Affinage

DCAF8

DDB1- and CUL4-associated factor 8 · UniProt Q5TAQ9

Length
597 aa
Mass
66.9 kDa
Annotated
2026-06-09
12 papers in source corpus 13 papers cited in narrative 13 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

DCAF8 is a WD40-repeat substrate-recognition adaptor of the CUL4-RBX1-DDB1 Cullin-RING ubiquitin ligase (CRL4DCAF8) that targets diverse substrates for polyubiquitination and proteasomal degradation, thereby controlling epigenetic gene silencing, cell cycle progression, stem cell maintenance, and muscle homeostasis (PMID:42228576, PMID:28178526). It engages DDB1 through an N-terminal helix-loop-helix motif that inserts into a pocket formed by the BPA and BPC domains of DDB1, an interface required for complex assembly and substrate ubiquitination, while the WD repeat region disease mutation p.R317C disrupts DDB1 binding and CRL4 ligase function (PMID:42228576, PMID:24500646). Through this complex DCAF8 degrades a broad substrate set: histone H3 ubiquitinated at K79 to enforce H3K9-methylation-dependent silencing of fetal liver and cell-cycle genes in hepatocytes (PMID:28178526), the de novo methyltransferase DNMT3A (targeting unstable variants) (PMID:34429321), the chromatin remodeler LSH in a manner antagonized by WDR76 during ferroptosis (PMID:33288900), the corepressor NcoR1 to derepress proinflammatory signaling (PMID:33061810), MLF1/MLF2 (PMID:32703400), CDC25A (PMID:42228576), the CDC42 GEF DOCK11 (PMID:40643159), and the nuclear receptor ERβ (PMID:37913652, PMID:41790307). CRL4DCAF8-mediated degradation of DOCK11 restrains CDC42 activity to preserve hematopoietic stem cell polarity and self-renewal, with Dock11 deletion rescuing the senescence and DNA-damage defects of Dcaf8-null stem cells (PMID:40643159). DCAF8 also acts as a substrate receptor within CUL4A complexes to drive myosin heavy chain degradation during muscle atrophy (PMID:31391242), and its degradation activity is opposed by the deubiquitinase USP11 on multiple substrates (PMID:32703400). Human DCAF8 mutation causes hereditary motor and sensory neuropathy type 2 with giant axons and neurofilament accumulation (PMID:24500646).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2012 Medium

    Established the subcellular trafficking behavior of DCAF8, showing it is not statically localized but shuttles between nucleus and cytoplasm, framing where its adaptor activity can occur.

    Evidence NLS/NES mutational analysis with co-IP of karyopherin import machinery and live-cell localization in cells

    PMID:22500989

    Open questions at the time
    • Does not connect shuttling to CRL4 substrate selection
    • No regulatory trigger for export/import identified
  2. 2014 Medium

    Linked DCAF8 to human disease and demonstrated its dependence on DDB1 binding, showing a WD-repeat mutation that weakens DDB1 association impairs CUL4 ligase function.

    Evidence Whole-exome/Sanger sequencing with linkage, plus co-IP of mutant vs wild-type DCAF8 with DDB1 in HEK293 cells

    PMID:24500646

    Open questions at the time
    • Substrate whose dysregulation causes neuropathy not identified
    • Single lab, no rescue in neurons
  3. 2017 High

    Identified the first physiological CRL4DCAF8 substrate and mechanism, showing it ubiquitinates histone H3 at K79 to maintain H3K9-methylation-dependent epigenetic silencing in liver.

    Evidence DCAF8 genetic inactivation, H3K79Ub assays, point mutant overexpression, inducible CRL4 deletion in mouse liver, and H3K9me ChIP

    PMID:28178526

    Open questions at the time
    • Direct enzymatic ubiquitination of H3 by reconstituted complex not shown
    • How DCAF8 recognizes H3 unresolved
  4. 2019 Medium

    Extended DCAF8 function to muscle, establishing it as a CUL4A substrate receptor partnering MuRF1 to drive myosin heavy chain degradation during atrophy.

    Evidence Unbiased interaction screens, reciprocal co-IP, co-localization, siRNA knockdown in C2C12 myotubes with atrophy readout, and cullin inhibition

    PMID:31391242

    Open questions at the time
    • Whether MyHC is a direct DCAF8 substrate vs indirect not resolved
    • Functional relationship between DCAF8 and MuRF1 ligase activity unclear
  5. 2020 High

    Defined multiple new substrates and a recurring regulatory theme, showing CRL4DCAF8 degrades LSH (antagonized by WDR76 during ferroptosis), NcoR1, and MLF1/MLF2 (opposed by USP11).

    Evidence Complex reconstitution and degradation assays for LSH; co-IP and ubiquitination assays plus in vivo sepsis model for NcoR1; co-IP and USP11 manipulation for MLF1/2

    PMID:32703400 PMID:33061810 PMID:33288900

    Open questions at the time
    • Substrate degron motifs not mapped
    • Each substrate characterized in a single context/lab
  6. 2021 High

    Showed DCAF8 acts as a quality-control adaptor for protein stability, targeting destabilized DNMT3A missense variants for proteasomal destruction.

    Evidence CRISPR screen and systematic stability profiling of 253 DNMT3A variants with ubiquitin-proteasome analysis

    PMID:34429321

    Open questions at the time
    • Structural basis for recognizing unstable variants not defined
    • Effect on wild-type DNMT3A turnover less clear
  7. 2023 Medium

    Connected DCAF8 to drug resistance, showing its CRL4-mediated degradation of ERβ is repressed during cisplatin treatment, creating an ERβ/Akt feedback loop that confers resistance.

    Evidence In vitro and in vivo cisplatin treatment with ERβ and DCAF8 knockdown/overexpression and PTEN/Akt pathway readouts in NSCLC

    PMID:37913652

    Open questions at the time
    • Direct ubiquitination of ERβ by reconstituted complex not shown
    • Single lab
  8. 2025 High

    Established a stem-cell maintenance role via genetic epistasis, showing DCAF8 degrades the CDC42 GEF DOCK11 to preserve HSC polarity and self-renewal.

    Evidence Dcaf8 knockout mouse, Dock11 double-knockout epistasis rescue, CDC42 activity and polarity assays, and HSC transplantation

    PMID:40643159

    Open questions at the time
    • Direct DOCK11 ubiquitination not biochemically reconstituted
    • Upstream regulation of DCAF8-DOCK11 axis unknown
  9. 2026 High

    Provided the structural basis for CRL4DCAF8 assembly, defining the N-terminal HLH-DDB1 interface and linking it to CDC25A ubiquitination and cell cycle control.

    Evidence 2.53 Å cryo-EM structure with interface mutagenesis, CDC25A ubiquitination assay, and cell cycle analysis

    PMID:42228576

    Open questions at the time
    • No structure with bound substrate
    • How the WD40 domain selects diverse substrates not visualized

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single WD40 adaptor achieves recognition of its structurally unrelated substrates, and which degrons it reads, remains unresolved.
  • No substrate-bound CRL4DCAF8 structure
  • Degron consensus across substrates not defined
  • Tissue-specific substrate selection mechanism unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 7 GO:0016874 ligase activity 3 GO:0060090 molecular adaptor activity 3
Localization
GO:0005634 nucleus 2 GO:0005829 cytosol 1
Pathway
R-HSA-392499 Metabolism of proteins 4 R-HSA-1640170 Cell Cycle 2 R-HSA-4839726 Chromatin organization 2
Partners
CUL4ADDB1MURF1RBX1USP11WDR76
Complex memberships
CRL4DCAF8 (CUL4-RBX1-DDB1-DCAF8)

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2026 Cryo-EM structure (2.53 Å) of DCAF8 in complex with DDB1 reveals that DCAF8 engages DDB1 primarily through an N-terminal helix-loop-helix (HLH) motif inserting into a conserved pocket formed by the BPA and BPC domains of DDB1. Disruption of this interface impairs CRL4DCAF8 complex assembly, attenuates CDC25A ubiquitination, and causes cell cycle defects. The conserved double DxR box of DCAF8 is positioned away from the DDB1 interface and is dispensable for adaptor binding. Cryo-EM structure determination + interface mutagenesis + CDC25A ubiquitination assay + cell cycle analysis Cell reports High 42228576
2017 CRL4DCAF8 ubiquitin ligase complex targets histone H3 for polyubiquitination at K79 in hepatocytes. Genetic inactivation of DCAF8 abrogates H3 ubiquitination, reactivates fetal liver and cell-cycle genes by interfering with methylated H3K9 occupancy, and leads to cell senescence. Restoring CRL4DCAF8 expression reinstates epigenetic gene silencing. Genetic inactivation (DCAF8 knockout/knockdown), H3K79 ubiquitination assays, H3K79 point mutant overexpression, inducible CRL4 deletion in mouse liver, ChIP for H3K9 methylation Cell reports High 28178526
2021 DCAF8 acts as an E3 ubiquitin ligase adaptor that mediates proteasomal degradation of DNMT3A. Unstable DNMT3A missense variants identified in a systematic screen are targeted for destruction via DCAF8, as uncovered by a CRISPR screen. CRISPR screen, protein stability assays of 253 DNMT3A variants, ubiquitin-proteasome pathway analysis Cancer discovery High 34429321
2014 The DCAF8 p.R317C mutation, located within the WD repeat region critical for DDB1 binding, reduces the association of DCAF8 with DDB1 and impairs CUL4-based E3 ubiquitin ligase function, causing hereditary motor and sensory neuropathy type 2 (HMSN2) with giant axons and neurofilament accumulation. Whole-exome sequencing, Sanger sequencing, co-immunoprecipitation of DCAF8 mutant vs. wild-type with DDB1 in HEK293 cells, linkage analysis Neurology Medium 24500646
2020 CRL4DCAF8 is a bona fide E3 ligase for chromatin remodeler LSH, promoting its polyubiquitination and proteasomal degradation. WDR76 antagonizes DCAF8-targeted LSH proteolysis through competitive inhibition of CRL4DCAF8-LSH complex assembly. During ferroptosis induced by lipid hydroperoxides, DNA hydroxymethylation promotes WDR76 interaction with LSH and an increased DCAF8:WDR76 ratio drives LSH degradation, linking oxidative damage sensing to epigenetic regulation. CRL4DCAF8 complex reconstitution, degradation assays, co-immunoprecipitation, transcriptomic epistasis, DCAF8/WDR76 manipulation (overexpression/knockdown) Cell death and differentiation High 33288900
2019 DCAF8 physically interacts with muscle-specific E3 ligase MuRF1 and both proteins co-localize in muscle cells. DCAF8 levels increase during muscle atrophy, and downregulation of DCAF8 substantially impedes muscle wasting and myosin heavy chain (MyHC) degradation in C2C12 myotubes. DCAF8 associates with CUL4A-containing ring ubiquitin ligase complex subunits and functions as a substrate receptor within CRL4A to promote MyHC degradation. Two unbiased protein interaction screens, co-immunoprecipitation, co-localization in muscle cells, siRNA knockdown in C2C12 myotubes with atrophy readout, cullin inhibition assay Journal of cell science Medium 31391242
2020 CRL4DCAF8 E3 ligase complex (CUL4A-RBX1-DDB1-DCAF8) ubiquitinates and degrades nuclear receptor corepressor NcoR1. Degradation of NcoR1 prevents its complex formation with SP1 transcription factor, leading to upregulation of HMGB1 and downstream proinflammatory cytokines in LPS-induced sepsis-induced myocardial dysfunction. Co-immunoprecipitation, ubiquitination assay, in vivo mouse model of SIMD, AlphaScreen small-molecule screen, PSSM0332 inhibition of CUL4A-RBX1 interaction International journal of biological sciences Medium 33061810
2020 CRL4DCAF8 strongly interacts with MLF2 and promotes its proteasomal degradation via the ubiquitin-proteasome pathway. USP11 deubiquitinase opposes this by associating with MLF2 and increasing its stability. DCAF8 also interacts with MLF1, suggesting CRL4DCAF8 regulates both MLF1 and MLF2 stability. Co-immunoprecipitation, proteasome inhibitor assays, USP11 overexpression/knockdown, MLF1/MLF2 stability assays Biochemical and biophysical research communications Medium 32703400
2023 ERβ transcriptionally represses DCAF8 expression in NSCLC cells upon cisplatin treatment. Reduced DCAF8 attenuates CRL4DCAF8-mediated proteasomal degradation of ERβ, causing ERβ accumulation and a positive feedback loop that activates Akt via PTEN inhibition, leading to cisplatin resistance. In vitro and in vivo cisplatin treatment, ERβ knockdown/overexpression, DCAF8 knockdown, PTEN/Akt pathway analysis, cisplatin-ERβ binding assay Drug resistance updates Medium 37913652
2012 WDR42A (DCAF8) contains a functional nuclear localization signal (114PRRRVQRKR122) and a nuclear export signal (39IEVEASDLSLSL50). Nuclear import is mediated by karyopherin-α1/β1 in conjunction with GTPase Ran, and nuclear export is CRM1-dependent, establishing DCAF8 as a nucleocytoplasmic shuttling protein. Mutational analysis, dominant-negative experiments, co-immunoprecipitation, GST pull-down, live-cell localization assays FEBS letters Medium 22500989
2025 DCAF8 mediates proteasomal degradation of DOCK11, a guanine nucleotide exchange factor for CDC42, in hematopoietic stem cells (HSCs). Loss of DCAF8 causes DOCK11 accumulation, elevated CDC42 activity, loss of HSC polarity, cellular senescence, and DNA damage with impaired self-renewal. Knockout of Dock11 rescues the senescence, DNA damage, and self-renewal defects of Dcaf8-/- HSCs. Dcaf8 knockout mouse, Dock11 knockout epistasis, CDC42 activity assay, polarity assays, senescence/DNA damage markers, HSC transplantation functional assays Blood High 40643159
2025 USP11 deubiquitinase counters CUL4-DCAF8 E3 ligase-mediated degradation of DNMT3A to maintain its protein stability. USP11 also enhances DNMT3A SUMOylation by promoting DNMT3A interaction with SUMO E3 ligases, and maintains DNMT3A DNA methyltransferase activity and its binding to the polycomb complex. Inhibition of E1 enzyme or stable USP11 expression partially rescues mislocalization of unstable DNMT3A mutants. E1 enzyme inhibition, USP11 stable overexpression, ubiquitination and SUMOylation assays, DNMT3A localization imaging, methyltransferase activity assay, co-immunoprecipitation with polycomb complex bioRxivpreprint Medium bio_10.1101_2025.03.05.641683
2026 DCAF8 loss in mouse mammary gland elevates ERβ expression, which inhibits ERα/PR signaling, resulting in delayed ductal elongation and abnormal branching morphogenesis. DCAF8 promotes proteasomal degradation of ERβ (consistent with its CRL4 adaptor role), and its absence leads to ERβ accumulation and downstream suppression of PR signaling effectors. Dcaf8 homozygous knockout mice, transcriptomic sequencing, biochemical experiments (Western blot/co-IP implied), mammary whole-mount analysis Journal of mammary gland biology and neoplasia Low 41790307

Source papers

Stage 0 corpus · 12 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2021 Systematic Profiling of DNMT3A Variants Reveals Protein Instability Mediated by the DCAF8 E3 Ubiquitin Ligase Adaptor. Cancer discovery 68 34429321
2017 CRL4DCAF8 Ubiquitin Ligase Targets Histone H3K79 and Promotes H3K9 Methylation in the Liver. Cell reports 31 28178526
2014 Ubiquitin ligase defect by DCAF8 mutation causes HMSN2 with giant axons. Neurology 30 24500646
2020 CRL4DCAF8 dependent opposing stability control over the chromatin remodeler LSH orchestrates epigenetic dynamics in ferroptosis. Cell death and differentiation 28 33288900
2023 Cisplatin-activated ERβ/DCAF8 positive feedback loop induces chemoresistance in non-small cell lung cancer via PTEN/Akt axis. Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy 27 37913652
2019 DCAF8, a novel MuRF1 interaction partner, promotes muscle atrophy. Journal of cell science 25 31391242
2020 CRL4DCAF8 and USP11 oppositely regulate the stability of myeloid leukemia factors (MLFs). Biochemical and biophysical research communications 13 32703400
2020 The small molecule PSSM0332 disassociates the CRL4ADCAF8 E3 ligase complex to decrease the ubiquitination of NcoR1 and inhibit the inflammatory response in a mouse sepsis-induced myocardial dysfunction model. International journal of biological sciences 8 33061810
2012 Characterization of nuclear import and export signals determining the subcellular localization of WD repeat-containing protein 42A (WDR42A). FEBS letters 7 22500989
2025 Loss of DCAF8 impairs hematopoietic stem cell function with cellular senescence via the DOCK11-CDC42 axis. Blood 2 40643159
2026 Role of DCAF8 in Mammary Ductal Elongation and Branching Morphogenesis. Journal of mammary gland biology and neoplasia 0 41790307
2026 DCAF8 binds DDB1 via an N-terminal helix-loop-helix motif to assemble CRL4 and promote cell cycle progression. Cell reports 0 42228576

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