unaddressed
  7. 2006 Medium

    Established the vertebrate requirement for CDC26 in both proliferating and quiescent cells, showing loss causes mitotic arrest with apoptosis and aberrant cell cycle re-entry.

    Evidence Zebrafish cdc26 loss-of-function mutant phenotyping

    PMID:17141209

    Open questions at the time
    • Molecular substrate-level mechanism not addressed
    • Cause of aberrant re-entry in differentiated cells unclear
  8. 2007 Medium

    Confirmed functional conservation across metazoa by showing the C. elegans orthologue causes meiotic metaphase I arrest on depletion and complements a yeast cdc26 deletion.

    Evidence RNAi phenotyping in C. elegans embryos and cross-species yeast complementation

    PMID:17374146

    Open questions at the time
    • Meiotic substrate specificity not defined
    • Single-lab study
  9. 2009 High

    Resolved CDC26's structural role: it stabilizes APC6 via an intermolecular TPR mimic in which each protein contributes one helix, an interaction required for complex assembly.

    Evidence Crystal structure, biophysics, and genetic studies of CDC26-APC6

    PMID:19668213

    Open questions at the time
    • Whether CDC26 contributes beyond APC6 stabilization unresolved
    • Regulation of the interaction not addressed
  10. 2010 High

    Explained CDC26 protein stability by showing its acetylated N-terminal methionine is sequestered within the APC6 TPR superhelix, shielding an N-degron from the Doa10 E3 ligase.

    Evidence Crystal structure of S. pombe Cut9-Hcn1 complex

    PMID:20924356

    Open questions at the time
    • Whether degron shielding operates identically in humans not tested
    • Turnover dynamics of free vs assembled CDC26 unmeasured
  11. 2015 High

    Identified a regulatory input on CDC26: LATS1/2 directly phosphorylate Thr7 to weaken the APC6 interaction and alter APC/C assembly, modulating substrate ubiquitination.

    Evidence In vitro kinase assay, LATS1/2 knockdown, co-IP, gel filtration, and PLK1 ubiquitination assay with a T7D phosphomimetic in human cells

    PMID:25723520

    Open questions at the time
    • Cellular contexts where this phosphorylation operates not mapped
    • Quantitative effect on global APC/C output unknown
  12. 2019 Medium

    Extended CDC26 function to plants and revealed translational control, showing AtCDC26 is encoded by a uORF whose translation is coordinated by AtTTM3 and is required for APC/C function in development.

    Evidence Loss-of-function mutants, co-IP for APC/C membership, target protein westerns, and polysome profiling in Arabidopsis

    PMID:30737513

    Open questions at the time
    • Whether uORF-based regulation occurs outside plants unknown
    • Mechanism of TTM3-mediated polysome recruitment not detailed
  13. 2021 Medium

    Linked CDC26 to oocyte aging, showing declining CDC26 correlates with aneuploidy and that overexpression partially rescues spindle and chromosomal defects.

    Evidence Single-cell RNA-seq, immunocytochemistry, and lentiviral CDC26 manipulation in human and mouse oocytes

    PMID:34590680

    Open questions at the time
    • Direct molecular mechanism beyond APC/C membership not established
    • Cause of age-related CDC26 decline unknown
  14. 2024 High

    Established CDC26 as a human disease gene, showing a homozygous p.R8H mutation disrupts APC12-APC6 binding and Securin ubiquitination, causing meiotic arrest and female infertility.

    Evidence Whole-exome sequencing, oocyte cRNA microinjection, co-IP, Securin westerns, mouse knockdown and Apc12+/- model with cRNA rescue

    PMID:39542389

    Open questions at the time
    • Penetrance and broader phenotypic spectrum in patients not defined
    • Whether other APC/C substrates are affected not fully mapped
  15. 2025 Medium

    Uncovered a cancer-relevant CDC26 function, showing it promotes ferroptosis in pancreatic cancer cells by facilitating ubiquitin-mediated degradation of SLC7A11.

    Evidence CDC26 overexpression, ROS and lipid peroxidation assays, and SLC7A11 ubiquitination assay in PDAC cells

    PMID:41249642

    Open questions at the time
    • Whether SLC7A11 degradation is APC/C-dependent not established
    • Single-lab, overexpression-based mechanism without loss-of-function validation

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CDC26 regulation (e.g. LATS-dependent phosphorylation) and its newly described ferroptosis/SLC7A11 role integrate with canonical APC/C cell cycle function across tissues remains unresolved.
  • No reconstitution linking SLC7A11 degradation to APC/C activity
  • Tissue-specific physiological consequences of CDC26 regulation undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3 GO:0140096 catalytic activity, acting on a protein 3 GO:0005198 structural molecule activity 2
Pathway
R-HSA-1640170 Cell Cycle 4 R-HSA-392499 Metabolism of proteins 3 R-HSA-5357801 Programmed Cell Death 1
Partners
APC6CDC16CDC23CDC27DOC1LATS1LATS2
Complex memberships
APC/C (anaphase-promoting complex/cyclosome)

Evidence

Reading pass · 15 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 CDC26 (Cdc26p) is a small heat-inducible subunit of the anaphase-promoting complex (APC/cyclosome) in Saccharomyces cerevisiae, a 36S particle functioning as a cell cycle-regulated ubiquitin-protein ligase required for entry into anaphase and B-type cyclin proteolysis. Biochemical purification and subunit identification of the yeast APC complex Science High 8895471
1997 Mutations in CDC26 prevent mitotic cyclin (Clb2) proteolysis in budding yeast, and Cdc26 associates in vivo with Doc1, Cdc16, Cdc23, and Cdc27, with the majority co-sedimenting at 20S on sucrose gradients, confirming it as an APC component. Temperature-sensitive mutant analysis, in vivo co-immunoprecipitation, sucrose gradient sedimentation Molecular biology of the cell High 9348530
1999 In budding yeast, cell cycle progression of bub2 cells in the presence of nocodazole requires the Cdc26 APC subunit, placing CDC26 in a pathway distinct from the Mad2 checkpoint branch; Cdc26 is specifically required for Bub2-dependent (but not Mad2-dependent) mitotic arrest bypass. Genetic epistasis using double mutants (bub2 cdc26, mad2 cdc26) treated with nocodazole; DNA re-replication assay The Journal of cell biology Medium 10352016
1997 In fission yeast, the Cdc26 orthologue Hcn1 can restore the assembly of the 20S APC/cyclosome when the cut9 mutant assembly is impaired, indicating a role in stabilizing or assembling the APC/C complex. Genetic suppression: elevated Hcn1 levels rescue cut9 mutant APC assembly defect; sucrose gradient analysis Journal of cell science Medium 9264466
2000 CDC26 was identified by mass spectrometry as a subunit of the human APC, confirming its conservation from yeast to vertebrates. Mass spectrometric identification of APC subunits from purified human APC Proceedings of the National Academy of Sciences of the United States of America Medium 10922056
2009 CDC26 stabilizes the structure of APC6 (a core TPR subunit of the APC/C) through an intermolecular TPR mimic composed of one helix from each protein; CDC26-APC6 association is required for APC assembly. Biophysical analysis, crystal structure determination, genetic studies Nature structural & molecular biology High 19668213
2010 Crystal structure of S. pombe Cut9 (Cdc16/APC6) in complex with Hcn1 (Cdc26 orthologue) reveals that Cdc16/Cut9 is a contiguous TPR superhelix of 14 TPR units; the C-terminal TPR block interacts with Hcn1, and the acetylated N-terminal Met of Hcn1 is enclosed within a chamber in the Cut9 TPR superhelix, making the N-acetyl-Met degron inaccessible to the Doa10 E3 ubiquitin ligase and thereby protecting Hcn1/Cdc26 from ubiquitin-dependent degradation. Crystal structure determination of Cut9-Hcn1 complex The EMBO journal High 20924356
2015 LATS1 and LATS2 directly phosphorylate CDC26 at Thr7 (T7) in human cells; this phosphorylation reduces the interaction of CDC26 with APC6, alters APC/C assembly as measured by gel filtration, and a phosphomimetic T7D mutant of CDC26 promotes ubiquitination of polo-like kinase 1 (a known APC/C substrate). In vitro kinase assay (LATS1 phosphorylates CDC26 T7), siRNA knockdown of LATS1/LATS2 in HeLa cells, co-immunoprecipitation of CDC26 with APC6, gel filtration of APC/C subunits, ubiquitination assay with T7D mutant PloS one High 25723520
2006 Loss-of-function mutations in zebrafish cdc26 result in mitotic arrest followed by apoptosis in dividing cells, and improper re-entry into the cell cycle in quiescent/differentiated cells, demonstrating APC/C requirement in both dividing and non-dividing vertebrate cells. Zebrafish genetic mutant analysis; phenotypic characterization of cdc26 loss-of-function Developmental biology Medium 17141209
2007 C. elegans B0511.9 (CDC-26 orthologue) shares N-terminal sequence conservation with Cdc26 orthologues, and strong RNAi inhibition causes metaphase I arrest in meiosis, phenocopying APC/C mutants; B0511.9 functionally complements the temperature-sensitive growth defect of a yeast cdc26Δ mutant. RNAi phenotypic analysis in C. elegans embryos, functional complementation of yeast cdc26Δ BMC developmental biology Medium 17374146
2019 In Arabidopsis, AtCDC26 (encoded by a uORF within the AtTTM3 transcript) is part of the plant APC/C, regulates accumulation of APC/C target proteins, and controls cell division, growth, and embryo development; AtTTM3 coordinates AtCDC26 translation by recruiting the transcript into polysomes. Loss-of-function mutant analysis, immunoprecipitation to show APC/C membership, western blotting for APC/C target protein levels, polysome profiling Nature plants Medium 30737513
2024 A homozygous missense mutation in APC12/CDC26 (p.R8H) disrupts the interaction between APC12 and APC6 and impairs APC/C-mediated Securin ubiquitination, causing meiotic metaphase I arrest in oocytes and female infertility; knockdown of APC12 in mouse oocytes and Apc12+/- mice recapitulate this arrest phenotype. Whole-exome sequencing, oocyte microinjection of mutant cRNA, co-immunoprecipitation (APC12–APC6 interaction), western blotting (Securin accumulation), siRNA knockdown in mouse oocytes, Apc12+/- mouse model, rescue by Apc12 cRNA injection American journal of obstetrics and gynecology High 39542389
2021 CDC26 protein levels are decreased in aged human and mouse oocytes, and loss of CDC26 is associated with increased aneuploidy during oocyte maturation; overexpression of CDC26 partially rescues oocyte aging defects including spindle and chromosomal abnormalities. Single-cell RNA-seq, immunocytochemistry, lentiviral overexpression in human oocytes, mouse oocyte in vitro maturation with CDC26 manipulation Human reproduction Medium 34590680
2025 CDC26 overexpression in human pancreatic ductal adenocarcinoma cells promotes ferroptosis by enhancing ROS and lipid peroxidation; mechanistically, CDC26 promotes ubiquitin-mediated degradation of SLC7A11 (a key ferroptosis inhibitor) and indirectly inhibits the cell cycle, sensitizing cells to ferroptosis. CDC26 overexpression experiments, ROS and lipid peroxidation assays, ubiquitination assay for SLC7A11, cell proliferation and invasion assays Clinical and experimental medicine Medium 41249642
1992 The CDC26 gene in S. cerevisiae is required for cell growth only at high temperature; disruption of the gene confers thermosensitive growth, and the CDC26 gene is the same locus as SCD26 (a dosage-dependent suppressor of cdc26). Gene disruption, cloning and sequencing, complementation analysis, identification of nonsense mutation in cdc26-1 Molecular & general genetics Medium 1736102

Source papers

Stage 0 corpus · 26 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1996 Identification of subunits of the anaphase-promoting complex of Saccharomyces cerevisiae. Science (New York, N.Y.) 240 8895471
2000 The RING-H2 finger protein APC11 and the E2 enzyme UBC4 are sufficient to ubiquitinate substrates of the anaphase-promoting complex. Proceedings of the National Academy of Sciences of the United States of America 156 10922056
1999 Budding yeast Bub2 is localized at spindle pole bodies and activates the mitotic checkpoint via a different pathway from Mad2. The Journal of cell biology 150 10352016
1999 Caveolin interacts with Trk A and p75(NTR) and regulates neurotrophin signaling pathways. The Journal of biological chemistry 137 9867838
1997 Distinct subunit functions and cell cycle regulated phosphorylation of 20S APC/cyclosome required for anaphase in fission yeast. Journal of cell science 114 9264466
1997 A novel yeast screen for mitotic arrest mutants identifies DOC1, a new gene involved in cyclin proteolysis. Molecular biology of the cell 79 9348530
2010 The APC/C subunit Cdc16/Cut9 is a contiguous tetratricopeptide repeat superhelix with a homo-dimer interface similar to Cdc27. The EMBO journal 64 20924356
2009 Insights into anaphase promoting complex TPR subdomain assembly from a CDC26-APC6 structure. Nature structural & molecular biology 46 19668213
2014 Structure of an APC3-APC16 complex: insights into assembly of the anaphase-promoting complex/cyclosome. Journal of molecular biology 31 25490258
1992 Ty element-induced temperature-sensitive mutations of Saccharomyces cerevisiae. Genetics 27 1325386
2019 Concerted expression of a cell cycle regulator and a metabolic enzyme from a bicistronic transcript in plants. Nature plants 26 30737513
2006 The anaphase-promoting complex is required in both dividing and quiescent cells during zebrafish development. Developmental biology 24 17141209
1992 The CDC26 gene of Saccharomyces cerevisiae is required for cell growth only at high temperature. Molecular & general genetics : MGG 14 1736102
2015 LATS1 and LATS2 phosphorylate CDC26 to modulate assembly of the tetratricopeptide repeat subcomplex of APC/C. PloS one 12 25723520
2007 Identification of the C. elegans anaphase promoting complex subunit Cdc26 by phenotypic profiling and functional rescue in yeast. BMC developmental biology 12 17374146
2021 miR-6769b-5p targets CCND-1 to regulate proliferation in cadmium-treated placental trophoblasts: Association with the impairment of fetal growth. Ecotoxicology and environmental safety 11 34953275
2020 Drug combinations as effective anti-leishmanials against drug resistant Leishmania mexicana. RSC medicinal chemistry 9 33479685
2021 CDC26 is a key factor in human oocyte aging. Human reproduction (Oxford, England) 8 34590680
2023 Identification of a circRNA-miRNA-mRNA network to explore the effects of circRNAs on Holstein bull testis after sexual maturity. Animal reproduction science 5 39492239
2022 Oncogenic Roles of Polycomb Repressive Complex 2 in Bladder Cancer and Upper Tract Urothelial Carcinoma. Biomedicines 5 36428492
1996 Fifteen open reading frames in a 30.8 kb region of the right arm of chromosome VI from Saccharomyces cerevisiae. Yeast (Chichester, England) 3 8686381
2024 Atypical cadherin, Fat2, regulates axon terminal organization in the developing Drosophila olfactory receptor neurons. iScience 2 39055932
2024 Homozygous missense variations of APC12 cause meiotic metaphase I arrest in oocytes and female infertility. American journal of obstetrics and gynecology 2 39542389
2025 Onvansertib and Navitoclax Combination as a New Therapeutic Option for Mucinous Ovarian Carcinoma. International journal of molecular sciences 1 39859203
2025 CDC26 facilitates ferroptosis through SLC7A11 degradation and cell cycle arrest. Clinical and experimental medicine 1 41249642
2026 Biallelic mutations in ANAPC13 cause female infertility characterized by oocyte maturation arrest both in humans and mice. American journal of obstetrics and gynecology 0 41997520

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