Affinage

CDAN1

Codanin-1 · UniProt Q8IWY9

Audit flag: ungrounded claim
Length
1227 aa
Mass
134.1 kDa
Annotated
2026-06-09
28 papers in source corpus 11 papers cited in narrative 11 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

Codanin-1 (CDAN1) is an essential, cell-cycle-regulated negative regulator of replication-coupled chromatin assembly that sequesters the histone H3-H4 chaperone ASF1 in the cytoplasm and governs terminal erythroid differentiation (PMID:22407294, PMID:34234671). It binds ASF1 through a conserved B-domain in a manner mutually exclusive with the ASF1-CAF-1 and ASF1-HIRA chaperone handoffs, and its depletion accelerates DNA replication and increases chromatin-bound ASF1, whereas its overexpression arrests S-phase progression (PMID:22407294). Cryo-EM shows that CDAN1 dimerizes and engages two ASF1 molecules per monomer using two B-domains and two histone-H3-mimicking helices, thereby occupying all functional ASF1 surfaces and explaining how it blocks histone delivery (PMID:40091041). CDAN1 also forms an obligate, near-stoichiometric heterodimer with CDIN1 (C15ORF41) via its C-terminus, sequestering CDIN1 in the cytoplasm and stabilizing it (PMID:32239177, PMID:41609415). The protein localizes to interphase heterochromatin, is excluded from condensed mitotic chromosomes upon phosphorylation, and peaks during S phase, consistent with cell-cycle-coupled function under E2F1 transcriptional control (PMID:19336738), and both CDAN1 and CDIN1 are enriched in nucleoli (PMID:32518175). In erythropoiesis, CDAN1 loss causes severe anemia, spongy heterochromatin, failed maturation, and derepression of differentiation inhibitors such as Gata2, and CDAN1 directly occupies erythroid gene regulatory regions including AHSP (PMID:34234671, PMID:41028447). Disease-causing mutations in CDAN1 or CDIN1 selectively disrupt the protein-protein interactions within this complex, defining the molecular basis of congenital dyserythropoietic anemia type I (PMID:22407294, PMID:41609415).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2009 Medium

    Establishing that Codanin-1 is a cell-cycle-coupled chromatin-associated protein placed it within the replication/chromatin axis before any biochemical partner was known.

    Evidence Immunofluorescence, immuno-EM, cell synchronization, ChIP and luciferase reporter assays in an E2F1-inducible system

    PMID:19336738

    Open questions at the time
    • Molecular function and binding partners not yet defined
    • Functional consequence of mitotic phosphorylation not established
  2. 2012 High

    Identifying CDAN1 as a B-domain ASF1 binder that sequesters ASF1 in the cytoplasm answered what CDAN1 does mechanistically and connected it to replication-coupled histone supply.

    Evidence Co-IP, pulldowns, cell fractionation, DNA replication assays, overexpression, siRNA depletion, and mutagenesis of disease alleles

    PMID:22407294

    Open questions at the time
    • Structural basis of ASF1 occupancy not resolved
    • Link from ASF1 sequestration to erythroid phenotype not shown
  3. 2020 High

    Discovery of an obligate CDAN1-CDIN1 heterodimer expanded the complex beyond ASF1 and identified CDIN1 as a stability-dependent cytoplasmically sequestered partner.

    Evidence Reciprocal Co-IP, in vitro reconstitution, fractionation, and immunofluorescence (nucleolar enrichment); plus patient-mutation interaction analysis

    PMID:32239177 PMID:32518175

    Open questions at the time
    • Catalytic or functional role of CDIN1 within the complex not defined
    • Relationship between CDIN1 binding and ASF1 binding not resolved
  4. 2021 High

    Erythroid-specific Cdan1 deletion demonstrated that CDAN1 is required in vivo for terminal erythroid differentiation by suppressing differentiation inhibitors.

    Evidence Conditional knockout mouse with EM, flow cytometry, apoptosis and gene-expression analysis, plus zebrafish morpholino knockdown

    PMID:34234671

    Open questions at the time
    • Mechanism linking chromatin-assembly control to derepression of Gata2/Pu.1/Runx1 not defined
    • Whether the phenotype depends on ASF1 or CDIN1 binding not tested
  5. 2021 Medium

    Patient-mutation modeling in human erythroid cells and patient-derived cultures tied CDAN1 dysfunction to chromatin accessibility changes, histone acetylation alterations, and nucleolar abnormalities recapitulating CDA-I.

    Evidence CRISPR editing of HUDEP2 cells and in vitro erythroid culture with immunofluorescence, ATAC-seq, histone modification and gene-expression analysis

    PMID:33075436 PMID:33121234

    Open questions at the time
    • Direct causal chain from mutation to chromatin/nucleolar defect not established
    • Single-lab models for each readout
  6. 2025 High

    Cryo-EM resolved how CDAN1 inhibits ASF1, showing a dimeric CDAN1 occupying all functional ASF1 surfaces via two B-domains and two H3-mimicking helices.

    Evidence Single-particle cryo-EM with biochemical reconstitution, AlphaFold-guided modeling and pulldowns (peer-reviewed; preceded by a 2024 bioRxiv preprint)

    PMID:39149339 PMID:40091041

    Open questions at the time
    • Differential ASF1A vs ASF1B engagement not mechanistically explained
    • Position of CDIN1 within the assembled structure not fully detailed
  7. 2025 Medium

    ChIP-seq evidence that CDAN1 directly occupies the AHSP regulatory region added a direct chromatin-level mode of erythroid gene regulation beyond cytoplasmic chaperone sequestration.

    Evidence siRNA knockdown in K562 and CD34+ erythroid cells with ChIP-seq, RNA-seq/qPCR, western blotting and morphologic analysis

    PMID:41028447

    Open questions at the time
    • Whether chromatin occupancy is direct DNA binding or complex-mediated unknown
    • Genome-wide scope of direct targets not defined
  8. 2026 Medium

    Biophysical characterization of the high-affinity CDIN1-CDAN1 C-terminal heterodimer and its disruption by CDA-I mutations defined loss of this complex as a disease mechanism.

    Evidence Biophysical methods (ITC/SEC-MALS or equivalent) with structural analysis and disease-variant mutagenesis

    PMID:41609415

    Open questions at the time
    • Downstream consequence of complex loss in erythroid cells not directly demonstrated
    • Single-lab biophysical dataset

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CDAN1-mediated ASF1 sequestration and direct chromatin occupancy mechanistically converge to control terminal erythroid differentiation and produce CDA-I pathology remains unresolved.
  • Causal link between replication/chromatin-assembly restraint and erythroid gene derepression unproven
  • Functional role of CDIN1 within the complex undefined
  • Mechanism of nucleolar function not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 2 GO:0140313 molecular sequestering activity 2 GO:0042393 histone binding 1
Localization
GO:0005829 cytosol 3 GO:0005730 nucleolus 2 GO:0005634 nucleus 1
Pathway
R-HSA-4839726 Chromatin organization 2 R-HSA-1266738 Developmental Biology 1 R-HSA-69306 DNA Replication 1
Partners
ASF1AASF1BCDIN1IPO4
Complex memberships
CDAN1-ASF1A/B complexCDAN1-CDIN1 heterodimer

Evidence

Reading pass · 11 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2012 Codanin-1 (CDAN1) was identified as a direct binding partner of the histone chaperone ASF1 (Anti-Silencing Function 1) via a conserved B-domain, forming part of a cytosolic Asf1-H3.1-H4-Importin-4 complex. This interaction is mutually exclusive with ASF1 binding to CAF-1 and HIRA. Codanin-1 acts as a negative regulator of ASF1 function by sequestering ASF1 in the cytoplasm and blocking histone delivery during DNA replication. Depletion of Codanin-1 accelerates DNA replication and increases chromatin-bound ASF1, while ectopic Codanin-1 expression arrests S-phase progression. Two CDAI disease-causing mutations impair complex formation with ASF1. Co-immunoprecipitation, pulldown assays, cell fractionation, DNA replication assays, ectopic overexpression, siRNA depletion, mutagenesis of disease-causing alleles The EMBO journal High 22407294
2009 Codanin-1 localizes to heterochromatin in interphase cells and undergoes phosphorylation at mitosis, coinciding with its exclusion from condensed chromosomes. Codanin-1 protein levels peak during S phase. The CDAN1 promoter contains E2F binding sites and is a direct transcriptional target of E2F1, as shown by chromatin immunoprecipitation and luciferase reporter assays. Immunofluorescence, immune electron microscopy, cell synchronization, chromatin immunoprecipitation (ChIP), luciferase reporter assay, E2F1-inducible cell line Haematologica Medium 19336738
2020 C15ORF41 (CDIN1) forms a tight, near-stoichiometric heterodimeric complex with the C-terminal region of Codanin-1 in human cells and in vitro. Codanin-1 sequesters C15ORF41 in the cytoplasm, analogous to its sequestration of ASF1. C15ORF41 protein stability depends on Codanin-1. Immunoprecipitation, in vitro biochemical reconstitution, western blotting, immunofluorescence, cell fractionation The Biochemical journal High 32239177
2020 Both Codanin-1 and C15ORF41 are enriched in the nucleolus. C15ORF41 stability depends on Codanin-1, and both proteins interact to form an obligate complex. Many CDA-I missense and in-frame mutations in Codanin-1 do not destabilize the entire protein but impair specific protein interactions. Immunoprecipitation, western blotting, immunofluorescence (nucleolar enrichment), patient mutation analysis Journal of medical genetics Medium 32518175
2021 Conditional erythroid-specific deletion of Cdan1 in mice (using ErGFPcre) causes embryonic lethality at E12.5-E13.5 due to severe anemia. Primitive erythroblasts display pathognomonic spongy heterochromatin by electron microscopy, increased apoptosis, failure of semi-synchronous maturation, delayed ζ-to-α globin switch, and increased expression of Gata2, Pu.1, and Runx1. Zebrafish cdan1 knockdown also increases gata2 expression, confirming a conserved role in suppressing inhibitors of terminal erythroid differentiation. Conditional knockout mouse (Cre-lox), transmission electron microscopy, flow cytometry, Annexin V staining, gene expression analysis, zebrafish morpholino knockdown Frontiers in physiology High 34234671
2020 CDAN1 mutations at R1042 (mirroring patient mutations) in HUDEP2 human erythroid cells cause decreased viability, increased intercellular bridges and binucleate cells, and alterations in histone acetylation associated with prematurely elevated erythroid gene expression including gamma-globin. This implicates CDAN1 in regulation of DNA replication and chromatin organization specifically during erythroid maturation. CRISPR/gene editing of HUDEP2 cells, immunofluorescence, flow cytometry, histone modification analysis, gene expression Experimental hematology Medium 33075436
2021 CDAN1 and CDIN1 proteins are enriched in nucleoli, which are structurally and functionally abnormal in CDA-I erythroid cells. Erythroid cells from CDA-I patients show delayed terminal erythroid differentiation, increased proliferation, and widespread changes in chromatin accessibility. In vitro erythroid culture system, electron microscopy, immunofluorescence, ATAC-seq (chromatin accessibility) Haematologica Medium 33121234
2025 Cryo-EM structural analysis reveals that CDAN1 dimerizes and assembles cytosolic complexes containing CDIN1 and multiple copies of ASF1A/B. A single CDAN1 engages two ASF1 molecules via two B-domains (acting as ASF1-binding motifs) and two helices that mimic histone H3 binding, thereby occupying all functional binding sites on ASF1 known to facilitate histone chaperoning. ASF1A and ASF1B have different requirements for CDAN1 engagement. Single-particle cryo-EM, biochemical reconstitution, structural predictions (AlphaFold), pulldown assays Nature communications High 40091041
2024 Cryo-EM structures of CDAN1 complexes show CDAN1 dimerizes and recruits two ASF1 molecules per monomer via two B-domains and two histone H3-mimicking helices, blocking all functional ASF1 binding surfaces. This explains the molecular mechanism by which CDAN1 sequesters and inhibits ASF1 chaperone function. (Preprint version of the 2025 Nature Communications paper.) Single-particle cryo-EM, biochemical reconstitution, structural predictions bioRxivpreprint High 39149339
2026 CDIN1 and the C-terminus of Codanin-1 form a high-affinity heterodimeric complex with equimolar stoichiometry. CDA-I-associated mutations in either CDIN1 or Codanin-1 disrupt this interaction, suggesting that loss of the CDIN1-Codanin-1 complex is a molecular mechanism underlying the disease. Biophysical techniques (ITC, SEC-MALS, or equivalent), structural analysis, mutagenesis of disease-associated variants The FEBS journal Medium 41609415
2025 Codanin-1 knockdown in K562 cells and primary human CD34+ erythroid cells causes morphologic changes resembling CDA-I, altered expression of key erythroid genes, and reduced AHSP (alpha-hemoglobin stabilizing protein) mRNA and protein. ChIP-seq showed increased Codanin-1 occupancy at the AHSP gene regulatory region, implicating direct chromatin-level regulation of erythroid gene expression by Codanin-1. siRNA knockdown, ChIP-seq, gene expression analysis (RNA-seq/qPCR), western blotting, morphologic analysis Annals of hematology Medium 41028447

Source papers

Stage 0 corpus · 28 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 Fecal calprotectin correlates more closely with the Simple Endoscopic Score for Crohn's disease (SES-CD) than CRP, blood leukocytes, and the CDAI. The American journal of gastroenterology 461 19755969
2011 RAPID3 (Routine Assessment of Patient Index Data 3) severity categories and response criteria: Similar results to DAS28 (Disease Activity Score) and CDAI (Clinical Disease Activity Index) in the RAPID 1 (Rheumatoid Arthritis Prevention of Structural Damage) clinical trial of certolizumab pegol. Arthritis care & research 77 21485024
2012 Codanin-1, mutated in the anaemic disease CDAI, regulates Asf1 function in S-phase histone supply. The EMBO journal 63 22407294
2017 Performances of Clinical Disease Activity Index (CDAI) and Simplified Disease Activity Index (SDAI) appear to be better than the gold standard Disease Assessment Score (DAS-28-CRP) to assess rheumatoid arthritis patients. International journal of rheumatic diseases 34 28608433
2019 Differences in disease activity measures in patients with rheumatoid arthritis who achieved DAS, SDAI, or CDAI remission but not Boolean remission. Seminars in arthritis and rheumatism 26 31590930
2014 CT enterography as a powerful tool for the evaluation of inflammatory activity in Crohn's disease: relationship of CT findings with CDAI and acute-phase reactants. La Radiologia medica 26 24408044
2009 Efficacy of tocilizumab and evaluation of clinical remission as determined by CDAI and MMP-3 level. Modern rheumatology 26 19609487
2009 Codanin-1, the protein encoded by the gene mutated in congenital dyserythropoietic anemia type I (CDAN1), is cell cycle-regulated. Haematologica 25 19336738
2022 A systematic comparison of different composite measures (DAS 28, CDAI, SDAI, and Boolean approach) for determining treatment effects on low disease activity and remission in rheumatoid arthritis. BMC rheumatology 16 36482451
2014 Visualization of DAS28, SDAI, and CDAI: the magic carpets of rheumatoid arthritis. Clinical rheumatology 16 24599677
2021 Recapitulation of erythropoiesis in congenital dyserythropoietic anaemia type I (CDA-I) identifies defects in differentiation and nucleolar abnormalities. Haematologica 15 33121234
2020 Genetic and functional insights into CDA-I prevalence and pathogenesis. Journal of medical genetics 15 32518175
2012 A case of congenital dyserythropoietic anemia type 1 in a Japanese adult with a CDAN1 gene mutation and an inappropriately low serum hepcidin-25 level. Internal medicine (Tokyo, Japan) 14 22504250
2020 A complex comprising C15ORF41 and Codanin-1: the products of two genes mutated in congenital dyserythropoietic anaemia type I (CDA-I). The Biochemical journal 12 32239177
2017 Identification of CDAN1, C15ORF41 and SEC23B mutations in Chinese patients affected by congenital dyserythropoietic anemia. Gene 11 29031773
2020 Codanin-1 mutations engineered in human erythroid cells demonstrate role of CDAN1 in terminal erythroid maturation. Experimental hematology 10 33075436
2021 Cdan1 Is Essential for Primitive Erythropoiesis. Frontiers in physiology 9 34234691
2008 Congenital dyserythropoietic anemia in a Chinese family with a mutation of the CDAN1-gene. Annals of hematology 9 18575862
2023 Combined use of CDAI and blood indices for assessing endoscopic activity in ileocolic Crohn's disease. BMC gastroenterology 6 37770845
2013 Congenital dyserythropoietic anemia type 1 with a novel mutation in the CDAN1 gene previously diagnosed as congenital hemolytic anemia. International journal of hematology 3 23605369
2025 Mechanism of ASF1 engagement by CDAN1. Nature communications 2 40091041
2025 Elevated DAS28, CDAI, RAPID3 and five of seven RA core data set measures in patients with positive screens for anxiety, depression or fibromyalgia on an MDHAQ. Rheumatology (Oxford, England) 2 40156145
2026 Anemia-associated mutations disrupt the CDIN1-Codanin1 complex in inherited congenital dyserythropoietic anemia I (CDA-I) disease. The FEBS journal 1 41609415
2024 Mechanism of ASF1 Inhibition by CDAN1. bioRxiv : the preprint server for biology 1 39149339
2021 [Whole exome sequencing analysis of compound heterozygous variants of CDAN1 gene in a Chinese family with non-immune hydrops fetalis]. Nan fang yi ke da xue xue bao = Journal of Southern Medical University 1 35012925
2020 Congenital dyserythropoiesis anemia type Ia with a novel CDAN1 mutation diagnosed by whole exome sequencing. Molecular genetics & genomic medicine 1 32160409
2025 Codanin-1, defective in congenital dyserythropoietic anemia I (CDA-I), regulates erythroid differentiation. Annals of hematology 0 41028447
2025 [Interpretable machine learning-based predictive model for assessing abdominal surgery risk and biologic therapy efficacy in CDAI 0 to 1 level Crohn disease patients]. Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences 0 41656804

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