Affinage

CUL4A

Cullin-4A · UniProt Q13619

Audit flag: ungrounded claim
Length
759 aa
Mass
87.7 kDa
Annotated
2026-06-09
100 papers in source corpus 38 papers cited in narrative 38 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

CUL4A is the cullin scaffold of a multisubunit Cullin-RING E3 ubiquitin ligase (CRL4A) in which DDB1 bridges the CUL4A-ROC1 catalytic core to interchangeable WD40-repeat substrate receptors (DCAFs) that dictate substrate choice; the DDB1 double-beta-propeller fold both binds CUL4A and presents these receptors, and the DDB1-CUL4A association is gated by CAND1 (PMID:16964240, PMID:15448697). Through this architecture CRL4A is a master regulator of genome maintenance and cell-cycle progression, restraining DNA repair capacity by degrading the nucleotide-excision-repair sensors DDB2 and XPC and the checkpoint effector p21, such that loss of CUL4A confers resistance to UV carcinogenesis (PMID:19481525), and licensing replication by targeting CDT1 for UV-induced degradation (PMID:15448697). The ligase couples to the p53 axis—accelerating p53 turnover within the MDM2 pathway and polyubiquitinating p53 with PCNA and CDT2/L2DTL—and degrades the CDK inhibitors p27Kip1 (in concert with SKP2, the COP9 signalosome, and DDB2/Artemis) and the homeodomain factor HOXA9, thereby coupling proliferation to differentiation in hematopoietic lineages (PMID:16861890, PMID:15548678, PMID:16537899, PMID:22134138, PMID:14609952). CUL4A controls a broad substrate range across stress and signaling—degrading the mTORC1 inhibitor REDD1, the NF2 tumor suppressor Merlin, and N-terminally acetylated Src-family kinases recognized by the DCAF10 receptor as an Ac/N-degron pathway—and drives metabolism and quality control through monoubiquitination events that activate PHGDH and target damaged-lysosome LAMP2 for lysophagy via WDFY1 (PMID:19557001, PMID:18332868, PMID:41484149, PMID:34720086, PMID:36103833). CUL4A promotes epithelial-mesenchymal transition, invasion, and metastasis in multiple carcinomas via chromatin and Hippo effects, including H3K4me3-driven ZEB1 transcription and downregulation of LATS1 (PMID:24305877, PMID:26840256), and is itself a transcriptional hub whose expression is driven by CREB/ERK feedback, IL-6/pSTAT3, and a CARM1-p300-c-Myc-Max complex (PMID:30666499, PMID:27418574, PMID:32140072). Its DDB1-DCAF1 arm is hijacked by HIV Vpr/Vpx to trigger G2 arrest and degrade restriction factors, and the DDB1 surface (C173) is exploitable for PROTAC-mediated targeted protein degradation (PMID:17626091, PMID:23986575).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2003 Medium

    Established that CUL4A is an active ubiquitin ligase scaffold with biological output by showing it controls turnover of a developmental transcription factor, linking it to hematopoietic differentiation before its detailed architecture was known.

    Evidence in vivo ubiquitination, domain mapping, and myeloid differentiation assays on HOXA9

    PMID:14609952

    Open questions at the time
    • Direct substrate receptor (DCAF) for HOXA9 not identified
    • No reconstituted ubiquitination with defined components
  2. 2004 High

    Defined how CUL4A achieves substrate specificity by showing DDB1 acts as a SKP1-like adaptor that directly binds and bridges substrates such as CDT1 to the cullin, and identified COP1/DET1 assembly degrading c-Jun, establishing the substrate-adaptor logic of the complex.

    Evidence in vitro binding with recombinant proteins, Co-IP, in vitro ubiquitination, and RNAi reporter assays for CDT1 and c-Jun

    PMID:14739464 PMID:15448697

    Open questions at the time
    • Generality of DDB1 as adaptor across substrates not yet shown
    • Role of CAND1 regulation mechanistically incomplete
  3. 2006 High

    Resolved the molecular architecture of the ligase, showing DDB1 uses one beta-propeller to grip CUL4A and a double-propeller to recruit an interchangeable family of WD40 DCAF substrate receptors, providing the structural framework for substrate diversity.

    Evidence X-ray crystallography of DDB1-CUL4A-ROC1 plus tandem-affinity purification/MS identification of DCAFs

    PMID:16964240

    Open questions at the time
    • Structures of substrate-bound DCAF complexes not determined
    • How CAND1 and neddylation cycle exchange receptors not resolved structurally
  4. 2006 Medium

    Connected CRL4A to cell-cycle control and tumor suppression by demonstrating degradation of the CDK inhibitor p27Kip1 (with SKP2 and the COP9 signalosome) and polyubiquitination of p53 within the MDM2/PCNA pathway.

    Evidence Co-IP, in vitro ubiquitination, siRNA epistasis, and cycloheximide chase for p27 and p53

    PMID:16467204 PMID:16537899 PMID:16861890

    Open questions at the time
    • Precise DCAF receptor for p27 not defined in these studies
    • Relative contribution of CRL4A vs SCF to p27 turnover unclear
  5. 2009 High

    Established the in vivo physiological role of CUL4A in genome maintenance by showing that conditional knockout stabilizes DDB2, XPC and p21 and confers UV-carcinogenesis resistance, and that loss causes G1/S delay, centrosome amplification and p53/p27 accumulation.

    Evidence conditional Cre-lox knockout mice and MEFs, UV carcinogenesis assay, dominant-negative p53 rescue, substrate western blots

    PMID:19430492 PMID:19481525

    Open questions at the time
    • Tissue-specific substrate hierarchies not dissected
    • Mechanism of centrosome amplification not defined molecularly
  6. 2009 Medium

    Extended the substrate repertoire into stress and growth signaling by identifying REDD1 (mTORC1 recovery) and Merlin/NF2 (ERK/Rac1 control) as CRL4A targets via dedicated cofactors.

    Evidence Co-IP, in vivo ubiquitination, siRNA, GSK3beta inhibition (REDD1) and VprBP/DCAF1-dependent ubiquitination with pathway readouts (Merlin)

    PMID:18332868 PMID:19557001

    Open questions at the time
    • Direct reconstitution of REDD1 and Merlin ubiquitination not shown
    • How phospho-degron recognition is coupled to DCAFs unclear
  7. 2009 Medium

    Revealed viral hijacking of the complex, showing HIV Vpr/Vpx recruit DDB1-DCAF1 to drive G2 arrest and degrade restriction factors, and that Vpr is itself stabilized by the complex.

    Evidence Co-IP, DCAF1/DDB1 siRNA, cell-cycle FACS, proteasome inhibition, and viral reverse-transcript quantification

    PMID:17626091 PMID:18524771 PMID:19264781

    Open questions at the time
    • Identity of the cellular target driving G2 arrest not fully defined here
    • Single-lab Co-IP evidence for some interactions
  8. 2011 Medium

    Demonstrated a direct role for CUL4A in meiotic and somatic DNA-damage responses, with localization to double-strand breaks and male infertility on knockout, plus a DDB2/Artemis route to p27 degradation.

    Evidence Cul4A knockout mice, immunofluorescence of CUL4A at DSBs, gammaH2AX staining, and Co-IP/siRNA p27 stability assays

    PMID:21291880 PMID:22134138

    Open questions at the time
    • Direct repair substrate at DSBs not identified
    • Whether CUL4A acts catalytically or structurally at DSBs unresolved
  9. 2013 Medium

    Linked CUL4A to chromatin-based transcriptional control and metastasis by showing it modulates H3K4me3 to activate ZEB1-driven EMT, monoubiquitinates p73 to restrain its activity, and works with H1.2/PAF1 to deposit activating histone marks.

    Evidence ChIP, in vivo mono- vs polyubiquitination assays, knockdown/overexpression, and xenograft/syngeneic tumor models

    PMID:23085759 PMID:24305877 PMID:24360965

    Open questions at the time
    • Direct histone ubiquitination targets of CRL4A at these loci not fully defined
    • Coupling of ligase activity to specific histone-modifying enzymes incomplete
  10. 2016 Medium

    Identified upstream transcriptional control of CUL4A itself, placing it within IL-6/pSTAT3, CREB/ERK feedback, and CARM1-p300-c-Myc-Max regulatory circuits that tune CRL4 ligase output.

    Evidence ChIP and luciferase promoter assays, ERK inhibitor (U0126) and siRNA epistasis, MS identification of the CPCM complex, and CRL4 activity/substrate (ST7) assays

    PMID:27418574 PMID:30666499 PMID:32140072

    Open questions at the time
    • Quantitative contribution of each transcriptional input in different tissues unknown
    • Feedback dynamics to ERK/CREB not modeled
  11. 2022 Medium

    Expanded CRL4A function into metabolism, organelle quality control, and chemoresistance through non-degradative monoubiquitination (PHGDH activation, LAMP2-driven lysophagy) and PCNA monoubiquitination promoting translesion synthesis.

    Evidence site-specific ubiquitination with mutagenesis, enzyme activity and metabolomics (PHGDH), proteomic screen and lysophagy assay (LAMP2/WDFY1), and siRNA epistasis with REV3L (PCNA/cytarabine)

    PMID:34720086 PMID:35519003 PMID:36103833

    Open questions at the time
    • DCAF receptors for PHGDH and PCNA not defined
    • How CRL4A switches between mono- and poly-ubiquitination outcomes unclear
  12. 2023 Medium

    Demonstrated phospho-degron and chemical-handle utility, with AKT-phosphorylated FAM13A recognized by DDB1-DCAF1 for degradation, and the DDB1 C173 surface exploited for PROTAC-mediated degradation of neo-substrates.

    Evidence phospho-dependent in vivo ubiquitination with S312 mutagenesis and lung injury model (FAM13A); cysteine chemoproteomics and PROTAC degradation with inhibitor controls (BRD4/AR, preprint)

    PMID:36749583 PMID:37614621

    Open questions at the time
    • Generality of DDB1-recruiter PROTAC approach across cell types not established (preprint)
    • Phospho-degron consensus for DCAF1 recognition not defined
  13. 2026 High

    Defined a new degradation logic, an Ac/N-degron pathway in which DCAF10 directs CRL4A to N-terminally acetylated Src-family kinases that fail myristoylation, coupling lipid-modification surveillance to ubiquitin-mediated turnover.

    Evidence peptide pull-downs, MS, AlphaFold3 modeling with mutagenesis, CRISPR/siRNA, and in vitro reconstituted ubiquitination of acetylated SFKs

    PMID:41484149

    Open questions at the time
    • In vivo physiological consequences of SFK Ac/N-degron turnover not established
    • Breadth of N-acetylated substrate set beyond SFKs unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the cell selects among CRL4A's many DCAF receptors and decides between mono- vs poly-ubiquitination, degradative vs activating outcomes, across tissues and stresses remains unresolved.
  • No unifying model of DCAF exchange dynamics in vivo
  • Determinants of mono- vs poly-ubiquitin chain output undefined
  • Tissue-specific substrate prioritization unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 6 GO:0016874 ligase activity 5 GO:0005198 structural molecule activity 1
Localization
GO:0005634 nucleus 3 GO:0005829 cytosol 1
Pathway
R-HSA-1640170 Cell Cycle 3 R-HSA-1643685 Disease 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-73894 DNA Repair 3 R-HSA-74160 Gene expression (Transcription) 2 R-HSA-69306 DNA Replication 1 R-HSA-9612973 Autophagy 1
Partners
CAND1DCAF1DCAF10DDB1DDB2PCNARBX1SKP2
Complex memberships
CRL4A (DDB1-CUL4A-ROC1/RBX1)CUL4A-DDB1-DCAF1 (VprBP)CUL4A-DDB1-DCAF10DET1-DDB1-CUL4A-ROC1-COP1

Evidence

Reading pass · 38 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 Crystal structure of the DDB1-CUL4A-ROC1 complex reveals that DDB1 uses one beta-propeller domain to bind the CUL4A cullin scaffold and a separate double-beta-propeller fold for substrate presentation. A family of WD40-repeat proteins (DCAFs) directly binds the double-propeller fold of DDB1 and serves as the substrate-recruiting module of the E3 ligase. X-ray crystallography combined with tandem-affinity purification and mass spectrometry Nature High 16964240
2004 Human DET1 assembles a multisubunit CUL4A ubiquitin ligase (DET1-DDB1-CUL4A-ROC1-COP1) that ubiquitinates and degrades the proto-oncogenic transcription factor c-Jun; RNAi knockdown of any subunit stabilizes c-Jun and increases c-Jun-dependent transcription. Co-immunoprecipitation, in vivo ubiquitination assay, RNAi knockdown with reporter assay Science High 14739464
2004 DDB1 associates stoichiometrically with CUL4A in a manner analogous to SKP1 binding to CUL1; DDB1 directly binds CDT1 in vitro and bridges CDT1 to CUL4A in vivo, targeting CDT1 for CUL4A-dependent ubiquitination and UV-induced rapid degradation. CAND1 negatively regulates the DDB1-CUL4A association. Co-immunoprecipitation, in vitro binding assay with recombinant proteins, in vitro ubiquitination assay, siRNA knockdown Nature Cell Biology High 15448697
2006 The CUL4A-DDB1 complex (with PCNA and L2DTL/CDT2) interacts physically with p53 and MDM2/HDM2, and isolated CUL4A complexes display potent polyubiquitination activity toward p53 in an L2DTL-, PCNA-, DDB1-, ROC1-, and MDM2-dependent manner. MDM2 is rapidly proteolyzed after UV irradiation in a CUL4/DDB1- and PCNA-dependent manner. Co-immunoprecipitation, in vitro ubiquitination assay, siRNA knockdown Cell Cycle High 16861890
2004 CUL4A physically associates with MDM2 and p53; CUL4A overexpression accelerates p53 decay and delays p53 accumulation after DNA damage, but fails to increase p53 decay in MDM2-null MEFs, placing CUL4A within the MDM2-dependent p53 proteolysis pathway. Co-immunoprecipitation, cycloheximide chase assay, MDM2-null MEF genetic epistasis Cancer Research Medium 15548678
2009 CUL4A ubiquitin ligase restricts DNA repair capacity by mediating selective degradation of the NER DNA-damage sensors DDB2 and XPC, and the checkpoint effector p21/CIP1/WAF1; Cul4a skin-specific knockout mice show dramatically increased resistance to UV-induced skin carcinogenesis. Conditional knockout mice (Cre-lox), UV carcinogenesis assay, western blot for substrate levels Molecular Cell High 19481525
2009 REDD1, an mTORC1 inhibitor, is ubiquitinated and degraded by the CUL4A-DDB1-ROC1-β-TRCP E3 ligase complex in a GSK3β-dependent manner; this degradation is required for restoration of mTOR signaling as cells recover from hypoxic stress. Co-immunoprecipitation, in vivo ubiquitination assay, siRNA knockdown, GSK3β pharmacological inhibition EMBO Reports Medium 19557001
2009 HIV-2/SIVsm Vpx assembles with the CUL4A-DDB1 ubiquitin ligase through recruitment of the DCAF1 adaptor protein; precluding Vpx from recruiting DCAF1 in macrophages blocks HIV-2 reverse transcript accumulation, indicating Vpx diverts CUL4A-DDB1(DCAF1) to inactivate a restriction factor. Co-immunoprecipitation, siRNA knockdown of DCAF1, viral infection assay with quantification of reverse transcripts Journal of Virology Medium 19264781
2007 HIV-1 Vpr induces G2 cell cycle arrest by assembling with DDB1 via DCAF1; siRNA-mediated reduction of DDB1 or CUL4A, but not DDB2, impairs Vpr-induced G2 arrest, and the arrest is blocked by a proteasome inhibitor, placing CUL4A-DDB1-DCAF1 as the E3 ligase mediating proteasome-dependent G2 arrest. Co-immunoprecipitation, siRNA knockdown, cell cycle analysis by FACS, proteasome inhibitor treatment Journal of Virology Medium 17626091
2008 VprBP/DCAF1 recruits the NF2 tumor suppressor Merlin to the ROC1-CUL4A-DDB1 E3 ligase complex via a direct interaction; serum stimulation promotes Merlin polyubiquitination and proteasome-mediated degradation through this complex, and VprBP depletion stabilizes Merlin and inhibits ERK and Rac1 activation. Co-immunoprecipitation, in vivo ubiquitination assay, siRNA knockdown, ERK/Rac1 activation assays Oncogene Medium 18332868
2008 Assembly of HIV-1 Vpr with the functional CUL4A-DDB1(DCAF1) complex stabilizes Vpr against proteasomal degradation; DCAF1 overexpression stabilizes wild-type Vpr and causes cytoplasmic accumulation, whereas DCAF1 or DDB1 siRNA decreases Vpr steady-state levels. Vpr(Q65R) defective for DCAF1 binding undergoes faster proteasomal degradation. Co-immunoprecipitation, siRNA knockdown, cycloheximide chase, immunofluorescence localization Journal of Biological Chemistry Medium 18524771
2006 CUL4A and DDB1 associate with SKP2 to promote degradation of the CDK inhibitor p27Kip1 via the COP9 signalosome; siRNA knockdown of DDB1, CUL4A, or CSN1 causes p27Kip1 accumulation, and DDB1-induced p27Kip1 proteolysis requires both CUL4A and functional signalosome. siRNA knockdown, co-immunoprecipitation, cycloheximide chase assay Molecular and Cellular Biology Medium 16537899
2006 CUL4A ubiquitin ligase directly targets p27Kip1 for degradation during erythropoiesis; CUL4A and p27 coimmunoprecipitate, CUL4A overexpression destabilizes p27 and promotes proliferation at the expense of terminal differentiation, while CUL4A declines during normal terminal erythroid differentiation allowing p27 accumulation. Co-immunoprecipitation, overexpression in hematopoietic cell line, cycloheximide chase, differentiation assay Blood Medium 16467204
2003 CUL4A ubiquitin machinery promotes ubiquitylation and proteasome-dependent degradation of the HOXA9 homeodomain protein; the homeodomain of HOXA9 is responsible for CUL4A-mediated degradation, and CUL4A interference (overexpression or RNAi) alters HOXA9 steady-state levels and impairs granulocytic differentiation of myeloid progenitors. In vivo ubiquitination assay, overexpression and RNAi, cycloheximide chase, myeloid differentiation assay EMBO Journal Medium 14609952
2013 CUL4A modulates histone H3K4me3 at the ZEB1 promoter to drive ZEB1 transcription and thereby promotes epithelial-mesenchymal transition, metastasis, and tumorigenesis in breast cancer; ZEB1 silencing blocks CUL4A-driven EMT and metastasis. Chromatin immunoprecipitation (ChIP), siRNA/shRNA knockdown, overexpression, mouse xenograft and syngeneic tumor models Cancer Research Medium 24305877
2011 CUL4A is essential for spermatogenesis; Cul4A-/- mice are male infertile with defects in meiotic recombination (persistent double-strand breaks in pachytene spermatocytes) and CUL4A localizes to DSBs generated in pre-pachytene spermatocytes, identifying a role in meiotic DSB repair. Cul4A knockout mouse, histology, immunofluorescence localization of CUL4A to DSBs, γH2AX staining Developmental Biology Medium 21291880
2009 Cells lacking CUL4A show proliferation defects, G1/S delay and early M-phase arrest; accumulation of p53 and p27Kip1 substrates is observed, and dominant-negative p53 reverses proliferation defects. Cul4A-deleted cells also show centrosome amplification, multipolar spindles, micronuclei, and reduced UV-induced unscheduled DNA synthesis. Conditional Cul4A knockout MEFs (Cre-lox), cell cycle analysis, dominant-negative p53 rescue, centrosome immunofluorescence, UDS assay Oncogene Medium 19430492
2013 The CUL4A-DDB1 E3 ligase complex monoubiquitylates p73 through a direct interaction between p73 and the DDB1 subunit; this modification does not affect p73 stability but negatively regulates p73-dependent transcriptional activity. Co-immunoprecipitation, in vivo ubiquitination assay (mono-ubiquitylation), DDB1 knockdown, p73 target gene expression analysis Oncogene Medium 23085759
2013 H1.2 linker histone stably interacts with CUL4A E3 ubiquitin ligase and PAF1 elongation complexes; this interaction potentiates target gene transcription via induction of H4K31 ubiquitylation, H3K4me3, and H3K79me2. H1.2 bridges CUL4A and PAF1 complexes by interacting with serine-2-phosphorylated RNAPII. Co-immunoprecipitation, ChIP, siRNA knockdown, histone modification analysis Cell Reports Medium 24360965
2011 Artemis directly interacts with DDB2 (a substrate receptor of CUL4A-DDB1) and with p27; both DDB2 and Artemis are required for CUL4A-DDB1-mediated degradation of p27, regulating G1-phase cell cycle progression in normally proliferating cells and after serum deprivation. Co-immunoprecipitation, siRNA knockdown, cell cycle analysis, p27 stability assay Cell Cycle Medium 22134138
2013 The inhibition of CUL4A neddylation by MLN4924 blocks Vpx-induced SAMHD1 degradation and maintains SAMHD1-mediated restriction of HIV-1 in myeloid cells; removal of the drug restores Vpx activity, supporting deoxynucleoside triphosphate pool depletion (not nucleolytic activity) as the primary SAMHD1 restriction mechanism. MLN4924 neddylation inhibitor treatment, western blot for SAMHD1 levels, viral infection assay Journal of Virology Medium 23986575
2014 CUL4A-DDB1-Rbx1 E3 ligase complex (CRL4A) controls the quality of the PTS2 receptor Pex7p by targeting dysfunctional Pex7p (including RCDP patient mutants) for ubiquitin-dependent proteasomal degradation; this quality control is essential for maintaining normal PTS2-import into peroxisomes. Ubiquitination assay, proteasome inhibitor treatment, co-immunoprecipitation, PTS2-import functional assay Biochemical Journal Medium 24989250
2021 CUL4A-based E3 ligase complex monoubiquitinates PHGDH at lysine 146, enhancing PHGDH activity by recruiting chaperone DNAJA1 to promote its tetrameric formation, thereby increasing serine, glycine, and S-adenosylmethionine (SAM) levels; elevated SAM upregulates adhesion gene expression via SETD1A-mediated H3K4 trimethylation to promote colorectal cancer metastasis. In vivo ubiquitination assay with K146 mutagenesis, Co-immunoprecipitation, PHGDH enzymatic activity assay, ChIP, metabolite measurement Journal of Clinical Investigation High 34720086
2022 A CUL4A-DDB1-WDFY1 E3 ubiquitin ligase complex initiates lysophagy by ubiquitinating LAMP2 on damaged lysosomes, recruiting autophagic machinery for clearance of damaged lysosomes. Proteomic screen with transfection reagent-coated beads, Co-immunoprecipitation, in vivo ubiquitination assay, knockdown with lysophagy functional assay Cell Reports Medium 36103833
2016 CUL4A promotes gastric cancer proliferation and EMT by downregulating LATS1-Hippo-YAP signaling; knockdown of CUL4A increases LATS1 levels and MST1 activity, while overexpression decreases them, and the effects are reversed by co-manipulation of YAP. siRNA/shRNA knockdown, overexpression, western blot, mouse xenograft model Oncotarget Low 26840256
2017 NRIP/DCAF6 displaces DDB2 from the androgen receptor (AR)-DDB2-DDB1-CUL4A complex to stabilize AR protein; NRIP and DDB2 compete for the same AR binding domain but both bind DDB1, so NRIP protects AR from CUL4A-mediated destabilization. Co-immunoprecipitation, competition binding assay, AR protein stability assay, immunohistochemistry Oncotarget Medium 28212551
2016 pSTAT3 binds to the CUL4A promoter and acts as a transcription factor to upregulate CUL4A expression in response to IL-6 stimulation; CUL4A knockdown abrogates IL-6-driven ZEB1 induction and cell invasion in colorectal cancer cells. ChIP assay, luciferase reporter assay for CUL4A promoter, siRNA knockdown, matrigel invasion assay Archives of Medical Research Medium 27418574
2019 CREB directly occupies cAMP response elements at the CUL4A promoter and positively regulates CUL4A transcription; ERK pathway inhibition reduces pCREB and CUL4A levels, and CUL4A in turn activates ERK/CREB through a positive feedback loop. ChIP assay, CREB overexpression/knockdown, ERK inhibitor (U0126) treatment, qPCR/western blot Medical Oncology Medium 30666499
2019 CUL4A interacts with PARP1 and reduces PARP1 expression under oxidative stress; this interaction is enhanced by H2O2 treatment, and CUL4A overexpression suppresses ROS generation and apoptosis in H9c2 cardiomyocytes. Co-immunoprecipitation, western blot, ROS measurement, flow cytometry apoptosis assay, adenoviral overexpression Oxidative Medicine and Cellular Longevity Low 31178959
2020 The CARM1-p300-c-Myc-Max (CPCM) transcriptional complex activates CUL4A/4B expression by binding their promoters; knockdown of any CPCM component decreases CUL4A/4B levels, impairs CRL4 E3 ligase activity, and causes accumulation of the CRL4 substrate ST7. Mass spectrometry, Co-immunoprecipitation, ChIP, siRNA knockdown, CRL4 E3 ligase activity assay International Journal of Biological Sciences Medium 32140072
2023 AKT phosphorylates FAM13A at serine 312, enabling recognition by the CUL4A/DDB1/DCAF1 E3 ligase complex, which ubiquitinates FAM13A and targets it for proteasomal degradation; reduced FAM13A accelerates lung epithelial cell proliferation during injury recovery. In vivo ubiquitination assay, site-directed mutagenesis (S312), Co-immunoprecipitation, AKT kinase assay, mouse lung injury model American Journal of Respiratory Cell and Molecular Biology Medium 36749583
2026 CUL4A-DDB1-DCAF10 constitutes an N-recognin E3 ligase complex that recognizes N-terminally acetylated Src-family kinases (SFKs); DCAF10 is the substrate receptor that specifically recognizes N-terminal acetylated glycine on SFKs that fail to be myristoylated. In vitro, the CUL4A-DDB1-DCAF10 complex ubiquitinates N-terminally acetylated SFKs, defining a novel Ac/N-degron pathway that monitors replacement of myristoylation by acetylation. Peptide pull-downs, mass spectrometry, AlphaFold3 structural predictions, siRNA knockdown, CRISPR/Cas9 knockout, inducible overexpression of Lyn-GFP variants, in vitro ubiquitination assay Nature Communications High 41484149
2023 CUL4A-DDB1 can be recruited via a covalent recruiter targeting C173 on DDB1 for PROTAC-mediated targeted degradation of neo-substrates BRD4 (short isoform selectively) and androgen receptor; degradation is proteasome-, neddylation-, and DDB1-dependent. Activity-based protein profiling, cysteine chemoproteomic screening, PROTAC degradation assay, proteasome/neddylation inhibitor treatment bioRxivpreprint Medium 37614621
2022 CUL4A promotes SAMHD1-independent resistance to cytarabine in AML cells by facilitating PCNA mono-ubiquitination, which promotes the polymerase switch toward error-prone translesion DNA polymerases; siRNA against CUL4A re-sensitizes AML cells to cytarabine similarly to siRNA against REV3L. siRNA screen (437 siRNAs), siRNA knockdown epistasis, western blot for PCNA ubiquitination, cell viability assay HemaSphere Medium 35519003
2022 Targeted inhibition of CUL4A results in significant downregulation of DDB2 (a DNA-damage recognition protein for NER), enhancing cisplatin-induced DNA damage and apoptosis; CUL4A knockdown or pevonedistat treatment phenocopies DDB2 silencing in sensitizing HNSCC cells to cisplatin, with in vivo tumor regression and long-term survival in mouse models. siRNA knockdown of CUL4A/DDB2, pevonedistat treatment, western blot for DDB2, γH2AX measurement, xenograft mouse model Cell Death & Disease Medium 35428778
2019 CUL4A directly interacts with and ubiquitinates ANXA10 (annexin A10) to promote its degradation in lung cancer cells; knockdown of CUL4A upregulates ANXA10, and ANXA10 knockdown reverses the inhibition of invasion/metastasis caused by CUL4A knockdown. Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, overexpression, mouse tail-vein metastasis model Cancers Medium 31052599
2014 In zebrafish, cul4a (but not cul4b) transcriptionally upregulates tbx5a; morpholino knockdown of cul4a reduces tbx5a expression and causes failure of heart looping and pectoral fin development with reduced cardiac cell proliferation. Morpholino knockdown in zebrafish, qPCR for tbx5a, rescue experiments, histology Human Molecular Genetics Medium 25274780
2023 CUL4A mediates LATS1 ubiquitination and degradation to promote glioma progression via Hippo pathway inhibition; S100A16 promotes this by interacting with CUL4A and LATS1, and CUL4A knockdown rescues LATS1 levels and inhibits YAP nuclear import. Co-immunoprecipitation, ubiquitination assay, western blot, siRNA knockdown, xenograft mouse model International Journal of Biological Sciences Low 37151881

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Molecular architecture and assembly of the DDB1-CUL4A ubiquitin ligase machinery. Nature 586 16964240
2004 Human De-etiolated-1 regulates c-Jun by assembling a CUL4A ubiquitin ligase. Science (New York, N.Y.) 319 14739464
2004 Targeted ubiquitination of CDT1 by the DDB1-CUL4A-ROC1 ligase in response to DNA damage. Nature cell biology 316 15448697
2017 A novel lncRNA uc.134 represses hepatocellular carcinoma progression by inhibiting CUL4A-mediated ubiquitination of LATS1. Journal of hematology & oncology 190 28420424
2013 CUL4A induces epithelial-mesenchymal transition and promotes cancer metastasis by regulating ZEB1 expression. Cancer research 175 24305877
2002 TFDP1, CUL4A, and CDC16 identified as targets for amplification at 13q34 in hepatocellular carcinomas. Hepatology (Baltimore, Md.) 162 12029633
2009 CUL4A abrogation augments DNA damage response and protection against skin carcinogenesis. Molecular cell 159 19481525
2009 REDD1, an inhibitor of mTOR signalling, is regulated by the CUL4A-DDB1 ubiquitin ligase. EMBO reports 121 19557001
2006 L2DTL/CDT2 and PCNA interact with p53 and regulate p53 polyubiquitination and protein stability through MDM2 and CUL4A/DDB1 complexes. Cell cycle (Georgetown, Tex.) 114 16861890
2009 The human immunodeficiency virus type 2 Vpx protein usurps the CUL4A-DDB1 DCAF1 ubiquitin ligase to overcome a postentry block in macrophage infection. Journal of virology 110 19264781
2007 DDB1 and Cul4A are required for human immunodeficiency virus type 1 Vpr-induced G2 arrest. Journal of virology 109 17626091
2015 Distinct and overlapping functions of the cullin E3 ligase scaffolding proteins CUL4A and CUL4B. Gene 99 26344709
2006 Cul4A and DDB1 associate with Skp2 to target p27Kip1 for proteolysis involving the COP9 signalosome. Molecular and cellular biology 95 16537899
2004 Cul4A physically associates with MDM2 and participates in the proteolysis of p53. Cancer research 91 15548678
2021 Cul4A-DDB1-mediated monoubiquitination of phosphoglycerate dehydrogenase promotes colorectal cancer metastasis via increased S-adenosylmethionine. The Journal of clinical investigation 88 34720086
2018 A Novel lncRNA, LINC00460, Affects Cell Proliferation and Apoptosis by Regulating KLF2 and CUL4A Expression in Colorectal Cancer. Molecular therapy. Nucleic acids 84 30092404
2009 Comprehensive characterization of the DNA amplification at 13q34 in human breast cancer reveals TFDP1 and CUL4A as likely candidate target genes. Breast cancer research : BCR 81 19995430
2006 Cul4A targets p27 for degradation and regulates proliferation, cell cycle exit, and differentiation during erythropoiesis. Blood 81 16467204
2002 CUL-4A is critical for early embryonic development. Molecular and cellular biology 80 12077329
2011 Cul4A is essential for spermatogenesis and male fertility. Developmental biology 78 21291880
2014 CUL4A ubiquitin ligase: a promising drug target for cancer and other human diseases. Open biology 74 24522884
2003 CUL-4A stimulates ubiquitylation and degradation of the HOXA9 homeodomain protein. The EMBO journal 64 14609952
2011 Cul4A is an oncogene in malignant pleural mesothelioma. Journal of cellular and molecular medicine 63 19929949
2016 Cullin 4A (CUL4A), a direct target of miR-9 and miR-137, promotes gastric cancer proliferation and invasion by regulating the Hippo signaling pathway. Oncotarget 61 26840256
2014 CUL4A overexpression enhances lung tumor growth and sensitizes lung cancer cells to erlotinib via transcriptional regulation of EGFR. Molecular cancer 58 25413624
2008 VprBP targets Merlin to the Roc1-Cul4A-DDB1 E3 ligase complex for degradation. Oncogene 58 18332868
2013 Linker Histone H1.2 cooperates with Cul4A and PAF1 to drive H4K31 ubiquitylation-mediated transactivation. Cell reports 54 24360965
2012 Oncogenic CUL4A determines the response to thalidomide treatment in prostate cancer. Journal of molecular medicine (Berlin, Germany) 49 22422151
2013 Involvement of CUL4A in regulation of multidrug resistance to P-gp substrate drugs in breast cancer cells. Molecules (Basel, Switzerland) 43 24368600
2013 Inhibition of CUL4A Neddylation causes a reversible block to SAMHD1-mediated restriction of HIV-1. Journal of virology 42 23986575
2019 Inflammation-dependent downregulation of miR-194-5p contributes to human intervertebral disc degeneration by targeting CUL4A and CUL4B. Journal of cellular physiology 41 30945295
2016 Jak-STAT3 pathway triggers DICER1 for proteasomal degradation by ubiquitin ligase complex of CUL4A(DCAF1) to promote colon cancer development. Cancer letters 41 26965998
2022 Identification of CUL4A-DDB1-WDFY1 as an E3 ubiquitin ligase complex involved in initiation of lysophagy. Cell reports 40 36103833
2009 Proliferation defects and genome instability in cells lacking Cul4A. Oncogene 38 19430492
2016 Dysregulation of CUL4A and CUL4B Ubiquitin Ligases in Lung Cancer. The Journal of biological chemistry 37 27974468
2014 CUL4A is overexpressed in human pituitary adenomas and regulates pituitary tumor cell proliferation. Journal of neuro-oncology 37 24420924
2008 Assembly with the Cul4A-DDB1DCAF1 ubiquitin ligase protects HIV-1 Vpr from proteasomal degradation. The Journal of biological chemistry 36 18524771
2022 LINC01468 drives NAFLD-HCC progression through CUL4A-linked degradation of SHIP2. Cell death discovery 35 36344496
2019 KDM5D inhibit epithelial-mesenchymal transition of gastric cancer through demethylation in the promoter of Cul4A in male. Journal of cellular biochemistry 35 30864186
2015 CUL4A facilitates hepatocarcinogenesis by promoting cell cycle progression and epithelial-mesenchymal transition. Scientific reports 35 26593394
2018 miR‑377 targets CUL4A and regulates metastatic capability in ovarian cancer. International journal of molecular medicine 31 29512715
2011 Artemis interacts with the Cul4A-DDB1DDB2 ubiquitin E3 ligase and regulates degradation of the CDK inhibitor p27. Cell cycle (Georgetown, Tex.) 31 22134138
2020 The CARM1-p300-c-Myc-Max (CPCM) transcriptional complex regulates the expression of CUL4A/4B and affects the stability of CRL4 E3 ligases in colorectal cancer. International journal of biological sciences 28 32140074
2022 Evodiamine inhibits ESCC by inducing M-phase cell-cycle arrest via CUL4A/p53/p21 axis and activating noxa-dependent intrinsic and DR4-dependent extrinsic apoptosis. Phytomedicine : international journal of phytotherapy and phytopharmacology 27 36265256
2012 The Cul4A-DDB1 E3 ubiquitin ligase complex represses p73 transcriptional activity. Oncogene 27 23085759
2017 NRIP/DCAF6 stabilizes the androgen receptor protein by displacing DDB2 from the CUL4A-DDB1 E3 ligase complex in prostate cancer. Oncotarget 26 28212551
2008 Cul4A is required for hematopoietic cell viability and its deficiency leads to apoptosis. Blood 26 18339895
2016 CUL4A functions as an oncogene in ovarian cancer and is directly regulated by miR-494. Biochemical and biophysical research communications 25 27983981
2002 Study of the G2/M cell cycle checkpoint in irradiated mammary epithelial cells overexpressing Cul-4A gene. International journal of radiation oncology, biology, physics 23 11849807
2002 Enforced expression of CUL-4A interferes with granulocytic differentiation and exit from the cell cycle. Blood 23 12393421
2021 lncRNA NEAT1 facilitates the progression of colorectal cancer via the KDM5A/Cul4A and Wnt signaling pathway. International journal of oncology 20 34109988
2020 Upregulated lncRNA DLX6-AS1 underpins hepatocellular carcinoma progression via the miR-513c/Cul4A/ANXA10 axis. Cancer gene therapy 20 33277615
2019 Cul4A Modulates Invasion and Metastasis of Lung Cancer Through Regulation of ANXA10. Cancers 20 31052599
2014 Lung tumourigenesis in a conditional Cul4A transgenic mouse model. The Journal of pathology 18 24648314
2020 Small molecule NSC1892 targets the CUL4A/4B-DDB1 interactions and causes impairment of CRL4DCAF4 E3 ligases to inhibit colorectal cancer cell growth. International journal of biological sciences 17 32140073
2017 CUL4A promotes proliferation and metastasis of colorectal cancer cells by regulating H3K4 trimethylation in epithelial-mesenchymal transition. OncoTargets and therapy 17 28223829
2014 CUL4A contributes to the biology of basal-like breast tumors through modulation of cell growth and antitumor immune response. Oncotarget 17 24870930
2013 Analysis of DNA repair-related genes in breast cancer reveals CUL4A ubiquitin ligase as a novel biomarker of trabectedin response. Molecular cancer therapeutics 17 23364677
2022 Targeted CUL4A inhibition synergizes with cisplatin to yield long-term survival in models of head and neck squamous cell carcinoma through a DDB2-mediated mechanism. Cell death & disease 15 35428778
2017 Loss of CUL4A expression is underlying cisplatin hypersensitivity in colorectal carcinoma cells with acquired trabectedin resistance. British journal of cancer 15 28095394
2017 Jumonji domain containing 2C promotes cell migration and invasion through modulating CUL4A expression in lung cancer. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 15 28236704
2015 Knockdown of Cul4A increases chemosensitivity to gemcitabine through upregulation of TGFBI in lung cancer cells. Oncology reports 15 26503734
2007 Cul4A is required for hematopoietic stem-cell engraftment and self-renewal. Blood 15 17616641
2014 Zebrafish cul4a, but not cul4b, modulates cardiac and forelimb development by upregulating tbx5a expression. Human molecular genetics 14 25274780
2013 The CUL4A ubiquitin ligase is a potential therapeutic target in skin cancer and other malignancies. Chinese journal of cancer 14 23845142
2022 Cul4a attenuates LPS-induced acute kidney injury via blocking NF-kB signaling pathway in sepsis. Journal of medical biochemistry 12 35611245
2019 A feedback regulation of CREB activation through the CUL4A and ERK signaling. Medical oncology (Northwood, London, England) 12 30666499
2019 Reduced miR-363-3p expression in non-small cell lung cancer is associated with gemcitabine resistance via targeting of CUL4A. European review for medical and pharmacological sciences 12 30720173
2019 Cul4a as a New Interaction Protein of PARP1 Inhibits Oxidative Stress-Induced H9c2 Cell Apoptosis. Oxidative medicine and cellular longevity 12 31178959
2017 Suppression of CUL4A attenuates TGF-β1-induced epithelial-to-mesenchymal transition in breast cancer cells. International journal of molecular medicine 12 28902348
2015 Knockdown of CUL4A inhibits invasion and induces apoptosis in osteosarcoma cells. International journal of immunopathology and pharmacology 12 26055549
2014 CUL4A-DDB1-Rbx1 E3 ligase controls the quality of the PTS2 receptor Pex7p. The Biochemical journal 12 24989250
2017 CUL4A promotes cell invasion in gastric cancer by activating the NF-κB signaling pathway. Biologics : targets & therapy 11 28442889
2011 Transgenic mice for cre-inducible overexpression of the Cul4A gene. Genesis (New York, N.Y. : 2000) 11 21381181
2015 Cul4A overexpression associated with Gli1 expression in malignant pleural mesothelioma. Journal of cellular and molecular medicine 10 26218750
2016 Aberrant Expression of CUL4A Is Associated with IL-6/ STAT3 Activation in Colorectal Cancer Progression. Archives of medical research 9 27418574
2011 Overexpression of the human ubiquitin E3 ligase CUL4A alleviates hypoxia-reoxygenation injury in pheochromocytoma (PC12) cells. Biochemical and biophysical research communications 9 22120631
2023 S100 Calcium Binding Protein A16 Promotes Cell Proliferation by triggering LATS1 ubiquitin degradation mediated by CUL4A ligase to inhibit Hippo pathway in Glioma development. International journal of biological sciences 8 37151881
2023 CUL4A-mediated ZEB1/microRNA-340-5p/HMGB1 axis promotes the development of osteoporosis. Journal of biochemical and molecular toxicology 8 37253097
2021 The CRBN, CUL4A and DDB1 Expression Predicts the Response to Immunomodulatory Drugs and Survival of Multiple Myeloma Patients. Journal of clinical medicine 8 34207079
2020 CUL4A promotes proliferation and inhibits apoptosis of colon cancer cells via regulating Hippo pathway. European review for medical and pharmacological sciences 8 33155207
2019 Cul4a promotes zebrafish primitive erythropoiesis via upregulating scl and gata1 expression. Cell death & disease 8 31101894
2015 Analysis of lung tumor initiation and progression in transgenic mice for Cre-inducible overexpression of Cul4A gene. Thoracic cancer 8 26273405
2023 AKT Phosphorylates FAM13A and Promotes Its Degradation via CUL4A/DDB1/DCAF1 E3 Complex. American journal of respiratory cell and molecular biology 7 36749583
2023 Targeted Protein Degradation through Recruitment of the CUL4A Complex Adaptor Protein DDB1. bioRxiv : the preprint server for biology 7 37614621
2020 CUL4A regulates endometrial cancer cell proliferation, invasion and migration by interacting with CSN6. Molecular medicine reports 6 33179082
2019 Effect of CUL4A on the metastatic potential of lung adenocarcinoma to the bone. Oncology reports 6 31894344
2015 CUL4A expression in pediatric osteosarcoma tissues and its effect on cell growth in osteosarcoma cells. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 6 26715273
2024 A novel tRNA-derived fragment tRF-3023b suppresses inflammation in RAW264.7 cells by targeting Cul4a through NF-κB signaling. Functional & integrative genomics 5 38221594
2020 CUL4A, ERCC5, and ERCC1 as Predictive Factors for Trabectedin Efficacy in Advanced Soft Tissue Sarcomas (STS): A Spanish Group for Sarcoma Research (GEIS) Study. Cancers 5 32365979
2020 CUL4A promotes the invasion of cervical cancer cells by regulating NF-κB signaling pathway. European review for medical and pharmacological sciences 5 33155196
2017 CUL4A as a marker and potential therapeutic target in multiple myeloma. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 5 28677427
2017 CUL4A enhances human trophoblast migration and is associated with pre-eclampsia. International journal of clinical and experimental pathology 4 31966394
2015 PR-Set7 is Degraded in a Conditional Cul4A Transgenic Mouse Model of Lung Cancer. Zhongguo fei ai za zhi = Chinese journal of lung cancer 4 26104890
2023 CUL4A silencing attenuates cervical carcinogenesis and improves Cisplatin sensitivity. Molecular and cellular biochemistry 3 37285039
2023 circSNTB2 and CUL4A Induces Dysfunction of Nucleus Pulposus Cells by Competitively Binding miR-665. Biochemical genetics 3 37507642
2022 The Nuclear Proteins TP73 and CUL4A Confer Resistance to Cytarabine by Induction of Translesion DNA Synthesis via Mono-ubiquitination of PCNA. HemaSphere 3 35519003
2021 Reduced miR-363-3p expression in non-small cell lung cancer is associated with gemcitabine resistance via targeting of CUL4A. European review for medical and pharmacological sciences 3 34787845
2015 Clinical significance of CUL4A in human prostate cancer. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 3 26036759
2026 CUL4A-DDB1-DCAF10 is an N-recognin for N-terminally acetylated Src kinases. Nature communications 1 41484149

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