Affinage

CUL4A

Cullin-4A · UniProt Q13619

Length
759 aa
Mass
87.7 kDa
Annotated
2026-04-28
100 papers in source corpus 33 papers cited in narrative 33 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CUL4A is the scaffold subunit of the CRL4A cullin-RING E3 ubiquitin ligase, assembling with the adaptor DDB1, the RING protein ROC1/RBX1, and interchangeable WD40-repeat DCAF substrate receptors to ubiquitinate a broad array of substrates that control DNA repair, replication licensing, cell cycle progression, chromatin remodeling, autophagy, and meiotic recombination (PMID:16964240, PMID:15448697, PMID:19481525, PMID:21291880). Through specific DCAF modules, CRL4A targets CDT1, DDB2, XPC, p21, p27, p53 (via MDM2), c-Jun, HOXA9, Merlin, REDD1, LATS1, PHGDH, LAMP2, DICER1, and FAM13A for polyubiquitination-dependent degradation or, in some cases, non-degradative monoubiquitination that modulates substrate activity, as demonstrated for p73 and PCNA (PMID:19481525, PMID:23085759, PMID:16537899, PMID:34720086, PMID:36103833, PMID:35519003). CUL4A neddylation is required for full ligase activity, and the complex is co-opted by HIV-1 Vpr and HIV-2 Vpx through DCAF1 to degrade host restriction factors including SAMHD1 (PMID:17626091, PMID:19264781, PMID:23986575). CUL4A is essential for mouse embryonic development, with homozygous deletion causing peri-implantation lethality and haploinsufficiency causing partial lethality, and also participates in chromatin regulation by cooperating with linker histone H1.2 and the PAF1 complex to catalyze H4K31 ubiquitylation and promote H3K4 trimethylation at target gene promoters (PMID:12077329, PMID:24360965).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 2002 High

    Establishing that CUL4A is an essential gene answered the fundamental question of whether this cullin family member has non-redundant developmental functions despite the existence of the paralog CUL4B.

    Evidence CUL4A knockout mice show peri-implantation lethality (4.5–7.5 dpc) and haploinsufficient lethality

    PMID:12077329

    Open questions at the time
    • Molecular substrates responsible for embryonic lethality not identified
    • Degree of functional overlap with CUL4B during development not resolved
  2. 2004 High

    Identification of DDB1 as the stoichiometric adaptor linking CUL4A to substrates such as CDT1 and c-Jun established the basic architecture of the CRL4A complex and its role in replication licensing and transcription factor turnover.

    Evidence In vitro binding, co-IP, and reconstituted ubiquitination assays in human cells showing DDB1–CUL4A association and CDT1/c-Jun as substrates

    PMID:14739464 PMID:15448697

    Open questions at the time
    • How substrate specificity is encoded beyond DDB1 was unclear
    • Whether other adaptors substitute for DDB1 not tested
  3. 2004 High

    Demonstrating that CUL4A promotes p53 degradation in an MDM2-dependent manner revealed a non-canonical p53 destruction pathway converging on the CRL4A ligase.

    Evidence Co-IP of CUL4A–MDM2–p53, pulse-chase in MDM2-null MEFs, p19ARF epistasis

    PMID:15548678

    Open questions at the time
    • Direct versus MDM2-bridged ubiquitination mechanism not fully resolved
    • In vivo contribution relative to canonical SCF-MDM2 pathway unknown
  4. 2006 High

    The crystal structure of DDB1–CUL4A–ROC1 and the proteomic identification of DCAF substrate receptors answered how a single adaptor (DDB1) can present dozens of substrates: a double-beta-propeller fold recruits interchangeable WD40-repeat DCAFs.

    Evidence X-ray crystallography at atomic resolution plus tandem-affinity purification/mass spectrometry identifying the DCAF family

    PMID:16964240

    Open questions at the time
    • Structural basis of individual DCAF–substrate recognition not resolved
    • How DCAF exchange on DDB1 is regulated remained unknown
  5. 2006 High

    Identification of p27 and HOXA9 as CRL4A substrates expanded the ligase's role to cell cycle CDK inhibitor control and hematopoietic differentiation.

    Evidence Co-IP, pulse-chase, and differentiation assays in erythroid progenitors and myeloid cells

    PMID:14609952 PMID:16467204 PMID:16537899

    Open questions at the time
    • Identity of the DCAF mediating p27 recognition by CRL4A was debated
    • Relative contribution of CRL4A versus SCF-Skp2 to p27 turnover not quantified
  6. 2007 High

    Discovery that HIV-1 Vpr hijacks CRL4A through DCAF1 to induce G2 arrest revealed viral co-option of the ubiquitin ligase and identified DCAF1 as the critical viral–host interface.

    Evidence siRNA knockdown of DDB1, CUL4A, DCAF1 each blocked Vpr-induced G2 arrest; proteasome inhibitor phenocopied

    PMID:17626091

    Open questions at the time
    • Cellular substrate(s) targeted by Vpr–CRL4A for G2 arrest not identified
    • Whether Vpr redirects CRL4A from endogenous DCAF1 substrates not tested
  7. 2008 High

    Extension of the viral hijacking paradigm to Merlin (NF2 tumor suppressor) degradation via DCAF1 demonstrated that the same DCAF used by HIV can also target endogenous tumor suppressors under growth-factor signaling.

    Evidence In vitro ubiquitination of Merlin by CRL4A-DCAF1, RNAi of VprBP stabilizing Merlin and blocking ERK/Rac

    PMID:18332868

    Open questions at the time
    • Whether Merlin and Vpr compete for the same DCAF1 interface not resolved
    • In vivo contribution to NF2-related tumorigenesis not tested
  8. 2009 High

    Conditional knockout in skin demonstrated that CUL4A controls nucleotide excision repair capacity through degradation of DDB2, XPC, and p21, and that its loss confers dramatic resistance to UV carcinogenesis — directly linking the ligase to cancer susceptibility in vivo.

    Evidence Skin-specific Cul4A conditional KO mice, UV carcinogenesis assays, substrate accumulation analysis

    PMID:19481525

    Open questions at the time
    • Whether CUL4B compensates partially in skin not determined
    • Kinetics of substrate re-accumulation after DNA repair completion unclear
  9. 2009 High

    Identification of REDD1 as a CRL4A-β-TRCP substrate in a GSK3β-dependent manner connected the ligase to mTORC1 reactivation after hypoxia, broadening its physiological scope beyond DNA damage.

    Evidence Reconstituted ubiquitination of REDD1 by CUL4A-DDB1-ROC1-β-TRCP, mTOR activity readout

    PMID:19557001

    Open questions at the time
    • Whether β-TRCP functions as a bona fide DCAF or bridges to SCF not fully resolved
    • In vivo verification in hypoxic tissues lacking
  10. 2009 High

    HIV-2 Vpx was shown to use the same CRL4A–DCAF1 platform to overcome macrophage post-entry restriction, establishing a conserved lentiviral strategy; Cul4A knockout MEF studies simultaneously revealed centrosome amplification and p53-dependent proliferation defects.

    Evidence Vpx–DCAF1 epistasis in macrophage infection; conditional KO MEFs with centrosome staining, UDS assay, dominant-negative p53 rescue

    PMID:19264781 PMID:19430492

    Open questions at the time
    • Host restriction factor (later identified as SAMHD1) was not yet named in these studies
    • How CUL4A loss causes centrosome defects mechanistically was unexplained
  11. 2011 High

    CUL4A knockout male mice are infertile with meiotic arrest and persistent DSBs in pachytene spermatocytes, establishing a non-redundant role for CRL4A in meiotic homologous recombination repair.

    Evidence Cul4A-/- mice, immunolocalization of CUL4A to DSBs, meiotic staging

    PMID:21291880

    Open questions at the time
    • Meiotic substrate(s) of CRL4A not identified
    • Whether CUL4B provides any meiotic function not tested
  12. 2013 High

    Discovery that CUL4A cooperates with linker histone H1.2 and PAF1 to catalyze H4K31 ubiquitylation and promote H3K4me3/H3K79me2 at gene promoters revealed a direct transcriptional activation mechanism beyond substrate degradation.

    Evidence Co-IP, ChIP for histone marks, in vitro ubiquitination of H4K31, RNAi epistasis

    PMID:24360965

    Open questions at the time
    • Genome-wide target gene repertoire of CUL4A-H1.2-PAF1 not mapped
    • Which DCAF mediates histone ubiquitylation in this context unclear
  13. 2013 Medium

    Pharmacological inhibition of CUL4A neddylation with MLN4924 blocked Vpx-induced SAMHD1 degradation, formally demonstrating that neddylation-dependent CRL4A activity is required for viral restriction factor destruction.

    Evidence MLN4924 treatment, SAMHD1 protein levels, HIV restriction assay

    PMID:23986575

    Open questions at the time
    • Off-target effects of MLN4924 on other cullins not excluded
    • Whether partial neddylation inhibition suffices not tested
  14. 2017 Medium

    CUL4A-mediated LATS1 ubiquitination links the ligase to Hippo pathway regulation; this activity is inhibited by lncRNA uc.134 binding to CUL4A residues 592–759, which blocks nuclear export of CUL4A.

    Evidence RNA pulldown, RNA immunoprecipitation, ubiquitination assay, localization assay

    PMID:28212424

    Open questions at the time
    • Structural basis of lncRNA–CUL4A interaction unknown
    • Whether other lncRNAs regulate CRL4A similarly not explored
  15. 2021 High

    CRL4A monoubiquitinates PHGDH at K146 to activate serine biosynthesis by promoting DNAJA1-dependent tetramerization, revealing a non-degradative catalytic activation mechanism that drives one-carbon metabolism and H3K4me3-dependent metastasis.

    Evidence In vitro ubiquitination, K146R mutagenesis, co-IP with DNAJA1, ChIP for H3K4me3, metabolite profiling

    PMID:34720086

    Open questions at the time
    • Which DCAF presents PHGDH to CRL4A not identified
    • Whether monoubiquitination is reversible by specific DUBs unknown
  16. 2022 High

    Identification of the CUL4A–DDB1–WDFY1 complex as a lysophagy initiator that ubiquitinates LAMP2 on damaged lysosomes added autophagy to the functional repertoire of CRL4A and identified WDFY1 as a new DCAF-like receptor.

    Evidence Proteomic screen with transfection-reagent-coated beads, co-IP, ubiquitination assay, functional lysophagy assay

    PMID:36103833

    Open questions at the time
    • Whether WDFY1 is a bona fide DCAF or acts through DDB1 not structurally confirmed
    • Ubiquitin chain type on LAMP2 not characterized
  17. 2022 Medium

    CUL4A monoubiquitinates PCNA to promote the translesion synthesis polymerase switch, providing a mechanistic basis for cytarabine resistance in AML and a rationale for neddylation inhibitor combination therapy.

    Evidence siRNA screen, PCNA ubiquitination analysis, pevonedistat synergy with cytarabine

    PMID:35519003

    Open questions at the time
    • Relative contribution of CRL4A versus RAD6-RAD18 to PCNA monoubiquitination not quantified
    • Patient-derived validation of neddylation inhibitor synergy pending

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major unresolved questions include: how DCAF exchange on DDB1 is regulated, the full scope of non-degradative (monoubiquitination) substrates, which specific substrates account for embryonic lethality and meiotic failure, and how CUL4A and CUL4B partition their substrate repertoires in vivo.
  • No systematic comparison of CUL4A versus CUL4B substrate specificity in matched tissues
  • Structural basis for DCAF exchange kinetics on DDB1 not determined
  • Monoubiquitination versus polyubiquitination selectivity rules unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 14
Localization
GO:0005634 nucleus 3 GO:0005694 chromosome 2 GO:0005829 cytosol 2
Pathway
R-HSA-392499 Metabolism of proteins 11 R-HSA-1640170 Cell Cycle 6 R-HSA-1266738 Developmental Biology 3 R-HSA-168256 Immune System 3 R-HSA-73894 DNA Repair 3 R-HSA-4839726 Chromatin organization 2 R-HSA-5357801 Programmed Cell Death 2 R-HSA-9612973 Autophagy 1
Partners
CDT2DCAF1DDB1DDB2HIST1H1CMDM2RBX1WDFY1
Complex memberships
CRL4A (CUL4A-DDB1-ROC1/RBX1)CRL4A-CDT2/L2DTLCRL4A-DCAF1CRL4A-H1.2-PAF1

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 Crystal structure of the DDB1-CUL4A-ROC1 complex revealed that DDB1 uses one beta-propeller domain for CUL4A scaffold binding and a separate double-beta-propeller fold for substrate presentation; tandem-affinity purification and mass spectrometry identified a novel family of WD40-repeat proteins (DCAFs) that bind the double-propeller fold of DDB1 and serve as substrate-recruiting modules for the CRL4A E3 ligase. X-ray crystallography, tandem-affinity purification, mass spectrometry Nature High 16964240
2004 Human DET1 assembles a multisubunit ubiquitin ligase containing DDB1, CUL4A, ROC1, and COP1 that promotes ubiquitination and proteasomal degradation of the proto-oncogenic transcription factor c-Jun; RNAi depletion of any subunit stabilized c-Jun and increased c-Jun-dependent transcription. Co-immunoprecipitation, in vitro ubiquitination assay, RNAi knockdown Science High 14739464
2004 DDB1 associates stoichiometrically with CUL4A in vivo, binds its amino-terminal region analogously to SKP1-CUL1, directly binds CDT1 in vitro, bridges CDT1 to CUL4A in vivo, and is required for UV-induced CDT1 ubiquitination and degradation by CUL4A; this interaction is negatively regulated by CAND1. Co-immunoprecipitation, in vitro binding assay, in vitro ubiquitination assay, RNAi knockdown Nature Cell Biology High 15448697
2006 L2DTL/CDT2 and PCNA associate with the CUL4A-DDB1-ROC1 complex and are required for CUL4A-mediated polyubiquitination of p53 and MDM2/HDM2; isolated CUL4A complexes displayed robust p53 polyubiquitination activity dependent on L2DTL, PCNA, DDB1, ROC1, and MDM2. Co-immunoprecipitation, in vitro ubiquitination assay, RNAi knockdown Cell Cycle High 16861890
2004 CUL4A associates with MDM2 and p53; depletion of CUL4A stabilizes p53, and CUL4A overexpression increases p53 decay rate in an MDM2-dependent manner; p19ARF blocks CUL4A-mediated p53 degradation. Co-immunoprecipitation, pulse-chase degradation assay, MDM2-null MEFs, RNAi Cancer Research High 15548678
2009 CUL4A ubiquitin ligase controls cellular nucleotide excision repair (NER) capacity by promoting degradation of the DDB2 and XPC DNA damage sensors and the p21/CIP1/WAF1 checkpoint effector; skin-specific Cul4a conditional knockout dramatically increased resistance to UV-induced skin carcinogenesis in mice. Conditional knockout mouse, UV carcinogenesis assay, protein degradation analysis Molecular Cell High 19481525
2009 REDD1 is ubiquitinated and degraded by the CUL4A-DDB1-ROC1-β-TRCP E3 ligase complex in a GSK3β-dependent manner; REDD1 degradation is required for restoration of mTORC1 signaling as cells recover from hypoxic stress. Co-immunoprecipitation, in vitro ubiquitination assay, RNAi, mTOR activity assay EMBO Reports High 19557001
2009 HIV-2 Vpx assembles with the CUL4A-DDB1 ubiquitin ligase through DCAF1 recruitment to overcome a post-entry restriction in macrophage infection; precluding Vpx from recruiting DCAF1 blocks HIV-2 reverse transcript accumulation. Co-immunoprecipitation, RNAi knockdown, viral infection assay, reverse transcript quantification Journal of Virology High 19264781
2007 HIV-1 Vpr assembles with DDB1 through interaction with DCAF1 to form a CUL4A-DDB1-DCAF1 E3 ubiquitin ligase complex; reduction of DDB1 or CUL4A by siRNA impairs Vpr-induced G2 arrest, and G2 arrest is blocked by proteasome inhibitor, indicating the complex targets cellular substrates for proteasomal degradation. Co-immunoprecipitation, RNAi knockdown, cell cycle analysis, proteasome inhibition Journal of Virology High 17626091
2008 HIV-1 Vpr stability is maintained through its assembly with the CUL4A-DDB1-DCAF1 ubiquitin ligase; DCAF1 overexpression stabilizes Vpr and causes cytoplasmic accumulation, while DCAF1 or DDB1 silencing decreases steady-state Vpr levels; a Vpr mutant (Q65R) defective for DCAF1 binding is degraded faster. Co-immunoprecipitation, RNAi, pulse-chase degradation assay, site-directed mutagenesis Journal of Biological Chemistry High 18524771
2008 The NF2 tumor suppressor Merlin is recruited to the ROC1-CUL4A-DDB1 E3 ligase complex through direct interaction with the WD40 adaptor protein VprBP/DCAF1 after serum stimulation, leading to Merlin polyubiquitination and proteasomal degradation; VprBP depletion stabilizes Merlin and inhibits ERK and Rac activation. Co-immunoprecipitation, in vitro ubiquitination assay, RNAi knockdown Oncogene High 18332868
2006 The DDB1-CUL4A-COP9 signalosome complex promotes proteolysis of p27Kip1 in mammalian cells; DDB1-induced p27 degradation requires CUL4A and the COP9 signalosome; Skp2 physically associates with CUL4A and DDB1 and is also required for this p27 degradation pathway. RNAi knockdown, co-immunoprecipitation, pulse-chase degradation assay Molecular and Cellular Biology High 16537899
2006 CUL4A ubiquitylation machinery promotes ubiquitylation and proteasome-dependent degradation of the HOXA9 homeodomain protein; the HOXA9 homeodomain is responsible for CUL4A-mediated degradation, and interference with CUL4A altered HOXA9 steady-state levels and impaired granulocytic differentiation of myeloid progenitor cells. Ectopic expression, RNAi, ubiquitination assay, differentiation assay The EMBO Journal High 14609952
2006 CUL4A ubiquitin ligase targets p27Kip1 for degradation during erythropoiesis; CUL4A and p27 co-immunoprecipitate, and enforced CUL4A expression destabilizes p27 and blocks terminal erythroid differentiation and cell cycle exit. Co-immunoprecipitation, ectopic expression, differentiation assay, cell cycle analysis Blood High 16467204
2013 H1.2 linker histone stably interacts with CUL4A E3 ubiquitin ligase and PAF1 elongation complexes; H1.2, CUL4A, and PAF1 cooperate to induce H4K31 ubiquitylation, H3K4me3, and H3K79me2 at target gene promoters to drive transcription; H1.2 bridges CUL4A and PAF1 complexes and recruits them to target genes by interacting with Ser2-phosphorylated RNAPII. Co-immunoprecipitation, ChIP, RNAi knockdown, in vitro ubiquitination Cell Reports High 24360965
2011 Artemis interacts with the CUL4A-DDB1 E3 ubiquitin ligase via direct binding to DDB2 and also interacts with p27; both DDB2 and Artemis are required for CUL4A-DDB1-mediated degradation of p27, and this regulation is important for G1 phase cell cycle progression. Co-immunoprecipitation, RNAi knockdown, cell cycle analysis, direct binding assay Cell Cycle Medium 22134138
2012 CUL4A-DDB1 E3 complex monoubiquitylates p73 through direct binding of p73 to DDB1; this monoubiquitylation does not affect p73 stability but negatively regulates p73-dependent transcriptional activity; DDB1 depletion induces p73 target gene expression in a p53-independent manner. Co-immunoprecipitation, in vitro ubiquitination assay, RNAi knockdown, reporter gene assay Oncogene High 23085759
2017 lncRNA uc.134 binds to CUL4A (residues 592-759) and inhibits its nuclear export; uc.134 inhibits CUL4A-mediated ubiquitination of LATS1, thereby increasing YAP S127 phosphorylation and silencing YAP target genes. RNA pulldown, RNA immunoprecipitation, ubiquitination assay, Western blot, localization assay Journal of Hematology & Oncology Medium 28420424
2013 CUL4A modulates H3K4me3 at the ZEB1 promoter in a manner associated with ZEB1 transcriptional activation; CUL4A-driven EMT and metastasis require ZEB1. ChIP, RNAi knockdown, overexpression, in vivo metastasis assay Cancer Research Medium 24305877
2021 CUL4A-based E3 ligase complex monoubiquitinates PHGDH at lysine 146, which enhances PHGDH activity by recruiting the chaperone DNAJA1 to promote PHGDH tetrameric formation, increasing serine, glycine, and SAM levels; elevated SAM promotes CRC metastasis via SET1A-mediated H3K4me3 at cell adhesion gene promoters. In vitro ubiquitination assay, site-directed mutagenesis, co-immunoprecipitation, ChIP, mass spectrometry Journal of Clinical Investigation High 34720086
2022 CUL4A-DDB1-WDFY1 forms an E3 ubiquitin ligase complex essential for initiating lysophagy; LAMP2 is ubiquitinated by this CUL4A E3 ligase complex on damaged lysosomes as a substrate to signal autophagic clearance. Proteomic screen with transfection-reagent-coated beads, co-immunoprecipitation, ubiquitination assay, functional autophagy assay Cell Reports High 36103833
2013 Inhibition of CUL4A neddylation with MLN4924 blocks Vpx-induced SAMHD1 degradation and maintains HIV restriction; removal of the drug releases the block, supporting dNTP pool depletion (not nucleolytic activity) as the primary SAMHD1 mechanism. Neddylation inhibitor treatment, protein degradation assay, viral restriction assay Journal of Virology Medium 23986575
2016 CUL4A-DDB1-DCAF1 E3 ligase complex promotes proteasomal degradation of DICER1 in colon cancer cells in response to IL-6/JAK-STAT3 pathway activation; PI3K-AKT signaling also contributes to DICER1 phosphorylation and degradation by this complex. Co-immunoprecipitation, ubiquitination assay, RNAi, xenograft model Cancer Letters Medium 26965998
2014 CUL4A-DDB1-Rbx1 (CRL4A) complex ubiquitinates dysfunctional Pex7p (including RCDP patient mutants) via a ubiquitin-dependent proteasomal pathway; CRL4A-mediated degradation of dysfunctional Pex7p is essential for maintaining normal PTS2 import. Ubiquitination assay, co-immunoprecipitation, proteasome inhibitor, functional PTS2 import assay Biochemical Journal Medium 24989250
2017 NRIP/DCAF6 stabilizes the androgen receptor (AR) protein by displacing DDB2 from the AR-DDB2-DDB1-CUL4A complex; NRIP and DDB2 compete for the same AR binding domain but not for DDB1 binding. Co-immunoprecipitation, competition binding assay, protein stability assay Oncotarget Medium 28212551
2011 Cul4A is essential for spermatogenesis; Cul4A-/- male mice are infertile with defects in meiotic progression through late prophase I; CUL4A localizes to double-strand breaks in pre-pachytene spermatocytes and is required for homologous recombination repair; persistent DSBs and apoptosis are observed in pachytene spermatocytes. Cul4A knockout mouse, immunolocalization, DSB analysis, meiosis staging Developmental Biology High 21291880
2009 Cul4A-deleted mouse embryonic fibroblasts show severe proliferation defects, slow S phase entry, deficiency in early M phase progression, deregulation of p53 and p27Kip1, aberrant centrosome number, multipolar spindles, micronuclei, and reduced UV-induced DNA repair (unscheduled DNA synthesis); dominant-negative p53 rescues proliferation defects. Conditional Cul4A knockout, cell cycle analysis, centrosome staining, UDS assay, dominant-negative epistasis Oncogene High 19430492
2023 FAM13A is phosphorylated at serine 312 by AKT kinase and is then recognized by the CUL4A/DDB1/DCAF1 E3 ligase complex, leading to ubiquitination-mediated FAM13A degradation; reduced FAM13A accelerates lung epithelial cell proliferation during recovery from injury. Co-immunoprecipitation, phosphorylation assay, ubiquitination assay, siRNA knockdown, murine lung injury models American Journal of Respiratory Cell and Molecular Biology Medium 36749583
2022 CUL4A promotes LATS1 ubiquitination and degradation, activating YAP nuclear import and downstream target genes CYR61 and CTGF; S100A16 recruits CUL4A to mediate this LATS1 ubiquitination, linking S100A16 to Hippo pathway inhibition in glioma. Co-immunoprecipitation, ubiquitination assay, immunofluorescence, RNAi International Journal of Biological Sciences Medium 37151881
2022 CUL4A mediates PCNA mono-ubiquitination to promote the polymerase switch toward error-prone translesion synthesis (TLS) polymerases, contributing to cytarabine resistance in AML; neddylation inhibition by pevonedistat blocks CUL4A activity and synergizes with cytarabine by inhibiting TLS. siRNA screen, RNAi knockdown, drug sensitivity assay, PCNA ubiquitination analysis HemaSphere Medium 35519003
2019 Cul4A interacts with ANXA10 (annexin A10) and promotes its ubiquitination-mediated degradation in lung cancer cells; knockdown of Cul4A upregulates ANXA10 and inhibits lung cancer invasion and metastasis. Co-immunoprecipitation, ubiquitination assay, RNAi, in vivo xenograft metastasis model Cancers Medium 31052599
2002 CUL-4A is required for early embryonic development; CUL-4A-/- mouse embryos die between 4.5 and 7.5 dpc despite viable CUL-4A-/- blastocysts; haploinsufficiency also causes approximately 44% lethality, establishing a dose-sensitive essential function. Gene knockout in mice, embryonic staging Molecular and Cellular Biology High 12077329
2023 A covalent recruiter targeting C173 on DDB1 was identified by chemoproteomic screening and used to develop PROTACs against BRD4 and androgen receptor that exploit the CUL4A-DDB1 complex; BRD4 PROTAC degradation was proteasome-, NEDDylation-, and DDB1-dependent. Activity-based protein profiling, cysteine chemoproteomics, PROTAC synthesis, proteasome/NEDDylation inhibitor assay bioRxivpreprint Medium 37614621

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 581 16964240
2004 Human De-etiolated-1 regulates c-Jun by assembling a CUL4A ubiquitin ligase. Science (New York, N.Y.) 317 14739464
2004 Targeted ubiquitination of CDT1 by the DDB1-CUL4A-ROC1 ligase in response to DNA damage. Nature cell biology 314 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.) 161 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 120 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 94 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 86 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 73 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
2008 VprBP targets Merlin to the Roc1-Cul4A-DDB1 E3 ligase complex for degradation. Oncogene 58 18332868
2014 CUL4A overexpression enhances lung tumor growth and sensitizes lung cancer cells to erlotinib via transcriptional regulation of EGFR. Molecular cancer 57 25413624
2013 Linker Histone H1.2 cooperates with Cul4A and PAF1 to drive H4K31 ubiquitylation-mediated transactivation. Cell reports 53 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
2009 Proliferation defects and genome instability in cells lacking Cul4A. Oncogene 38 19430492
2022 Identification of CUL4A-DDB1-WDFY1 as an E3 ubiquitin ligase complex involved in initiation of lysophagy. Cell reports 36 36103833
2016 Dysregulation of CUL4A and CUL4B Ubiquitin Ligases in Lung Cancer. The Journal of biological chemistry 36 27974468
2014 CUL4A is overexpressed in human pituitary adenomas and regulates pituitary tumor cell proliferation. Journal of neuro-oncology 36 24420924
2008 Assembly with the Cul4A-DDB1DCAF1 ubiquitin ligase protects HIV-1 Vpr from proteasomal degradation. The Journal of biological chemistry 36 18524771
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
2022 LINC01468 drives NAFLD-HCC progression through CUL4A-linked degradation of SHIP2. Cell death discovery 31 36344496
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
2012 The Cul4A-DDB1 E3 ubiquitin ligase complex represses p73 transcriptional activity. Oncogene 27 23085759
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 26 32140074
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
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 25 36265256
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
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
2021 lncRNA NEAT1 facilitates the progression of colorectal cancer via the KDM5A/Cul4A and Wnt signaling pathway. International journal of oncology 19 34109988
2014 Lung tumourigenesis in a conditional Cul4A transgenic mouse model. The Journal of pathology 18 24648314
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
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 16 32140073
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 13 23845142
2022 Cul4a attenuates LPS-induced acute kidney injury via blocking NF-kB signaling pathway in sepsis. Journal of medical biochemistry 12 35611245
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
2019 A feedback regulation of CREB activation through the CUL4A and ERK signaling. Medical oncology (Northwood, London, England) 11 30666499
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
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 CUL4A-mediated ZEB1/microRNA-340-5p/HMGB1 axis promotes the development of osteoporosis. Journal of biochemical and molecular toxicology 7 37253097
2023 Targeted Protein Degradation through Recruitment of the CUL4A Complex Adaptor Protein DDB1. bioRxiv : the preprint server for biology 7 37614621
2021 The CRBN, CUL4A and DDB1 Expression Predicts the Response to Immunomodulatory Drugs and Survival of Multiple Myeloma Patients. Journal of clinical medicine 7 34207079
2023 AKT Phosphorylates FAM13A and Promotes Its Degradation via CUL4A/DDB1/DCAF1 E3 Complex. American journal of respiratory cell and molecular biology 6 36749583
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
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
2024 A novel tRNA-derived fragment tRF-3023b suppresses inflammation in RAW264.7 cells by targeting Cul4a through NF-κB signaling. Functional & integrative genomics 3 38221594
2023 CUL4A silencing attenuates cervical carcinogenesis and improves Cisplatin sensitivity. Molecular and cellular biochemistry 3 37285039
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
2023 circSNTB2 and CUL4A Induces Dysfunction of Nucleus Pulposus Cells by Competitively Binding miR-665. Biochemical genetics 2 37507642
2017 miR-181a-2 downregulates the E3 ubiquitin ligase CUL4A transcript and promotes cell proliferation. Medical oncology (Northwood, London, England) 1 28730334