Affinage

DCAF11

DDB1- and CUL4-associated factor 11 · UniProt Q8TEB1

Length
546 aa
Mass
61.7 kDa
Annotated
2026-06-09
26 papers in source corpus 17 papers cited in narrative 17 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

DCAF11 (WDR23) is the substrate-recognition receptor of a CUL4-DDB1-RBX1 (CRL4) E3 ubiquitin ligase that controls the abundance and activity of a defined set of substrates governing stress response, cell cycle, and chromatin (PMID:19273594, PMID:27203182, PMID:28446751). Its founding role, defined through the C. elegans ortholog WDR-23, is repression of the NRF2/SKN-1 antioxidant transcription factor: DCAF11 routes NRF2 for CRL4-mediated turnover by engaging the DIDLID sequence in the NRF2 Neh2 domain, distinct from the KEAP1-binding motifs, with the conserved C-terminal domain of WDR23 required for ligase coupling (PMID:28453520, PMID:32839090); in C. elegans it can additionally bind SKN-1 through its β-propeller and directly block its DNA binding independent of the proteasome (PMID:24912676). Beyond NRF2, DCAF11 acts through phosphorylation-primed substrate recognition: it degrades SLBP at the end of S phase in a manner requiring SLBP Thr61 phosphorylation (PMID:27254819), ubiquitinates p21Cip1 at defined lysines to promote cell-cycle progression (PMID:28446751), and targets phospho-Ser68-primed CENP-A at K49/K124 to enforce centromeric identity, with its loss causing CENP-A mislocalization (PMID:34758320). It also degrades KAP1 in early embryos to derepress Zscan4 and enable telomere lengthening (PMID:33357405). Distinct nuclear and cytoplasmic isoforms partition proteasome-dependent and proteasome-independent functions (PMID:31409866, PMID:32839090). DCAF11 is a productive handle for targeted protein degradation: specific cysteines can be covalently engaged by electrophilic PROTACs to redirect the ligase toward neo-substrates including FKBP12, the androgen receptor, and BRD4 (PMID:33783207, PMID:38036533, PMID:38907538).

Mechanistic history

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

    Established DCAF11/WDR-23 as a CRL4-associated negative regulator of the NRF2/SKN-1 stress-response transcription factor, defining its core biological role.

    Evidence Genetic screen, Co-IP and loss-of-function epistasis in C. elegans

    PMID:19273594

    Open questions at the time
    • Proteasomal degradation was presumptive, not directly reconstituted
    • Did not map the WDR-23–SKN-1 interaction interface
  2. 2014 Medium

    Showed DCAF11 has a proteasome-independent mode—directly binding SKN-1c via its β-propeller and blocking DNA binding—revealing dual mechanisms of substrate control.

    Evidence Forward genetics, biochemical interaction and DNA-binding competition assays, homology modeling in C. elegans

    PMID:24912676

    Open questions at the time
    • Structural model based on homology, not experimental structure
    • Relative contribution of degradation vs. DNA-block in vivo not quantified
  3. 2016 High

    Defined SLBP as a mammalian substrate, demonstrating DCAF11 both activates SLBP function via ubiquitylation and later degrades it in a phospho-Thr61-dependent manner, linking the ligase to histone supply and cell-cycle timing.

    Evidence In vitro ubiquitylation reconstitution, Co-IP, GST pull-down with phospho-peptides, siRNA, mutant validation

    PMID:27203182 PMID:27254819

    Open questions at the time
    • Kinase generating the Thr61 phosphomark not identified
    • How non-degradative vs. degradative ubiquitylation of SLBP is switched is unresolved
  4. 2017 High

    Extended the substrate repertoire to cell-cycle regulators (p21Cip1) and mapped the NRF2 recognition determinant, distinguishing the DCAF11 pathway from KEAP1.

    Evidence In vitro/in vivo ubiquitination with lysine-mapping mutagenesis, domain-deletion Co-IP, shRNA, cell-cycle analysis in human cells and C. elegans

    PMID:28446751 PMID:28453520

    Open questions at the time
    • Whether p21 and NRF2 recognition require phosphorylation not established
    • Physiological balance between KEAP1 and DCAF11 control of NRF2 unclear
  5. 2019 Medium

    Resolved that nuclear and cytoplasmic WDR-23 isoforms execute proteasome-dependent and proteasome-independent functions respectively, and identified GEN-1 as a conserved substrate.

    Evidence Isoform-specific expression constructs, genetic loss-of-function, DSB-repair and stress assays in C. elegans; TFEB regulation in cells

    PMID:31409866 PMID:31586112

    Open questions at the time
    • TFEB-DCAF11 regulation is correlative, not mechanistically reconstituted
    • Conservation of GEN-1 targeting in mammals untested
  6. 2020 High

    Connected DCAF11 to chromatin and telomere biology by showing KAP1 degradation derepresses Zscan4 and drives telomere lengthening, and confirmed direct NRF2 binding with isoform-resolved localization in human cells.

    Evidence Dcaf11 KO mice/ESCs, telomere FISH, H3K9me3 ChIP, KAP1 ubiquitination, T-SCE, HSC assays; Co-IP and immunostaining in HeLa/Hep3B

    PMID:32839090 PMID:33357405

    Open questions at the time
    • Recognition signal on KAP1 not defined
    • Tissue-specific substrate selectivity not mapped
  7. 2021 High

    Demonstrated phospho-primed recognition of CENP-A enforces centromeric identity, and identified covalent cysteine engagement that converts DCAF11 into a programmable degradation receptor.

    Evidence Ubiquitination assays with site mutagenesis, DCAF11 KO cells, immunofluorescence; PROTAC screening with MS-based cysteine mapping and degradation of FKBP12/AR; Sp1→CUL4A epistasis on NRF2

    PMID:33783207 PMID:33895141 PMID:34758320

    Open questions at the time
    • Kinase priming CENP-A Ser68 in this context not identified
    • Structural basis of covalent cysteine ligand engagement undefined
  8. 2024 Medium

    Consolidated DCAF11 as a versatile targeted-degradation handle accommodating diverse electrophilic chemistries, and linked WDR23-NRF2 proteostasis to hepatic insulin metabolism via IDE.

    Evidence Chemical proteomics and ternary-complex/mutagenesis studies (BRD2/3/4, BTK, BLK, BRD4); Wdr23 KO mice with NRF2→IDE axis and chemical rescue

    PMID:38036533 PMID:38767782 PMID:38907538

    Open questions at the time
    • Cysteine residues engaged by distinct chemistries not uniformly mapped
    • Physiological NRF2-IDE axis tested in single model system

Open questions

Synthesis pass · forward-looking unresolved questions
  • An experimental structure of DCAF11 bound to substrates or covalent ligands, and a unifying account of how phospho-degron recognition is shared across its diverse substrates, remain to be established.
  • No experimental structure of the DCAF11 β-propeller with any substrate
  • Common rules of phospho-degron recognition across SLBP, CENP-A, and others not unified
  • Endogenous substrate landscape likely incomplete

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 4 GO:0016874 ligase activity 3 GO:0098772 molecular function regulator activity 3
Localization
GO:0005634 nucleus 2 GO:0005829 cytosol 2
Pathway
R-HSA-1640170 Cell Cycle 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-4839726 Chromatin organization 2 R-HSA-8953897 Cellular responses to stimuli 2
Partners
CENP-ACUL4ACUL4BDDB1KAP1NRF2RBX1SLBP
Complex memberships
CRL4-DCAF11 (CUL4-DDB1-RBX1-DCAF11) E3 ubiquitin ligase

Evidence

Reading pass · 17 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2009 WDR-23 (DCAF11 ortholog in C. elegans) interacts with the CUL-4/DDB-1 ubiquitin ligase complex to repress SKN-1 protein levels, nuclear accumulation, and transcriptional activity, presumably targeting SKN-1 for proteasomal degradation. Genetic screen, co-immunoprecipitation, loss-of-function analysis in C. elegans Molecular and cellular biology Medium 19273594
2014 WDR-23 directly interacts with SKN-1c through a β-propeller structure (top face) and four motifs at the termini of SKN-1c, blocking SKN-1c binding to target DNA promoter sequences in a mechanism independent of the ubiquitin-proteasome system. Forward genetics, biochemical interaction assays, homology modeling, DNA-binding competition assays Molecular and cellular biology Medium 24912676
2016 CRL4(WDR23) (the mammalian DCAF11-containing E3 ligase) binds and ubiquitylates SLBP (stem-loop binding protein) in vitro and in vivo, activating SLBP function in histone mRNA 3' end processing without affecting SLBP protein levels, thereby ensuring histone supply during DNA replication. In vitro ubiquitylation assay, co-immunoprecipitation, siRNA knockdown, cell-based histone mRNA processing assays Molecular cell High 27203182
2016 DCAF11 acts as the substrate receptor of CRL4 to mediate proteasomal degradation of SLBP at the end of S phase; this interaction requires phosphorylation of SLBP at Thr61, and DCAF11 cannot bind the Thr61Ala mutant SLBP that is stable at S/G2. GST pull-down with phosphorylated SLBP fragment, co-immunoprecipitation, ectopic expression, siRNA knockdown Cell cycle Medium 27254819
2017 CUL4B forms an E3 ligase complex with RBX1, DDB1, and DCAF11 (CRL4B-DCAF11) in human osteosarcoma cells; this complex specifically ubiquitinates p21Cip1 at K16, K154, K161, and K163 (but not K75 or K141), promoting p21 degradation and cell cycle progression. In vitro and in vivo ubiquitination assays, site-directed mutagenesis of p21 lysine residues, shRNA knockdown of complex components, cell cycle analysis Scientific reports High 28446751
2017 WDR23 (DCAF11) binds the DIDLID sequence within the Neh2 domain of NRF2 to regulate NRF2 stability via the DDB1-CUL4 complex, independent of the KEAP1-binding DLG and ETGE motifs; the conserved C-terminal domain of WDR23 is required for this CUL4 complex-mediated regulation. Co-immunoprecipitation, domain deletion analysis, human cell culture models, C. elegans genetic experiments PLoS genetics Medium 28453520
2019 Nuclear WDR-23B isoform promotes proteasome-dependent ubiquitination and turnover of substrates (including SKN-1), while cytoplasmic WDR-23A performs a proteasome-independent role; GEN-1 (a Holliday junction resolvase) is identified as an evolutionarily conserved WDR-23 substrate. Isoform-specific C. elegans expression constructs, genetic loss-of-function, double-strand break repair assays, stress survival assays Scientific reports Medium 31409866
2019 TFEB represses DCAF11 at both protein and mRNA levels, reducing DCAF11-mediated ubiquitination of NRF2 and thereby stabilizing NRF2 protein. Stable cell lines expressing TFEB, western blot for ubiquitinated NRF2 fractions, mRNA and protein level measurements of DCAF11 Scientific reports Low 31586112
2020 Dcaf11 targets KAP1 (KRAB-associated protein 1) for ubiquitination-mediated degradation in early mouse embryos, leading to activation of the Zscan4 downstream enhancer and removal of heterochromatic H3K9me3 marks at telomere/subtelomere regions, enabling telomere sister-chromatid exchange and telomere lengthening. Dcaf11 knockout mice and ESCs, telomere FISH, ChIP for H3K9me3, ubiquitination assays for KAP1, T-SCE analysis, hematopoietic stem cell functional assays Cell stem cell High 33357405
2020 WDR23 (DCAF11) physically interacts with NRF2 in mammalian cells (HeLa and Hep3B) and knockdown of WDR23 stabilizes NRF2 protein and alters expression of drug-metabolizing enzymes; WDR23 isoform 1 localizes to the cytoplasm and isoform 2 to the nucleus. Co-immunoprecipitation, siRNA knockdown, immunostaining, western blot Drug metabolism and pharmacokinetics Medium 32839090
2021 Electrophilic PROTACs covalently modify specific cysteines in DCAF11, enabling DCAF11 (acting as a CUL4 E3 ligase substrate adaptor) to support ligand-induced proteasomal degradation of multiple endogenous proteins including FKBP12 and the androgen receptor in human prostate cancer cells. Functional PROTAC screening, mass spectrometry-based cysteine identification, cellular degradation assays, mechanistic target validation Journal of the American Chemical Society High 33783207
2021 DCAF11 mediates polyubiquitination of CENP-A at K49 and K124, with this ubiquitination primed by phosphorylation of CENP-A Ser68; deletion of DCAF11 impairs CENP-A degradation during mitosis and causes CENP-A mislocalization to non-centromeric regions. Co-immunoprecipitation, ubiquitination assays, site-directed mutagenesis (K49R/K124R), DCAF11 knockout cell lines, immunofluorescence microscopy Cell reports High 34758320
2021 Sp1 regulates CUL4A expression via the Sp1_M4 binding site, modulating the activity of the CRL4A-WDR23 (DCAF11) ubiquitin ligase complex toward NRF2; WDR23 knockdown abrogates the Sp1-dependent effect on NRF2 protein levels. Keap1/Sp1 knockdown, promoter-reporter assays, Co-IP, western blot, genetic epistasis (double knockdown) The Journal of biological chemistry Medium 33895141
2023 Arylidene-indolinone compounds covalently bind DCAF11 as a substrate receptor in the CUL4A/B-RBX1-DDB1-DCAF11 E3 ligase, enabling PROTAC-mediated ubiquitin-proteasome-dependent degradation of target proteins (BRD2/3/4, BTK, BLK). Target identification by chemical proteomics, cellular degradation assays, mechanistic studies confirming UPS pathway Nature communications Medium 38036533
2024 PLX-3618 induces selective UPS-mediated degradation of BRD4 by forming a BRD4:PLX-3618:DCAF11 ternary complex; mutational studies of DCAF11 provide further mechanistic insights into this degradation mechanism. Cell-based degradation assays, protein-protein interaction studies (ternary complex), DCAF11 mutagenesis, in vivo tumor models Molecular cancer therapeutics Medium 38907538
2024 Loss of WDR23 (DCAF11) in mouse liver increases IDE (insulin-degrading enzyme) expression via NRF2-mediated transcriptional upregulation, leading to reduced circulating insulin and dysregulated insulin signaling; NRF2 is a direct target of WDR23-CUL4 proteostasis that mediates this hepatic IDE regulatory axis. Wdr23KO mice, human cell models with WDR23 deletion, IDE chemical inhibition, phosphorylation analysis of insulin signaling cascade proteins GeroScience Medium 38767782
2024 SNAr covalent warheads appended to small molecule inhibitors can recruit DCAF11 (among other E3 ligases) to induce targeted protein degradation, demonstrating that DCAF11 can accommodate diverse electrophilic chemistries for covalent engagement. Chemical biology screening, cellular degradation assays, E3 ligase identification by proteomics bioRxivpreprint Low bio_10.1101_2024.09.25.615094

Source papers

Stage 0 corpus · 26 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 The WD40 repeat protein WDR-23 functions with the CUL4/DDB1 ubiquitin ligase to regulate nuclear abundance and activity of SKN-1 in Caenorhabditis elegans. Molecular and cellular biology 167 19273594
2021 DCAF11 Supports Targeted Protein Degradation by Electrophilic Proteolysis-Targeting Chimeras. Journal of the American Chemical Society 147 33783207
2017 WDR23 regulates NRF2 independently of KEAP1. PLoS genetics 89 28453520
2020 Dcaf11 activates Zscan4-mediated alternative telomere lengthening in early embryos and embryonic stem cells. Cell stem cell 54 33357405
2023 Discovery of a Drug-like, Natural Product-Inspired DCAF11 Ligand Chemotype. Nature communications 45 38036533
2017 CRL4BDCAF11 E3 ligase targets p21 for degradation to control cell cycle progression in human osteosarcoma cells. Scientific reports 45 28446751
2019 TFEB activates Nrf2 by repressing its E3 ubiquitin ligase DCAF11 and promoting phosphorylation of p62. Scientific reports 39 31586112
2016 CRL4(WDR23)-Mediated SLBP Ubiquitylation Ensures Histone Supply during DNA Replication. Molecular cell 26 27203182
2016 DDB1 and CUL4 associated factor 11 (DCAF11) mediates degradation of Stem-loop binding protein at the end of S phase. Cell cycle (Georgetown, Tex.) 23 27254819
2024 Discovery of a DCAF11-dependent cyanoacrylamide-containing covalent degrader of BET-proteins. Bioorganic & medicinal chemistry letters 20 38729317
2021 Phosphorylation at Ser68 facilitates DCAF11-mediated ubiquitination and degradation of CENP-A during the cell cycle. Cell reports 20 34758320
2019 Nuclear and cytoplasmic WDR-23 isoforms mediate differential effects on GEN-1 and SKN-1 substrates. Scientific reports 18 31409866
2021 Sp1 is a substrate of Keap1 and regulates the activity of CRL4AWDR23 ubiquitin ligase toward Nrf2. The Journal of biological chemistry 15 33895141
2020 WDR23 regulates the expression of Nrf2-driven drug-metabolizing enzymes. Drug metabolism and pharmacokinetics 13 32839090
2018 WDR-23 and SKN-1/Nrf2 Coordinate with the BLI-3 Dual Oxidase in Response to Iodide-Triggered Oxidative Stress. G3 (Bethesda, Md.) 13 30166349
2025 Replacing a Cereblon Ligand by a DDB1 and CUL4 Associated Factor 11 (DCAF11) Recruiter Converts a Selective Histone Deacetylase 6 PROTAC into a Pan-Degrader. ChemMedChem 8 39973224
2014 Direct interaction between the WD40 repeat protein WDR-23 and SKN-1/Nrf inhibits binding to target DNA. Molecular and cellular biology 8 24912676
2024 WDR23 mediates NRF2 proteostasis and cytoprotective capacity in the hippocampus. Mechanisms of ageing and development 7 38301772
2013 A negative-feedback loop between the detoxification/antioxidant response factor SKN-1 and its repressor WDR-23 matches organism needs with environmental conditions. Molecular and cellular biology 7 23836880
2024 Discovery of Monovalent Direct Degraders of BRD4 that Act via the Recruitment of DCAF11. Molecular cancer therapeutics 6 38907538
2024 Hepatic WDR23 proteostasis mediates insulin homeostasis by regulating insulin-degrading enzyme capacity. GeroScience 3 38767782
2023 WDR23 mediates NRF2 proteostasis and cytoprotective capacity in the hippocampus. bioRxiv : the preprint server for biology 2 37873429
2025 Loss of WDR23 slows the rate of age-related cognitive decline with elevated amyloid burden. Journal of Alzheimer's disease : JAD 1 40320794
2024 Loss of WDR23 proteostasis impacts mitochondrial homeostasis in the mouse brain. Cellular signalling 1 38242270
2026 Arylidene-Thiazoldione Scaffold Acts as the E3 Ligand of DCAF11 for PROTAC Design. Journal of medicinal chemistry 0 41628916
2026 Flow-dependent NRF2 dysfunction via KEAP1/WDR23 dual repression contributes to endothelial oxidative damage in venous disease. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 0 41740371

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