Affinage

CDAN1

Codanin-1 · UniProt Q8IWY9

Length
1227 aa
Mass
134.1 kDa
Annotated
2026-04-28
28 papers in source corpus 10 papers cited in narrative 10 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CDAN1 (Codanin-1) is a cell cycle–regulated negative regulator of chromatin replication that controls histone supply during S phase and is essential for erythroid differentiation. CDAN1 dimerizes and assembles cytosolic complexes with its obligate partner CDIN1 and multiple copies of the histone H3-H4 chaperone ASF1, sequestering ASF1 by simultaneously occupying its B-domain binding site and mimicking histone H3 binding, thereby blocking ASF1 interaction with downstream chaperones CAF-1 and HIRA and limiting histone delivery to replicating chromatin (PMID:22407294, PMID:40091041). CDAN1 expression peaks in S phase under E2F1 transcriptional control, and it localizes to heterochromatin in interphase while being phosphorylated and excluded from condensed chromosomes during mitosis (PMID:19336738). Loss-of-function mutations in CDAN1 cause congenital dyserythropoietic anemia type I (CDA-I), characterized by spongy heterochromatin, aberrant chromatin accessibility, disrupted erythroid gene expression, and failure of terminal erythroid maturation (PMID:34234671, PMID:33075436, PMID:32518175).

Mechanistic history

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

    The question of where and when CDAN1 acts was answered by showing it is an S-phase-peaking, E2F1-driven, heterochromatin-associated protein that is phosphorylated and excluded from chromosomes at mitosis, establishing it as a cell cycle–regulated chromatin factor.

    Evidence Immunofluorescence, immune EM, synchronized HeLa cells, ChIP, and luciferase reporter assays

    PMID:19336738

    Open questions at the time
    • Functional consequence of mitotic phosphorylation not determined
    • Identity of the kinase responsible for mitotic phosphorylation unknown
    • Molecular targets of CDAN1 at heterochromatin not identified
  2. 2012 High

    The central molecular function of CDAN1 was established: it directly binds ASF1 via a B-domain interaction, sequesters ASF1-H3.1-H4-Importin-4 in the cytoplasm in a manner mutually exclusive with CAF-1/HIRA binding, and thereby negatively regulates histone delivery and DNA replication rate.

    Evidence Co-IP, in vitro binding, cellular fractionation, siRNA knockdown with replication rate measurement, overexpression with S-phase analysis; CDA-I mutations shown to impair ASF1 binding

    PMID:22407294

    Open questions at the time
    • Structural basis of CDAN1-ASF1 interaction not resolved
    • How disease mutations mechanistically impair complex formation at atomic level unknown
    • Regulation of ASF1 release from the complex not addressed
  3. 2020 High

    CDIN1 was identified as an obligate, near-stoichiometric binding partner of CDAN1 whose stability depends on CDAN1 and which CDAN1 sequesters in the cytoplasm, analogous to ASF1 sequestration; CDA-I disease mutations were shown to disrupt this interaction, establishing disruption of the CDAN1–CDIN1 complex as a disease mechanism.

    Evidence Co-IP, in vitro reconstitution, western blotting, IF, fractionation, genetic analysis of patient mutations across two independent studies

    PMID:32239177 PMID:32518175

    Open questions at the time
    • Functional role of CDIN1 within the complex not determined
    • Whether CDIN1 and ASF1 binding to CDAN1 are independent or cooperative unknown
    • Structural details of the CDAN1–CDIN1 interface not resolved
  4. 2020 Medium

    CDAN1 mutations in erythroid cells were shown to cause intercellular bridges, binuclearity, altered histone acetylation, and premature erythroid gene expression, connecting CDAN1 loss to specific chromatin and cytokinesis defects in erythropoiesis.

    Evidence CRISPR-engineered HUDEP2 cells with deletion or R1042 mutation; flow cytometry, IF, histone modification analysis

    PMID:33075436

    Open questions at the time
    • Direct link between altered histone acetylation and ASF1 sequestration defect not established
    • Mechanism of cytokinesis failure not determined
    • Single cell line model without in vivo validation
  5. 2021 High

    In vivo requirement of CDAN1 for erythropoiesis was demonstrated: erythroid-specific Cdan1 knockout is embryonic lethal with spongy heterochromatin, increased apoptosis, derepressed transcription factors (Gata2, Pu.1, Runx1), and delayed globin switching, while patient-derived cells showed nucleolar abnormalities and widespread chromatin accessibility changes.

    Evidence Conditional Cre/lox knockout mice, TEM, flow cytometry, gene expression analysis, zebrafish knockdown; CDA-I patient erythroid cultures with ATAC-seq

    PMID:33121234 PMID:34234671

    Open questions at the time
    • Whether chromatin accessibility changes are direct or secondary to differentiation arrest unknown
    • Nucleolar function of the CDAN1–CDIN1 complex not mechanistically explained
    • Connection between spongy heterochromatin phenotype and ASF1 misregulation not formally demonstrated
  6. 2025 High

    Cryo-EM structures revealed that CDAN1 dimerizes and engages multiple ASF1 copies through two B-domains plus histone H3–mimicking helices per monomer, fully occupying all ASF1 functional sites and explaining the molecular basis of ASF1 sequestration, with differential requirements for ASF1A versus ASF1B engagement.

    Evidence Single-particle cryo-EM, in vitro reconstitution, biochemical validation

    PMID:40091041

    Open questions at the time
    • Regulatory signals controlling complex assembly and disassembly not identified
    • Functional significance of differential ASF1A vs ASF1B binding not explored in vivo
    • Structural basis of how CDA-I mutations disrupt the complex at atomic resolution not fully mapped
  7. 2025 Medium

    ChIP-seq evidence established that CDAN1 occupies erythroid gene regulatory regions such as the AHSP locus, with knockdown reducing AHSP expression, providing direct evidence for chromatin-level gene regulation beyond cytoplasmic ASF1 sequestration.

    Evidence siRNA knockdown in K562 and CD34+ cells, ChIP-seq, gene expression profiling

    PMID:41028447

    Open questions at the time
    • Whether CDAN1 chromatin occupancy is direct DNA binding or mediated through partners not established
    • Genome-wide targets beyond AHSP not characterized
    • Relationship between nuclear chromatin-regulatory and cytoplasmic ASF1-sequestering functions not reconciled
  8. 2026 Medium

    Biophysical characterization confirmed equimolar high-affinity CDIN1–CDAN1 C-terminus heterodimer formation and demonstrated that multiple CDA-I mutations in either protein disrupt this interface, solidifying the CDIN1–CDAN1 interaction as a common disease-relevant node.

    Evidence Biophysical complementary methods, structural analysis, disease mutation functional assays

    PMID:41609415

    Open questions at the time
    • Single study; independent replication of affinity measurements needed
    • Enzymatic or regulatory function of CDIN1 within the complex remains unknown
    • Whether complex disruption directly causes chromatin pathology or acts through an intermediate not determined

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the regulatory signals controlling CDAN1 complex assembly/disassembly during S phase, the enzymatic or functional role of CDIN1, the relationship between CDAN1's cytoplasmic ASF1-sequestering activity and its nuclear chromatin occupancy, and the precise molecular pathway linking CDAN1 loss to spongy heterochromatin and erythroid differentiation failure.
  • Mechanism of CDAN1 complex regulation during cell cycle transitions unknown
  • Functional role of CDIN1 not determined
  • Link between cytoplasmic ASF1 sequestration and nuclear chromatin phenotypes not mechanistically established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140313 molecular sequestering activity 3 GO:0042393 histone binding 2 GO:0098772 molecular function regulator activity 2
Localization
GO:0005829 cytosol 3 GO:0005730 nucleolus 2 GO:0005694 chromosome 1
Pathway
R-HSA-4839726 Chromatin organization 3 R-HSA-1640170 Cell Cycle 2 R-HSA-69306 DNA Replication 1
Partners
ASF1AASF1BCDIN1IPO4
Complex memberships
CDAN1-CDIN1-ASF1 complex

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2012 Codanin-1 (CDAN1) directly binds ASF1 via a conserved B-domain, forming a cytosolic complex with ASF1-H3.1-H4-Importin-4. This interaction is mutually exclusive with ASF1 binding to the chaperones CAF-1 and HIRA. Codanin-1 acts as a negative regulator of ASF1 function in chromatin assembly by sequestering ASF1 in the cytoplasm, thereby limiting histone delivery and DNA replication. Two CDA-I disease mutations impair complex formation with ASF1. Co-immunoprecipitation, in vitro binding assays, cellular fractionation, siRNA knockdown with DNA replication rate measurement, ectopic overexpression with S-phase progression analysis The EMBO journal High 22407294
2009 Codanin-1 localizes to heterochromatin in interphase cells and is cell cycle-regulated, with peak expression in S phase. At mitosis, codanin-1 undergoes phosphorylation coinciding with its exclusion from condensed chromosomes. The CDAN1 promoter is a direct transcriptional target of E2F1, which binds five putative E2F sites in the proximal promoter region. Immunofluorescence, immune electron microscopy, synchronized HeLa cell analysis, chromatin immunoprecipitation (ChIP), luciferase reporter assay, E2F1-inducible cell line Haematologica High 19336738
2020 C15ORF41 (CDIN1) forms a tight, near-stoichiometric complex with Codanin-1 in human cells, interacting with the C-terminal region of Codanin-1. Codanin-1 sequesters C15ORF41 in the cytoplasm, analogous to its sequestration of ASF1. C15ORF41 stability depends on Codanin-1. Co-immunoprecipitation, in vitro reconstitution, western blotting, immunofluorescence, cellular fractionation The Biochemical journal High 32239177
2020 C15ORF41 (CDIN1) relies on Codanin-1 for its stability and both proteins interact to form an obligate complex enriched in the nucleolus. Many CDA-I missense and in-frame mutations do not destabilize the entire Codanin-1 protein but disrupt interaction with C15ORF41. Western blotting, immunoprecipitation, immunofluorescence, genetic analysis of patient mutations Journal of medical genetics Medium 32518175
2021 Cdan1 is required for primitive erythropoiesis in vivo. Erythroid-specific Cdan1 knockout mice die at E12.5-E13.5 from severe anemia. Loss of Cdan1 causes pathognomonic spongy heterochromatin in primitive erythroblasts, increased apoptosis, and failure of semi-synchronous erythroid maturation. Cdan1 depletion leads to increased expression of Gata2, Pu.1, and Runx1, known inhibitors of terminal erythroid differentiation, and delayed globin switching. Conditional Cre/lox knockout (ErGFPcre), transmission electron microscopy, flow cytometry, Annexin V staining, gene expression analysis, zebrafish cdan1 knockdown Frontiers in physiology High 34234671
2020 CDAN1 mutant erythroid cell lines (HUDEP2) with deletion or R1042 mutation exhibit decreased viability, increased intercellular bridges, binucleate cells, and alterations in histone acetylation associated with prematurely elevated erythroid gene expression including gamma globin, implicating CDAN1 in regulation of DNA replication and chromatin organization during erythroid maturation. CRISPR-engineered HUDEP2 cell lines, flow cytometry, immunofluorescence, histone modification analysis Experimental hematology Medium 33075436
2021 CDAN1 and CDIN1 proteins are enriched in nucleoli that are structurally and functionally abnormal in CDA-I patient-derived erythroid cells. Loss of CDAN1/CDIN1 function causes delay in terminal erythroid differentiation with increased proliferation and widespread changes in chromatin accessibility. Immunofluorescence, electron microscopy, ATAC-seq, erythroid culture system recapitulating CDA-I features Haematologica Medium 33121234
2025 Cryo-EM structural analysis reveals that CDAN1 dimerizes and assembles into cytosolic complexes with CDIN1 and multiple copies of ASF1A/B. One CDAN1 engages two ASF1 molecules through two B-domains and two helices that mimic histone H3 binding, 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, biochemistry, structural predictions, in vitro reconstitution Nature communications High 40091041
2026 CDIN1 and Codanin-1 C-terminus form a high-affinity heterodimeric complex with equimolar stoichiometry. CDA-I-associated mutations in either CDIN1 or Codanin-1 disrupt this interaction, suggesting disruption of the CDIN1-Codanin1 complex as a molecular mechanism underlying the disease. Biophysical techniques (complementary methods), structural analysis, functional assays with disease mutations The FEBS journal Medium 41609415
2025 Codanin-1 is required for erythroid progenitor development and normal erythroid differentiation. Codanin-1 knockdown causes reduced AHSP gene expression at both mRNA and protein levels, and ChIP-seq reveals increased Codanin-1 occupancy at the AHSP gene regulatory region, implicating direct chromatin-level regulation of erythroid gene expression. siRNA knockdown in K562 and CD34+ cells, gene expression profiling, ChIP-seq 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 459 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
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
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 25 31590930
2009 Codanin-1, the protein encoded by the gene mutated in congenital dyserythropoietic anemia type I (CDAN1), is cell cycle-regulated. Haematologica 25 19336738
2014 Visualization of DAS28, SDAI, and CDAI: the magic carpets of rheumatoid arthritis. Clinical rheumatology 16 24599677
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 15 36482451
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 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
2025 Mechanism of ASF1 engagement by CDAN1. Nature communications 1 40091041
2024 Mechanism of ASF1 Inhibition by CDAN1. bioRxiv : the preprint server for biology 1 39149339
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
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 0 35012925