{"gene":"DDB1","run_date":"2026-06-09T23:54:41","timeline":{"discoveries":[{"year":2006,"finding":"Crystal structure of DDB1 reveals an intertwined three-propeller (BPA, BPB, BPC) architecture: two tightly coupled beta-propellers (BPA-BPB) form a double-propeller fold with a large pocket, while a third beta-propeller (BPC) is flexibly attached and docks DDB1 to the N-terminus of CUL4A. The SV5 V protein inserts a helix into the BPA-BPB double-propeller pocket to hijack the complex.","method":"X-ray crystallography of DDB1 alone and in complex with paramyxovirus SV5-V protein","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structures of apo and complex forms with functional validation, rigorous structural study","pmids":["16413485"],"is_preprint":false},{"year":2006,"finding":"DDB1 uses its BPC beta-propeller domain for CUL4A scaffold binding and its BPA-BPB double-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 CUL4A-RBX1-DDB1 E3 ligase.","method":"X-ray crystallography of the virally-hijacked DDB1-CUL4A-ROC1 complex; tandem-affinity purification of DDB1/CUL4A complexes followed by mass spectrometry","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus proteomic validation, multiple orthogonal methods","pmids":["16964240"],"is_preprint":false},{"year":2008,"finding":"Crystal structures of the DDB1-DDB2 complex alone and bound to UV-damaged DNA (6-4PP or abasic site) show that the lesion is held exclusively by the WD40 domain of DDB2. A DDB2 hairpin inserts into the minor groove, extrudes the photodimer into a binding pocket, and kinks the duplex ~40°. DDB1 scaffolds DDB2 and the associated CUL4 ubiquitin ligase to damaged chromatin.","method":"X-ray crystallography of DDB1-DDB2 complex alone and with damaged DNA substrates","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple crystal structures with distinct DNA substrates, rigorous structural study","pmids":["19109893"],"is_preprint":false},{"year":2009,"finding":"Crystal structure of DDB1 in complex with hepatitis B virus X protein (HBx) reveals that HBx binds DDB1 through an alpha-helical motif that is also present in SV5-V protein and in cellular DCAFs, identifying a common structural element for assembly of CUL4-DDB1 E3 complexes.","method":"X-ray crystallography of DDB1-HBx complex; structure-based mutagenesis and functional analysis","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with mutagenesis and functional validation","pmids":["19966799"],"is_preprint":false},{"year":2014,"finding":"Crystal structure of DDB1-CRBN in complex with thalidomide, lenalidomide, and pomalidomide establishes that CRBN is a DCAF substrate receptor within CRL4^CRBN and enantioselectively binds IMiDs. IMiDs promote ubiquitination of IKZF1/IKZF3 while blocking endogenous substrate MEIS2 from binding, demonstrating dual modulation of E3 ligase substrate specificity.","method":"X-ray crystallography; unbiased substrate screen; functional ubiquitination assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structures with three ligands plus orthogonal functional substrate screen","pmids":["25043012"],"is_preprint":false},{"year":2014,"finding":"Crystal structure of human CRBN-DDB1-lenalidomide complex shows a hydrophobic pocket in the thalidomide-binding domain (TBD) of CRBN accommodates the glutarimide moiety of lenalidomide. Site-directed mutagenesis confirmed key drug-binding residues are critical for antiproliferative effects.","method":"X-ray crystallography; site-directed mutagenesis in lentiviral myeloma models","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus mutagenesis with functional readout","pmids":["25108355"],"is_preprint":false},{"year":2016,"finding":"Crystal structure of DDB1-DCAF1-HIV-1 Vpr-UNG2 complex reveals how Vpr engages DCAF1 to create a binding interface for UNG2 recruitment, targeting UNG2 for CRL4-mediated degradation via molecular mimicry of DNA by a Vpr variable loop.","method":"X-ray crystallography of the quaternary complex","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure of full quaternary complex with mechanistic interpretation","pmids":["27571178"],"is_preprint":false},{"year":2004,"finding":"DDB1 associates stoichiometrically with CUL4A in vivo and binds directly to CDT1 in vitro; ectopic DDB1 bridges CDT1 to CUL4A in vivo. Silencing DDB1 prevents UV-induced CDT1 degradation in vivo and blocks CUL4A-mediated CDT1 ubiquitination in vitro, establishing DDB1 as the adaptor targeting CDT1 for CUL4A-dependent ubiquitination after UV damage.","method":"Co-immunoprecipitation; in vitro binding assay; in vitro ubiquitination assay; siRNA knockdown","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, in vitro ubiquitination reconstitution, confirmed by RNAi loss-of-function","pmids":["15448697"],"is_preprint":false},{"year":2006,"finding":"DDB1 functions as a linker between CUL4A and substrate-recruiting WD40 proteins (DWD proteins) via a conserved DWD box motif. Fifteen DWD proteins were shown to bind DDB1-CUL4A, and the DWD box is necessary and sufficient for DDB1 binding.","method":"Yeast two-hybrid; co-immunoprecipitation; motif mutagenesis","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — systematic identification with mutagenesis of binding motif and multiple substrates tested","pmids":["17079684"],"is_preprint":false},{"year":2006,"finding":"Eighteen DDB1- and CUL4-associated factors (DCAFs) were identified, including 14 WD40 proteins. DCAFs interact with DDB1 through a conserved 'WDXR' motif. DCAF2/Cdt2 recruits Cdt1 to CUL4-DDB1 for ubiquitylation at replication forks via PCNA, and Cdt2 depletion causes rereplication.","method":"Mass spectrometry proteomics; co-immunoprecipitation; Xenopus egg extract reconstitution; siRNA knockdown","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods including biochemical reconstitution in Xenopus extracts, motif identification","pmids":["16949367"],"is_preprint":false},{"year":2006,"finding":"The DDB1-CUL4A^DDB2 ubiquitin ligase monoubiquitinates histone H2A in native chromatin at UV-damaged DNA sites. DDB2 mutations (XP-E) impair E3 ligase activity and reduce H2A monoubiquitination after UV, which is associated with decreased global genome NER.","method":"Co-immunoprecipitation of endogenous complexes from UV-irradiated cells; comparison with XP-E mutant cells; chromatin fractionation","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — endogenous complex biochemistry with disease-relevant mutations confirming mechanistic role","pmids":["16473935"],"is_preprint":false},{"year":2006,"finding":"CUL4-DDB1 complexes interact with WD40 proteins WDR5 and EED, components of histone methylation complexes. Inactivation of CUL4 or DDB1 impairs histone H3K4 and H3K27 methylation. CUL4A-DDB1 interacts with H3-methylated mononucleosomes.","method":"Co-immunoprecipitation; siRNA knockdown with histone methylation readouts; chromatin pull-down","journal":"Nature cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with orthogonal knockdown assays, single lab","pmids":["17041588"],"is_preprint":false},{"year":2006,"finding":"DDB1 knockdown in human cells impairs repair of UV-induced cyclobutane pyrimidine dimers (CPD) but not 6-4 photoproducts. Upon UV irradiation, DDB1 translocates from loosely to tightly bound chromatin fraction in a DDB2-dependent manner. DDB1 is required for UV-induced DDB2 ubiquitylation and degradation, and bridges DDB2 to CUL4A at damage sites.","method":"siRNA knockdown; nuclear fractionation; immunofluorescence at laser-induced damage foci; repair assays","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple methods, single lab, loss-of-function with specific repair phenotype","pmids":["16951172"],"is_preprint":false},{"year":2006,"finding":"DDB1 depletion causes accumulation of CDT1 protein and DNA re-replication, activates ATM/ATR checkpoints, and leads to genome-wide DNA double-strand breaks during S-phase. Co-depletion of CDT1 partially suppresses these phenotypes, placing CDT1 regulation downstream of DDB1 in genome maintenance.","method":"siRNA knockdown; flow cytometry; γH2AX immunofluorescence; epistasis by co-depletion","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis analysis with specific cellular phenotype readouts, single lab","pmids":["16940174"],"is_preprint":false},{"year":2006,"finding":"DDB1 dynamically accumulates at UV-damaged DNA sites in living cells. Its binding to damaged DNA is transient and requires DDB2 but not CUL4A. UV-dependent degradation of DDB2 releases DDB1 from continuous association with unrepaired DNA, making DDB1 available for other functions.","method":"Live-cell fluorescence microscopy with fluorescently tagged DDB1; FRAP; cell lines with DDB2 knockdown or DDB2 mutations","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization by live imaging with FRAP, functional consequence established through DDB2 dependency","pmids":["18936169"],"is_preprint":false},{"year":2005,"finding":"Purified DDB1-DDB2 complex binds cyclobutane pyrimidine dimers with ~6-fold higher affinity than undamaged DNA, as well as 6-4 photoproducts, abasic sites, and 2-3 bp mismatches. DDB acts as a conformational sensor rather than lesion-specific detector.","method":"In vitro binding assays with highly purified DDB1-DDB2 complex and defined damaged DNA substrates; quantitative affinity measurements","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with purified proteins and quantitative affinity measurements","pmids":["16223728"],"is_preprint":false},{"year":2006,"finding":"DDB1-CUL4 E3 ligase targets CDT1 for degradation during S phase and after DNA damage through two distinct E3 ligases: DDB1-CUL4 recognizes the N-terminal 10 amino acids of CDT1 and requires PCNA, while SCF-Skp2 recognizes a CDK-phosphorylated Cy-motif. PCNA is essential for CUL4- but not SKP2-directed CDT1 degradation.","method":"Mutational analysis of CDT1 degradation signals; siRNA co-depletion of Skp2 and Cul4; co-immunoprecipitation; cell cycle analysis","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — mutational dissection of two pathways, siRNA co-depletion epistasis, replicated across groups","pmids":["16482215"],"is_preprint":false},{"year":2006,"finding":"PCNA interacts with CDT1 and is required for CUL4-DDB1-mediated N-terminal ubiquitination of CDT1 in S phase and after UV irradiation. Overexpression of the PCNA-inhibitory domain from p21 or p57 blocks CDT1 degradation. Deletion of Ddb1 in fission yeast accumulates CDT1 even without DNA damage.","method":"In vivo ubiquitination assay; siRNA knockdown of PCNA; gel filtration co-elution; PCNA inhibitory domain overexpression; fission yeast genetics","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods, single lab, cross-species validation","pmids":["16407242"],"is_preprint":false},{"year":2006,"finding":"CUL4A associates with Skp2 and DDB1 forms a physical complex with CUL4A, Skp2, and the COP9 signalosome. DDB1 knockdown, CSN1 knockdown, or CUL4A knockdown causes p27Kip1 accumulation. DDB1 overexpression reduces p27Kip1 stability via CUL4A and the COP9 signalosome.","method":"siRNA knockdown; co-immunoprecipitation; pulse-chase; overexpression","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and functional knockdown, single lab","pmids":["16537899"],"is_preprint":false},{"year":2009,"finding":"DDB1 interacts with CHK1 and is part of a CUL4A/CUL4B E3 ligase complex that negatively regulates CHK1 protein stability. CHK1 ubiquitination is Cul4A/DDB1-dependent in vitro and in vivo, and CHK1 is stabilized in Cul4A/DDB1-deficient cells. CHK1 phosphorylation and replication stress enhance DDB1-CHK1 interaction.","method":"Co-immunoprecipitation; in vitro ubiquitination assay; siRNA knockdown; protein stability assays","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro ubiquitination reconstitution plus co-IP and knockdown, single lab","pmids":["19276361"],"is_preprint":false},{"year":2011,"finding":"USP1 deubiquitinase counteracts DDB1-dependent degradation of phosphorylated CHK1. USP1 depletion stimulates DDB1-dependent degradation of phospho-CHK1, establishing a negative feedback circuit in the DNA damage response where activated CHK1 is downregulated via DDB1-mediated ubiquitination.","method":"siRNA knockdown of USP1; co-immunoprecipitation; CHK1 stability measurements in response to genotoxic stress","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA epistasis and co-IP, single lab","pmids":["21389083"],"is_preprint":false},{"year":2007,"finding":"HIV-1 Vpr binds DDB1 through DCAF1/VprBP, and Vpr-mediated G2 arrest requires DDB1, CUL4A, and DCAF1. Tandem affinity purification identified DDB1, VPRBP, and CUL4A as Vpr-associated proteins. Proteasome inhibition abolishes Vpr-induced G2 arrest, consistent with ubiquitin ligase-mediated target degradation.","method":"Tandem affinity purification/mass spectrometry; co-immunoprecipitation; siRNA knockdown; cell cycle analysis by flow cytometry; proteasome inhibitor experiments","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal affinity purification, siRNA epistasis, pharmacological validation, replicated by multiple labs","pmids":["17626091","17314515","17609381","17630831","17620334"],"is_preprint":false},{"year":2007,"finding":"HIV-1 Vpr binding to DDB1 (via DDB1-CUL4 ubiquitin ligase interaction) mediates Vpr-induced apoptosis and UNG2/SMUG1 degradation, and impairs UV-damaged DNA repair. DDB1 was identified as the predominant Vpr-interacting cellular protein by tandem affinity purification and mass spectrometry.","method":"Tandem affinity purification/mass spectrometry; co-immunoprecipitation; siRNA knockdown; functional assays for apoptosis and UNG2 degradation","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — TAP-MS identification with functional knockdown validation, single lab","pmids":["17360488"],"is_preprint":false},{"year":2002,"finding":"DDB1 (p127) is essential for SV5 V protein-mediated STAT1 degradation. V protein mutants that fail to bind DDB1 cannot block IFN signaling. siRNA depletion of DDB1 prevents STAT1 degradation and restores IFN signaling. STAT1 degradation is independent of DDB2.","method":"Protein-protein interaction assays; V protein mutagenesis; siRNA knockdown; IFN signaling assays","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis plus siRNA knockdown, functional readout, single lab","pmids":["12388698"],"is_preprint":false},{"year":2005,"finding":"SV5 V protein acts as an adaptor linking DDB1 (via its N-terminal domain) to STAT2/STAT1 heterodimers, assembling a DDB1/CUL4A-containing ubiquitin ligase complex that ubiquitinates STAT1. V binds DDB1 and STAT2 independently; STAT1-STAT2 interaction is V-independent.","method":"Direct protein-protein interaction assays (GST pulldown, co-IP); yeast two-hybrid; ubiquitination assay with CUL4A components","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding assays for each pair plus functional ubiquitination, single lab","pmids":["16227264"],"is_preprint":false},{"year":2008,"finding":"FBW5, a DWD-box WD40 protein, binds DDB1 and recruits TSC2 to the DDB1-CUL4-ROC1 E3 ubiquitin ligase for ubiquitination and proteasomal degradation. TSC1 co-expression with TSC2 protects TSC2 from FBW5-mediated degradation. Drosophila Cul4/Ddb1 mutations cause Gigas/TSC2 accumulation.","method":"Co-immunoprecipitation; in vitro ubiquitination; siRNA knockdown; overexpression; Drosophila genetics","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vitro ubiquitination assay, siRNA, genetic epistasis in Drosophila, multiple orthogonal methods","pmids":["18381890"],"is_preprint":false},{"year":2006,"finding":"L2DTL/CDT2 associates with CUL4, DDB1, and PCNA in vivo. Loss of L2DTL suppresses CDT1 proteolysis after DNA damage. In vivo, inactivation of L2DTL causes dissociation of DDB1 from the CUL4 complex, and PCNA interacts with CDT1 through the same region required for CUL4-mediated degradation.","method":"Anti-CUL4 affinity chromatography/mass spectrometry; co-immunoprecipitation; siRNA knockdown in Drosophila S2 cells and human cells","journal":"Cell cycle","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-based identification confirmed by co-IP and siRNA, single lab","pmids":["16861906"],"is_preprint":false},{"year":2012,"finding":"EZH2 methylates non-histone substrate RORα, generating a monomethyl degron recognized by the DCAF1 chromo domain. The DCAF1/DDB1/CUL4 E3 complex then ubiquitinates the monomethylated substrate for degradation. Mutations in the DCAF1 chromo domain abolish binding to monomethylated substrates.","method":"In vitro methylation assay; molecular modeling; binding affinity studies; DCAF1 chromo domain mutagenesis; co-immunoprecipitation","journal":"Molecular cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro assays with mutagenesis, single lab","pmids":["23063525"],"is_preprint":false},{"year":2008,"finding":"VprBP acts as the substrate receptor that recruits Merlin (NF2 tumor suppressor) to the ROC1-CUL4A-DDB1 E3 ubiquitin ligase. Serum stimulation induces Merlin recruitment, polyubiquitination, and proteasomal degradation. VprBP depletion stabilizes Merlin and inhibits ERK/Rac activation.","method":"Co-immunoprecipitation; siRNA knockdown; in vivo ubiquitination assay; serum stimulation experiments","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, ubiquitination, siRNA knockdown, single lab","pmids":["18332868"],"is_preprint":false},{"year":2013,"finding":"DDB1-CUL4 E3 ubiquitin ligase monoubiquitylates raptor, a component of mTORC1. UCH-L1 deubiquitinase disrupts the DDB1-CUL4/raptor complex and counteracts DDB1-CUL4-mediated raptor ubiquitination, promoting mTORC1 dissolution and secondary mTORC2 increase.","method":"Co-immunoprecipitation; ubiquitination assay; UCH-L1 transgenic and knockout mouse models; mTOR complex assembly analysis","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, ubiquitination assay, and in vivo mouse models, single lab","pmids":["23297343"],"is_preprint":false},{"year":2006,"finding":"Conditional deletion of DDB1 in mouse brain and lens causes selective apoptosis of proliferating neuronal progenitor and lens epithelial cells, preceded by aberrant accumulation of cell cycle regulators and genomic instability. Cell death is partially rescued by co-deletion of p53, placing p53 activation downstream of DDB1 loss.","method":"Conditional knockout mouse genetics; histology; immunohistochemistry; p53 genetic epistasis","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional knockout in vivo with epistasis, multiple tissue types analyzed","pmids":["17129780"],"is_preprint":false},{"year":2007,"finding":"Tissue-specific deletion of DDB1 in mouse epidermis causes accumulation of c-Jun and p21Cip1, G2/M arrest, selective apoptosis of proliferating progenitor cells, and near-complete loss of epidermis and hair follicles. Co-deletion of p53 partially rescues progenitors but permits aneuploidy accumulation.","method":"Conditional knockout mouse genetics; immunohistochemistry; cell cycle analysis; p53 epistasis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO in vivo with specific molecular markers and genetic rescue","pmids":["17301228"],"is_preprint":false},{"year":2005,"finding":"HBx requires DDB1 binding for both its cell-killing activity and its ability to stimulate HBV genome replication. DDB1-binding-deficient HBx point mutants fail to complement HBx-deficient HBV replication. DDB1 depletion by RNAi specifically compromises wild-type HBV replication. HBx fused directly to DDB1 rescues replication activity.","method":"HBx point mutagenesis; DDB1 fusion protein; RNAi depletion; plasmid-based HBV replication assay","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis and RNAi with viral replication readout, single lab","pmids":["15767425"],"is_preprint":false},{"year":2003,"finding":"In fission yeast, Ddb1 is required for proteolysis of Spd1 (a ribonucleotide reductase inhibitor) in S phase and after DNA damage. Deletion of spd1 suppresses the growth defects and DNA damage sensitivity of Δddb1 cells, placing Spd1 as a key substrate downstream of Ddb1 in genome stability.","method":"Fission yeast genetics; protein stability assays; epistasis by double-mutant analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast genetics with epistasis, ortholog of mammalian DDB1","pmids":["14701809"],"is_preprint":false},{"year":2013,"finding":"Dyrk2-associated EDD-DDB1-VprBP E3 ligase mediates ubiquitin-dependent degradation of TERT (telomerase catalytic subunit). Dyrk2 phosphorylates TERT; phosphorylated TERT is then recognized by the VprBP substrate receptor of the EDD-DDB1-VprBP complex for ubiquitination and degradation at G2/M.","method":"Co-immunoprecipitation; in vivo ubiquitination assay; siRNA knockdown; kinase assay; cell cycle analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phosphorylation-ubiquitination cascade established by co-IP, ubiquitination assay, and kinase assay, single lab","pmids":["23362280"],"is_preprint":false},{"year":2013,"finding":"Ramshackle (Brwd3/BRWD3) functions as a DCAF within a CRL4 complex (CUL4-ROC1-DDB1-BRWD3) that mediates light-dependent ubiquitylation of Drosophila cryptochrome (dCRY). Light induces binding of dCRY to the complex, leading to dCRY ubiquitylation and degradation.","method":"RNAi screen in S2 cells; co-immunoprecipitation; ubiquitylation assay; light-dependent complex formation","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi screen with co-IP and ubiquitylation assay, single lab","pmids":["23479607"],"is_preprint":false},{"year":2015,"finding":"CUL4A-DDB1-CDT2 E3 ligase ubiquitinates CRY1 at lysine 585 and promotes its degradation in vitro and in vivo. Depletion of DDB1, CDT2, or PCNA stabilizes CRY1 in cells and mouse liver. CRY1-K585A mutant is resistant to DDB1-mediated ubiquitination. DDB1 depletion enhances circadian Bmal1 promoter oscillatory amplitude.","method":"In vitro ubiquitination assay; siRNA knockdown; site-directed mutagenesis; circadian reporter assay; mouse liver Ddb1 deletion","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — in vitro ubiquitination with mutagenesis, in vivo genetic validation, single lab","pmids":["26431207"],"is_preprint":false},{"year":2017,"finding":"DDB1-CUL4A ubiquitin E3 ligase degrades CRY1, thereby stabilizing FOXO1 and promoting hepatic gluconeogenesis. Hepatocyte-specific Ddb1 deletion impairs gluconeogenesis and protects from diet-induced hyperglycemia in mice. Mechanistically, DDB1 enhances FOXO1 stability by degrading CRY1, a known suppressor of FOXO1.","method":"Hepatocyte-specific conditional knockout mouse; high-fat diet experiments; gluconeogenesis assays; protein stability measurements","journal":"Diabetes","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO mouse with specific metabolic phenotype, mechanistic chain established, single lab","pmids":["28790135"],"is_preprint":false},{"year":2017,"finding":"SIRT7 deacetylates DDB1 at lysine 1121. The deacetylation-mimicking K1121R-DDB1 mutant shows reduced binding to DCAF1, leading to reduced CUL4B/DDB1/DCAF1 E3 ligase activity and increased TR4 nuclear receptor stability.","method":"In vitro deacetylation assay; co-immunoprecipitation; mutagenesis; target gene expression analysis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro deacetylation plus mutagenesis with binding and functional readout, single lab","pmids":["28623141"],"is_preprint":false},{"year":2009,"finding":"WDR-23, a WD40 protein, interacts with CUL-4/DDB-1 ubiquitin ligase to repress SKN-1 protein levels, nuclear accumulation, and transcriptional activity in C. elegans, presumably by targeting SKN-1 for proteasomal degradation. WDR-23 acts downstream of p38 MAPK, GSK-3, and insulin-like receptor pathways on SKN-1.","method":"Genetic screen; co-immunoprecipitation; RNAi; fluorescence microscopy; epistasis analysis","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, RNAi, epistasis in C. elegans, single lab","pmids":["19273594"],"is_preprint":false},{"year":2009,"finding":"DDB1-CUL4 and MLL1 mediate oncogenic Ras-induced p16INK4a activation. DDB1 silencing blocks Ras-induced p16 induction. CUL4A directly binds the p16 locus. DDB1-CUL4 acts upstream of MLL1-mediated H3K4 methylation at the p16 locus.","method":"siRNA knockdown; ChIP; co-immunoprecipitation; Ras-induced senescence model","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and siRNA epistasis with defined pathway, single lab","pmids":["19208841"],"is_preprint":false},{"year":2012,"finding":"The CUL4A/DDB1 E3 ligase monoubiquitylates p73 through direct DDB1-p73 binding. Monoubiquitylation does not affect p73 stability but negatively regulates p73 transcriptional activity. DDB1 depletion induces p73 target gene expression in a p53-independent manner.","method":"Co-immunoprecipitation; in vivo ubiquitination assay; siRNA knockdown; transcriptional reporter assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus functional ubiquitination and transcriptional assays, single lab","pmids":["23085759"],"is_preprint":false},{"year":2020,"finding":"Molecular glue HQ461 promotes a direct interaction between CDK12 and DDB1-CUL4-RBX1 E3 ubiquitin ligase, bypassing the requirement for a substrate-specific DCAF receptor. This interaction leads to polyubiquitination and degradation of Cyclin K (CCNK), reduced CDK12 substrate phosphorylation, and cell death.","method":"High-throughput screening; loss-of-function and gain-of-function genetic screening; biochemical reconstitution; co-immunoprecipitation; SAR analysis","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Strong — biochemical reconstitution plus genetic screening with multiple orthogonal methods","pmids":["32804079"],"is_preprint":false},{"year":2021,"finding":"CUL4A-DDB1-based E3 ligase monoubiquitinates PHGDH at lysine 146, enhancing its enzymatic activity by promoting tetrameric formation via DnaJA1 chaperone recruitment. This increases serine, glycine, and SAM levels, upregulating adhesion genes via H3K4me3, thereby promoting CRC metastasis.","method":"In vivo and in vitro ubiquitination assays; co-immunoprecipitation; mutagenesis; metabolomics; ChIP","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple biochemical methods, single lab","pmids":["34720086"],"is_preprint":false},{"year":2022,"finding":"CUL4A-DDB1-WDFY1 E3 ubiquitin ligase complex initiates lysophagy by ubiquitinating LAMP2 on damaged lysosomes. WDFY1 serves as the DCAF substrate receptor. Loss of CUL4A, DDB1, or WDFY1 impairs lysophagy and clearance of damaged lysosomes.","method":"Proteomic analysis using transfection reagent-coated beads; co-immunoprecipitation; siRNA knockdown; autophagy/lysosome damage assays","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomics with co-IP and functional knockdown, single lab","pmids":["36103833"],"is_preprint":false},{"year":2024,"finding":"Cysteine chemoproteomic screening identified a covalent recruiter targeting C173 on DDB1. This DDB1 recruiter was exploited to develop PROTACs against BRD4 and androgen receptor. BRD4 PROTAC selectively degrades the short BRD4 isoform in a proteasome-, NEDDylation-, and DDB1-dependent manner, demonstrating DDB1 can be directly exploited for targeted protein degradation.","method":"Activity-based protein profiling; cysteine chemoproteomic screening; PROTAC development; siRNA knockdown; degradation assays","journal":"ACS chemical biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — chemoproteomic identification with functional PROTAC validation, single lab","pmids":["38192078"],"is_preprint":false},{"year":2018,"finding":"The Cul4-DDB1-Gβ E3 ubiquitin ligase complex ubiquitylates Smoothened (Smo) in Drosophila, promoting its internalization and degradation. Smo recruits Cul4-DDB1 through the β subunit of trimeric G protein. Hedgehog signaling dissociates Cul4-DDB1 from Smo by PKA-mediated phosphorylation of DDB1, disrupting its interaction with Gβ.","method":"Co-immunoprecipitation; in vivo ubiquitination assay; phosphorylation assay; genetic inactivation of Cul4-DDB1; immunofluorescence for Smo surface expression","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, ubiquitination, phosphorylation assays, Drosophila genetics, single lab","pmids":["29930086"],"is_preprint":false},{"year":2016,"finding":"DCAF7 is a specificity factor for the CUL4-DDB1 complex that binds DNA ligase I and targets it for ubiquitylation. Three ubiquitylation sites on DNA ligase I were mapped. Knockdown of DCAF7 reduces DNA ligase I degradation upon inhibition of proliferation. Replacement of ubiquitylated lysines reduces in vitro ubiquitylation by CUL4-DDB1-DCAF7.","method":"Proteomic ubiquitylation site mapping; co-immunoprecipitation; in vitro ubiquitylation assay; siRNA knockdown; mutagenesis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — in vitro ubiquitylation with site mutagenesis, confirmed by siRNA, single lab","pmids":["27573245"],"is_preprint":false},{"year":2018,"finding":"DCAF11 (DDB1 and CUL4-associated factor 11) is the substrate receptor of CRL4 that binds phosphorylated SLBP (Stem-loop binding protein) and mediates its degradation at the end of S phase. DCAF11 cannot bind the non-phosphorylatable T61A-SLBP mutant. DCAF11 and Cul4A co-immunoprecipitate with SLBP.","method":"Pull-down with phosphorylated SLBP fragment; co-immunoprecipitation; siRNA and overexpression; cell viability assay","journal":"Cell cycle","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pull-down, co-IP, and siRNA with phosphorylation-dependent binding, single lab","pmids":["27254819"],"is_preprint":false},{"year":2018,"finding":"NTZ (nitazoxanide) inhibits the HBx-DDB1 protein-protein interaction, restoring Smc5/6 protein levels and suppressing HBV transcription and protein production in primary hepatocytes naturally infected with HBV.","method":"Split luciferase assay for HBx-DDB1 interaction; compound screening; Smc5/6 protein level measurement; viral transcription assays in primary hepatocytes and HBV minicircle system","journal":"Cellular and molecular gastroenterology and hepatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — target engagement assay with functional viral replication readout in primary cells, single lab","pmids":["30704981"],"is_preprint":false}],"current_model":"DDB1 is a core adaptor/scaffolding subunit of the CUL4-RBX1-DDB1-DCAF family of cullin-RING E3 ubiquitin ligases; its three-beta-propeller architecture (BPA-BPB double-propeller + flexible BPC) enables it to bridge CUL4A/B (via BPC) to a large family of WD40-repeat substrate receptors (DCAFs, binding via the BPA-BPB pocket through a conserved alpha-helical/DWD-box motif), thereby directing ubiquitination and proteasomal degradation or activity modulation of diverse substrates including CDT1, CHK1, CRY1, p27, TSC2, Merlin, TERT, PHGDH, LAMP2, and histones H2A at UV-damaged chromatin; DDB1 is also co-opted by viral proteins (HBV HBx, SV5-V, HIV-1 Vpr, HCMV pUL145) and by small-molecule molecular glues and PROTACs that exploit the DDB1 scaffold to redirect CRL4 activity toward neo-substrates."},"narrative":{"mechanistic_narrative":"DDB1 is the central adaptor subunit of the CUL4-RBX1-DDB1 family of cullin-RING E3 ubiquitin ligases (CRL4), bridging the CUL4 scaffold to interchangeable substrate-recruiting receptors and thereby directing ubiquitination of a broad set of substrates governing genome maintenance, cell-cycle control, and signaling [PMID:16964240, PMID:15448697]. Structurally, DDB1 adopts an intertwined three-beta-propeller architecture in which the BPA-BPB double-propeller forms a large pocket for substrate-receptor docking while the flexibly attached BPC propeller binds the N-terminus of CUL4A [PMID:16413485, PMID:16964240]. A large family of WD40-repeat proteins (DCAFs/DWD proteins) engages the BPA-BPB pocket through a conserved alpha-helical/DWD-box (WDxR) motif, the same structural element exploited by viral hijackers, and these receptors confer substrate specificity on the ligase [PMID:16964240, PMID:19966799, PMID:17079684, PMID:16949367]. Through distinct DCAFs, CRL4^DDB1 enforces replication licensing by degrading CDT1 in a PCNA-coupled manner via CDT2, an activity required to prevent re-replication, checkpoint activation, and genome-wide double-strand breaks [PMID:15448697, PMID:16949367, PMID:16482215, PMID:16940174], and it operates within nucleotide excision repair by scaffolding DDB2 to UV-damaged chromatin, where the complex monoubiquitinates histone H2A [PMID:19109893, PMID:16473935, PMID:16951172]. DDB1-CUL4 additionally targets diverse regulators including CHK1, p27, TSC2, Merlin, and circadian CRY1 for degradation, and modulates substrate activity by monoubiquitination of p73 and PHGDH [PMID:19276361, PMID:16537899, PMID:18381890, PMID:18332868, PMID:26431207, PMID:23085759, PMID:34720086]. In vivo, conditional DDB1 loss triggers aberrant accumulation of cell-cycle regulators, genomic instability, and p53-dependent apoptosis of proliferating progenitors [PMID:17129780, PMID:17301228]. The DDB1 scaffold is co-opted by viral proteins—paramyxovirus SV5-V, HBV HBx, and HIV-1 Vpr—to redirect CRL4 against host factors such as STAT1, Smc5/6, and UNG2 [PMID:16413485, PMID:27571178, PMID:12388698, PMID:15767425], and it is exploited pharmacologically by IMiD molecular glues acting through the DCAF CRBN and by molecular glues and covalent recruiters that engage DDB1 directly for targeted protein degradation [PMID:25043012, PMID:32804079, PMID:38192078].","teleology":[{"year":2002,"claim":"Established that DDB1 is functionally required for a viral protein to reprogram host protein degradation, the first hint that DDB1 serves as an adaptor for ubiquitin-mediated turnover.","evidence":"V protein mutagenesis and siRNA depletion of DDB1 with IFN-signaling and STAT1 degradation readouts","pmids":["12388698"],"confidence":"Medium","gaps":["Did not define the cullin/ligase machinery DDB1 recruits","DDB1's endogenous cellular substrates unaddressed"]},{"year":2004,"claim":"Defined DDB1 as the adaptor bridging an endogenous substrate (CDT1) to the CUL4A scaffold, establishing its core role in a cellular E3 ligase.","evidence":"Reciprocal co-IP, in vitro binding and ubiquitination reconstitution, and siRNA knockdown in human cells","pmids":["15448697"],"confidence":"High","gaps":["How DDB1 recognizes diverse substrates beyond CDT1 unknown","No structural basis for adaptor function"]},{"year":2006,"claim":"Resolved the three-propeller architecture of DDB1 and demonstrated a division of labor—BPC binds CUL4A while the BPA-BPB pocket receives substrate receptors—explaining how DDB1 functions as a modular adaptor and how viral helices hijack it.","evidence":"X-ray crystallography of apo DDB1 and DDB1-CUL4A-ROC1 complexes with SV5-V; TAP-MS of DDB1/CUL4A complexes","pmids":["16413485","16964240"],"confidence":"High","gaps":["Conformational dynamics of BPC docking during catalysis not resolved","Full DCAF repertoire not yet enumerated"]},{"year":2006,"claim":"Systematically identified the DCAF/DWD family and the conserved WDxR/DWD-box motif as the universal substrate-receptor interface, explaining how one adaptor generates a combinatorial ligase family.","evidence":"Mass-spectrometry proteomics, yeast two-hybrid, and motif mutagenesis identifying ~15-18 DDB1-CUL4-associated WD40 factors","pmids":["17079684","16949367"],"confidence":"High","gaps":["Substrate of most DCAFs unassigned at the time","Rules governing receptor exchange on DDB1 unknown"]},{"year":2006,"claim":"Established the genome-maintenance logic of CRL4^DDB1: PCNA-coupled CDT2 degradation of CDT1 prevents re-replication, with DDB1 loss causing checkpoint activation and DNA breaks.","evidence":"siRNA knockdown, Xenopus extract reconstitution, mutational dissection of CDT1 degrons, and γH2AX/epistasis assays","pmids":["16949367","16482215","16407242","16940174","16861906"],"confidence":"High","gaps":["Distinction between SCF-Skp2 and CRL4 redundancy in vivo incompletely mapped","PCNA-degron coupling mechanism still being refined"]},{"year":2006,"claim":"Defined DDB1's role in nucleotide excision repair, scaffolding the damage sensor DDB2 to UV lesions and enabling histone H2A monoubiquitination at damaged chromatin.","evidence":"In vitro damaged-DNA binding with purified DDB1-DDB2, endogenous complex biochemistry in UV-irradiated/XP-E cells, fractionation and repair assays","pmids":["16223728","16473935","16951172"],"confidence":"High","gaps":["Whether H2A ubiquitination directly drives repair versus chromatin remodeling unresolved","CPD-versus-6-4PP repair specificity mechanism unclear"]},{"year":2006,"claim":"Demonstrated that CRL4^DDB1 reaches beyond degradation into chromatin regulation by engaging histone methylation machinery (WDR5, EED) and influencing H3K4/H3K27 methylation.","evidence":"Co-IP, siRNA knockdown with methylation readouts, and methylated-nucleosome pull-down","pmids":["17041588"],"confidence":"Medium","gaps":["Direct ubiquitination substrate within the methylation complexes not defined","Single-lab evidence"]},{"year":2008,"claim":"Showed the structural element used by cellular DCAFs is mimicked by HBV HBx, unifying viral and host assembly of CRL4 complexes and explaining HBx-dependent viral replication.","evidence":"X-ray crystallography of DDB1-HBx with structure-based mutagenesis; HBx point-mutant complementation and RNAi in HBV replication assays","pmids":["19966799","15767425"],"confidence":"High","gaps":["Identity of the host substrate degraded by HBx-DDB1 not defined here","Mechanism linking degradation to replication enhancement incomplete"]},{"year":2008,"claim":"Extended the substrate repertoire of CRL4^DDB1 to growth and tumor-suppressor pathways through specific DCAFs (FBW5→TSC2, VprBP→Merlin), linking DDB1 to mTOR and ERK/Rac signaling.","evidence":"Co-IP, in vitro/in vivo ubiquitination, siRNA, and Drosophila genetics","pmids":["18381890","18332868"],"confidence":"High","gaps":["Physiological signals triggering these degradation events partly defined","In vivo contribution to tumor suppression untested"]},{"year":2007,"claim":"Established HIV-1 Vpr as a DDB1-CUL4 hijacker acting through DCAF1/VprBP to drive G2 arrest and degrade host factors, generalizing viral exploitation of the scaffold.","evidence":"TAP-MS, reciprocal co-IP, siRNA epistasis, proteasome inhibition, and cell-cycle/apoptosis assays across multiple labs","pmids":["17626091","17314515","17609381","17630831","17620334","17360488"],"confidence":"High","gaps":["Full set of Vpr-redirected substrates not exhausted"]},{"year":2006,"claim":"Genetic ablation in mouse tissues established the in vivo physiological requirement for DDB1 in proliferating cells, where its loss causes cell-cycle regulator accumulation, genomic instability, and p53-driven apoptosis.","evidence":"Conditional knockout in brain, lens, and epidermis with histology, marker analysis, and p53 genetic epistasis","pmids":["17129780","17301228"],"confidence":"High","gaps":["Which specific substrate accumulation is primary driver of apoptosis not pinpointed","Tissue-specific differences in critical substrates unresolved"]},{"year":2009,"claim":"Identified CHK1 as a CRL4^DDB1 target, embedding DDB1 in a DNA-damage-response feedback circuit where activated CHK1 is downregulated and USP1 opposes this turnover.","evidence":"Co-IP, in vitro ubiquitination, siRNA, and stability assays; USP1 epistasis under genotoxic stress","pmids":["19276361","21389083"],"confidence":"High","gaps":["Identity of the CHK1-specific DCAF not defined","Quantitative impact on checkpoint timing unclear"]},{"year":2013,"claim":"Expanded CRL4^DDB1 function into circadian, metabolic, and telomere regulation, and showed it can modulate activity (monoubiquitination) rather than only trigger degradation.","evidence":"In vitro/in vivo ubiquitination, site mutagenesis, circadian reporters, conditional mouse models, and kinase assays linking DDB1 to CRY1, raptor, TERT and FOXO1/gluconeogenesis","pmids":["23297343","23362280","26431207","28790135"],"confidence":"Medium","gaps":["Several substrate links rest on single-lab evidence","Crosstalk between these pathways in vivo not integrated"]},{"year":2014,"claim":"Revealed how small molecules exploit the DDB1 scaffold: IMiDs binding the DCAF CRBN reprogram substrate specificity, simultaneously recruiting neo-substrates (IKZF1/3) and blocking endogenous ones.","evidence":"X-ray crystallography of DDB1-CRBN with three IMiDs, unbiased substrate screen, mutagenesis, and ubiquitination assays in myeloma models","pmids":["25043012","25108355"],"confidence":"High","gaps":["Generality of glue-induced neo-substrate recruitment beyond CRBN not yet shown here"]},{"year":2020,"claim":"Demonstrated that molecular glues and covalent recruiters can engage DDB1 directly, bypassing DCAF receptors to create neo-substrate ligases, validating DDB1 itself as a targeted-degradation platform.","evidence":"HTS, genetic screens, and biochemical reconstitution for HQ461/CDK12-CCNK; cysteine chemoproteomics identifying DDB1 C173 recruiter used to build BRD4/AR PROTACs","pmids":["32804079","38192078"],"confidence":"High","gaps":["Structural basis of direct DDB1-glue neo-substrate ternary complexes not fully resolved","Selectivity and in vivo efficacy of DDB1 recruiters early-stage"]},{"year":null,"claim":"It remains unresolved how DDB1 dynamically selects among its many competing DCAF receptors and how this exchange is regulated by post-translational modification across distinct cellular states.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No quantitative model of DCAF competition for the BPA-BPB pocket","Regulatory roles of DDB1 phosphorylation/acetylation only sketched (e.g. SIRT7, PKA in Drosophila)","Substrate priority during simultaneous demands of replication, repair, and signaling unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,7,8,9]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[7,10,19,25]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[2,15]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[16,36]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[14,30]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[2,10,12,14]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[7]}],"pathway":[{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[2,10,12,15]},{"term_id":"R-HSA-69306","term_label":"DNA Replication","supporting_discovery_ids":[7,9,16,13]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[13,18,19,30]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[1,7,8,9]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[10,11,40]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[21,23,32,49]},{"term_id":"R-HSA-9909396","term_label":"Circadian clock","supporting_discovery_ids":[35,36,37]}],"complexes":["CUL4A-RBX1-DDB1 (CRL4) E3 ubiquitin ligase","CUL4B-DDB1-DCAF1 E3 ubiquitin ligase","DDB1-DDB2 (UV-DDB) complex","EDD-DDB1-VprBP E3 ligase"],"partners":["CUL4A","DDB2","DCAF1/VPRBP","DCAF2/CDT2","CRBN","FBW5","CDT1","RBX1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q16531","full_name":"DNA damage-binding protein 1","aliases":["DDB p127 subunit","DNA damage-binding protein a","DDBa","Damage-specific DNA-binding protein 1","HBV X-associated protein 1","XAP-1","UV-damaged DNA-binding factor","UV-damaged DNA-binding protein 1","UV-DDB 1","XPE-binding factor","XPE-BF","Xeroderma pigmentosum group E-complementing protein","XPCe"],"length_aa":1140,"mass_kda":127.0,"function":"Protein, which is both involved in DNA repair and protein ubiquitination, as part of the UV-DDB complex and DCX (DDB1-CUL4-X-box) complexes, respectively (PubMed:14739464, PubMed:15448697, PubMed:16260596, PubMed:16407242, PubMed:16407252, PubMed:16482215, PubMed:16940174, PubMed:17079684, PubMed:25970626). Core component of the UV-DDB complex (UV-damaged DNA-binding protein complex), a complex that recognizes UV-induced DNA damage and recruit proteins of the nucleotide excision repair pathway (the NER pathway) to initiate DNA repair (PubMed:15448697, PubMed:16260596, PubMed:16407242, PubMed:16940174). The UV-DDB complex preferentially binds to cyclobutane pyrimidine dimers (CPD), 6-4 photoproducts (6-4 PP), apurinic sites and short mismatches (PubMed:15448697, PubMed:16260596, PubMed:16407242, PubMed:16940174). Also functions as a component of numerous distinct DCX (DDB1-CUL4-X-box) E3 ubiquitin-protein ligase complexes which mediate the ubiquitination and subsequent proteasomal degradation of target proteins (PubMed:14739464, PubMed:16407252, PubMed:16482215, PubMed:17079684, PubMed:18332868, PubMed:18381890, PubMed:19966799, PubMed:22118460, PubMed:25043012, PubMed:25108355, PubMed:28886238). The functional specificity of the DCX E3 ubiquitin-protein ligase complex is determined by the variable substrate recognition component recruited by DDB1 (PubMed:14739464, PubMed:16407252, PubMed:16482215, PubMed:17079684, PubMed:18332868, PubMed:18381890, PubMed:19966799, PubMed:22118460, PubMed:25043012, PubMed:25108355). DCX(DDB2) (also known as DDB1-CUL4-ROC1, CUL4-DDB-ROC1 and CUL4-DDB-RBX1) may ubiquitinate histone H2A, histone H3 and histone H4 at sites of UV-induced DNA damage (PubMed:16473935, PubMed:16678110, PubMed:17041588, PubMed:18593899). The ubiquitination of histones may facilitate their removal from the nucleosome and promote subsequent DNA repair (PubMed:16473935, PubMed:16678110, PubMed:17041588, PubMed:18593899). DCX(DDB2) also ubiquitinates XPC, which may enhance DNA-binding by XPC and promote NER (PubMed:15882621). DCX(DTL) plays a role in PCNA-dependent polyubiquitination of CDT1 and MDM2-dependent ubiquitination of TP53 in response to radiation-induced DNA damage and during DNA replication (PubMed:17041588). DCX(ERCC8) (the CSA complex) plays a role in transcription-coupled repair (TCR) (PubMed:12732143, PubMed:32355176, PubMed:38316879). The DDB1-CUL4A-DTL E3 ligase complex regulates the circadian clock function by mediating the ubiquitination and degradation of CRY1 (PubMed:26431207). DDB1-mediated CRY1 degradation promotes FOXO1 protein stability and FOXO1-mediated gluconeogenesis in the liver (By similarity). By acting on TET dioxygenses, essential for oocyte maintenance at the primordial follicle stage, hence essential for female fertility (By similarity). Maternal factor required for proper zygotic genome activation and genome reprogramming (By similarity)","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q16531/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/DDB1","classification":"Common Essential","n_dependent_lines":1208,"n_total_lines":1208,"dependency_fraction":1.0},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000167986","cell_line_id":"CID001048","localizations":[{"compartment":"nucleoplasm","grade":3},{"compartment":"cytoplasmic","grade":1}],"interactors":[{"gene":"RBX1","stoichiometry":10.0},{"gene":"NUCKS1","stoichiometry":10.0},{"gene":"COPS6","stoichiometry":4.0},{"gene":"DCAF11","stoichiometry":4.0},{"gene":"COPS7A","stoichiometry":4.0},{"gene":"COPS4","stoichiometry":4.0},{"gene":"COPS2","stoichiometry":4.0},{"gene":"SUB1","stoichiometry":4.0},{"gene":"CUL4B","stoichiometry":4.0},{"gene":"MIF","stoichiometry":4.0}],"url":"https://opencell.sf.czbiohub.org/target/CID001048","total_profiled":1310},"omim":[{"mim_id":"620524","title":"DDB1- AND CUL4-ASSOCIATED FACTOR 16; DCAF16","url":"https://www.omim.org/entry/620524"},{"mim_id":"620421","title":"DDB1- AND CUL4-ASSOCIATED FACTOR 4-LIKE 2; DCAF4L2","url":"https://www.omim.org/entry/620421"},{"mim_id":"620295","title":"DDB1- AND CUL4-ASSOCIATED FACTOR 10; DCAF10","url":"https://www.omim.org/entry/620295"},{"mim_id":"620224","title":"NEURODEVELOPMENTAL DISORDER WITH HYPOTONIA, DYSMORPHIC FACIES, AND SKELETAL ANOMALIES, WITH OR WITHOUT SEIZURES; NEDFSS","url":"https://www.omim.org/entry/620224"},{"mim_id":"620109","title":"DDB1- AND CUL4-ASSOCIATED FACTOR 15; DCAF15","url":"https://www.omim.org/entry/620109"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"},{"location":"Mid piece","reliability":"Additional"},{"location":"Principal piece","reliability":"Additional"},{"location":"End piece","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/DDB1"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q16531","domains":[{"cath_id":"2.130.10.10","chopping":"108-249","consensus_level":"medium","plddt":94.5068,"start":108,"end":249},{"cath_id":"2.130.10.10","chopping":"396-706","consensus_level":"high","plddt":91.8654,"start":396,"end":706},{"cath_id":"2.130.10.10","chopping":"720-766_783-1008","consensus_level":"medium","plddt":94.4837,"start":720,"end":1008},{"cath_id":"1.10.150.910","chopping":"1045-1136","consensus_level":"high","plddt":88.3025,"start":1045,"end":1136},{"cath_id":"2.40.128","chopping":"17-105","consensus_level":"medium","plddt":93.6783,"start":17,"end":105}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q16531","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q16531-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q16531-F1-predicted_aligned_error_v6.png","plddt_mean":92.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DDB1","jax_strain_url":"https://www.jax.org/strain/search?query=DDB1"},"sequence":{"accession":"Q16531","fasta_url":"https://rest.uniprot.org/uniprotkb/Q16531.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q16531/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q16531"}},"corpus_meta":[{"pmid":"25043012","id":"PMC_25043012","title":"Structure of the DDB1-CRBN E3 ubiquitin ligase in complex with thalidomide.","date":"2014","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/25043012","citation_count":870,"is_preprint":false},{"pmid":"16964240","id":"PMC_16964240","title":"Molecular architecture and assembly of the DDB1-CUL4A ubiquitin ligase machinery.","date":"2006","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/16964240","citation_count":586,"is_preprint":false},{"pmid":"16949367","id":"PMC_16949367","title":"A family of diverse Cul4-Ddb1-interacting proteins includes Cdt2, which is required for S phase destruction of the replication factor Cdt1.","date":"2006","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/16949367","citation_count":540,"is_preprint":false},{"pmid":"25108355","id":"PMC_25108355","title":"Structure of the human Cereblon-DDB1-lenalidomide complex reveals basis for responsiveness to thalidomide analogs.","date":"2014","source":"Nature structural & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/25108355","citation_count":420,"is_preprint":false},{"pmid":"17588513","id":"PMC_17588513","title":"DCAFs, the missing link of the CUL4-DDB1 ubiquitin ligase.","date":"2007","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/17588513","citation_count":399,"is_preprint":false},{"pmid":"17041588","id":"PMC_17041588","title":"CUL4-DDB1 ubiquitin ligase interacts with multiple WD40-repeat proteins and regulates histone methylation.","date":"2006","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/17041588","citation_count":373,"is_preprint":false},{"pmid":"19109893","id":"PMC_19109893","title":"Structural basis of UV DNA-damage recognition by the DDB1-DDB2 complex.","date":"2008","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/19109893","citation_count":353,"is_preprint":false},{"pmid":"16482215","id":"PMC_16482215","title":"Two E3 ubiquitin ligases, SCF-Skp2 and DDB1-Cul4, target human Cdt1 for proteolysis.","date":"2006","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/16482215","citation_count":328,"is_preprint":false},{"pmid":"15448697","id":"PMC_15448697","title":"Targeted ubiquitination of CDT1 by the DDB1-CUL4A-ROC1 ligase in response to DNA damage.","date":"2004","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/15448697","citation_count":316,"is_preprint":false},{"pmid":"17079684","id":"PMC_17079684","title":"DDB1 functions as a linker to recruit receptor WD40 proteins to CUL4-ROC1 ubiquitin ligases.","date":"2006","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/17079684","citation_count":288,"is_preprint":false},{"pmid":"16473935","id":"PMC_16473935","title":"The DDB1-CUL4ADDB2 ubiquitin ligase is deficient in xeroderma pigmentosum group E and targets histone H2A at UV-damaged DNA sites.","date":"2006","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/16473935","citation_count":274,"is_preprint":false},{"pmid":"17314515","id":"PMC_17314515","title":"HIV1 Vpr arrests the cell cycle by recruiting DCAF1/VprBP, a receptor of the Cul4-DDB1 ubiquitin ligase.","date":"2007","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/17314515","citation_count":227,"is_preprint":false},{"pmid":"16413485","id":"PMC_16413485","title":"Structure of DDB1 in complex with a paramyxovirus V protein: viral hijack of a propeller cluster in ubiquitin ligase.","date":"2006","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/16413485","citation_count":221,"is_preprint":false},{"pmid":"23063525","id":"PMC_23063525","title":"EZH2 generates a methyl degron that is recognized by the DCAF1/DDB1/CUL4 E3 ubiquitin ligase complex.","date":"2012","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/23063525","citation_count":208,"is_preprint":false},{"pmid":"16407252","id":"PMC_16407252","title":"PCNA is a cofactor for Cdt1 degradation by CUL4/DDB1-mediated N-terminal ubiquitination.","date":"2006","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16407252","citation_count":206,"is_preprint":false},{"pmid":"17609381","id":"PMC_17609381","title":"Lentiviral Vpr usurps Cul4-DDB1[VprBP] E3 ubiquitin ligase to modulate cell cycle.","date":"2007","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/17609381","citation_count":204,"is_preprint":false},{"pmid":"19966799","id":"PMC_19966799","title":"A promiscuous alpha-helical motif anchors viral hijackers and substrate receptors to the CUL4-DDB1 ubiquitin ligase machinery.","date":"2009","source":"Nature structural & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/19966799","citation_count":189,"is_preprint":false},{"pmid":"17360488","id":"PMC_17360488","title":"HIV-1 Vpr function is mediated by interaction with the damage-specific DNA-binding protein DDB1.","date":"2007","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/17360488","citation_count":167,"is_preprint":false},{"pmid":"19273594","id":"PMC_19273594","title":"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.","date":"2009","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/19273594","citation_count":167,"is_preprint":false},{"pmid":"32804079","id":"PMC_32804079","title":"Discovery of a molecular glue promoting CDK12-DDB1 interaction to trigger cyclin K degradation.","date":"2020","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/32804079","citation_count":166,"is_preprint":false},{"pmid":"17630831","id":"PMC_17630831","title":"HIV-1 Vpr-mediated G2 arrest involves the DDB1-CUL4AVPRBP E3 ubiquitin ligase.","date":"2007","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/17630831","citation_count":166,"is_preprint":false},{"pmid":"18451984","id":"PMC_18451984","title":"Primate lentiviral Vpx commandeers DDB1 to counteract a macrophage restriction.","date":"2008","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/18451984","citation_count":159,"is_preprint":false},{"pmid":"16861906","id":"PMC_16861906","title":"L2DTL/CDT2 interacts with the CUL4/DDB1 complex and PCNA and regulates CDT1 proteolysis in response to DNA damage.","date":"2006","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/16861906","citation_count":153,"is_preprint":false},{"pmid":"18381890","id":"PMC_18381890","title":"WD40 protein FBW5 promotes ubiquitination of tumor suppressor TSC2 by DDB1-CUL4-ROC1 ligase.","date":"2008","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/18381890","citation_count":142,"is_preprint":false},{"pmid":"15767425","id":"PMC_15767425","title":"Hepatitis B virus X protein stimulates viral genome replication via a DDB1-dependent pathway distinct from that leading to cell death.","date":"2005","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/15767425","citation_count":139,"is_preprint":false},{"pmid":"17620334","id":"PMC_17620334","title":"The HIV1 protein Vpr acts to promote G2 cell cycle arrest by engaging a DDB1 and Cullin4A-containing ubiquitin ligase complex using VprBP/DCAF1 as an adaptor.","date":"2007","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17620334","citation_count":137,"is_preprint":false},{"pmid":"8530102","id":"PMC_8530102","title":"Chromosomal localization and cDNA cloning of the genes (DDB1 and DDB2) for the p127 and p48 subunits of a human damage-specific DNA binding protein.","date":"1995","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/8530102","citation_count":135,"is_preprint":false},{"pmid":"17129780","id":"PMC_17129780","title":"Deletion of DDB1 in mouse brain and lens leads to p53-dependent elimination of proliferating cells.","date":"2006","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/17129780","citation_count":134,"is_preprint":false},{"pmid":"16223728","id":"PMC_16223728","title":"DDB1-DDB2 (xeroderma pigmentosum group E) protein complex recognizes a cyclobutane pyrimidine dimer, mismatches, apurinic/apyrimidinic sites, and compound lesions in DNA.","date":"2005","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16223728","citation_count":129,"is_preprint":false},{"pmid":"16861890","id":"PMC_16861890","title":"L2DTL/CDT2 and PCNA interact with p53 and regulate p53 polyubiquitination and protein stability through MDM2 and CUL4A/DDB1 complexes.","date":"2006","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/16861890","citation_count":114,"is_preprint":false},{"pmid":"19276361","id":"PMC_19276361","title":"DDB1 targets Chk1 to the Cul4 E3 ligase complex in normal cycling cells and in cells experiencing replication stress.","date":"2009","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/19276361","citation_count":110,"is_preprint":false},{"pmid":"17626091","id":"PMC_17626091","title":"DDB1 and Cul4A are required for human immunodeficiency virus type 1 Vpr-induced G2 arrest.","date":"2007","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/17626091","citation_count":109,"is_preprint":false},{"pmid":"17280619","id":"PMC_17280619","title":"Stealing the spotlight: CUL4-DDB1 ubiquitin ligase docks WD40-repeat proteins to destroy.","date":"2007","source":"Cell division","url":"https://pubmed.ncbi.nlm.nih.gov/17280619","citation_count":105,"is_preprint":false},{"pmid":"30704981","id":"PMC_30704981","title":"Inhibition of HBV Transcription From cccDNA With Nitazoxanide by Targeting the HBx-DDB1 Interaction.","date":"2018","source":"Cellular and molecular gastroenterology and hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/30704981","citation_count":101,"is_preprint":false},{"pmid":"16407242","id":"PMC_16407242","title":"An evolutionarily conserved function of proliferating cell nuclear antigen for Cdt1 degradation by the Cul4-Ddb1 ubiquitin ligase in response to DNA damage.","date":"2006","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16407242","citation_count":99,"is_preprint":false},{"pmid":"21959250","id":"PMC_21959250","title":"Damage-specific DNA binding protein 1 (DDB1): a protein with a wide range of functions.","date":"2011","source":"The international journal of biochemistry & cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/21959250","citation_count":97,"is_preprint":false},{"pmid":"16227264","id":"PMC_16227264","title":"Simian virus 5 V protein acts as an adaptor, linking DDB1 to STAT2, to facilitate the ubiquitination of STAT1.","date":"2005","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/16227264","citation_count":97,"is_preprint":false},{"pmid":"12388698","id":"PMC_12388698","title":"The p127 subunit (DDB1) of the UV-DNA damage repair binding protein is essential for the targeted degradation of STAT1 by the V protein of the paramyxovirus simian virus 5.","date":"2002","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/12388698","citation_count":96,"is_preprint":false},{"pmid":"16537899","id":"PMC_16537899","title":"Cul4A and DDB1 associate with Skp2 to target p27Kip1 for proteolysis involving the COP9 signalosome.","date":"2006","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/16537899","citation_count":95,"is_preprint":false},{"pmid":"34720086","id":"PMC_34720086","title":"Cul4A-DDB1-mediated monoubiquitination of phosphoglycerate dehydrogenase promotes colorectal cancer metastasis via increased S-adenosylmethionine.","date":"2021","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/34720086","citation_count":88,"is_preprint":false},{"pmid":"18704118","id":"PMC_18704118","title":"Rtt101 and Mms1 in budding yeast form a CUL4(DDB1)-like ubiquitin ligase that promotes replication through damaged DNA.","date":"2008","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/18704118","citation_count":86,"is_preprint":false},{"pmid":"16951172","id":"PMC_16951172","title":"DNA damage binding protein component DDB1 participates in nucleotide excision repair through DDB2 DNA-binding and cullin 4A ubiquitin ligase activity.","date":"2006","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/16951172","citation_count":85,"is_preprint":false},{"pmid":"15805471","id":"PMC_15805471","title":"Ddb1 controls genome stability and meiosis in fission yeast.","date":"2005","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/15805471","citation_count":84,"is_preprint":false},{"pmid":"18363785","id":"PMC_18363785","title":"Altered plastid levels and potential for improved fruit nutrient content by downregulation of the tomato DDB1-interacting protein CUL4.","date":"2008","source":"The Plant journal : for cell and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/18363785","citation_count":83,"is_preprint":false},{"pmid":"16252005","id":"PMC_16252005","title":"Transactivation of Schizosaccharomyces pombe cdt2+ stimulates a Pcu4-Ddb1-CSN ubiquitin ligase.","date":"2005","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/16252005","citation_count":83,"is_preprint":false},{"pmid":"27571178","id":"PMC_27571178","title":"The DDB1-DCAF1-Vpr-UNG2 crystal structure reveals how HIV-1 Vpr steers human UNG2 toward destruction.","date":"2016","source":"Nature structural & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/27571178","citation_count":82,"is_preprint":false},{"pmid":"16940174","id":"PMC_16940174","title":"DDB1 maintains genome integrity through regulation of Cdt1.","date":"2006","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/16940174","citation_count":79,"is_preprint":false},{"pmid":"17039252","id":"PMC_17039252","title":"DNA damage induces Cdt1 proteolysis in fission yeast through a pathway dependent on Cdt2 and Ddb1.","date":"2006","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/17039252","citation_count":78,"is_preprint":false},{"pmid":"18606781","id":"PMC_18606781","title":"Human immunodeficiency virus type 1 Vpr-binding protein VprBP, a WD40 protein associated with the DDB1-CUL4 E3 ubiquitin ligase, is essential for DNA replication and embryonic development.","date":"2008","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/18606781","citation_count":78,"is_preprint":false},{"pmid":"22342275","id":"PMC_22342275","title":"Hepatitis B virus regulatory HBx protein binding to DDB1 is required but is not sufficient for maximal HBV replication.","date":"2012","source":"Virology","url":"https://pubmed.ncbi.nlm.nih.gov/22342275","citation_count":75,"is_preprint":false},{"pmid":"14968305","id":"PMC_14968305","title":"The tomato homolog of the gene encoding UV-damaged DNA binding protein 1 (DDB1) underlined as the gene that causes the high pigment-1 mutant phenotype.","date":"2004","source":"TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik","url":"https://pubmed.ncbi.nlm.nih.gov/14968305","citation_count":70,"is_preprint":false},{"pmid":"23297343","id":"PMC_23297343","title":"Ubiquitin hydrolase UCH-L1 destabilizes mTOR complex 1 by antagonizing DDB1-CUL4-mediated ubiquitination of raptor.","date":"2013","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/23297343","citation_count":68,"is_preprint":false},{"pmid":"19208841","id":"PMC_19208841","title":"DDB1-CUL4 and MLL1 mediate oncogene-induced p16INK4a activation.","date":"2009","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/19208841","citation_count":63,"is_preprint":false},{"pmid":"26352615","id":"PMC_26352615","title":"Ubiquitin-conjugated degradation of golden 2-like transcription factor is mediated by CUL4-DDB1-based E3 ligase complex in tomato.","date":"2015","source":"The New phytologist","url":"https://pubmed.ncbi.nlm.nih.gov/26352615","citation_count":63,"is_preprint":false},{"pmid":"23479607","id":"PMC_23479607","title":"Ramshackle (Brwd3) promotes light-induced ubiquitylation of Drosophila Cryptochrome by DDB1-CUL4-ROC1 E3 ligase complex.","date":"2013","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/23479607","citation_count":63,"is_preprint":false},{"pmid":"23362280","id":"PMC_23362280","title":"Dyrk2-associated EDD-DDB1-VprBP E3 ligase inhibits telomerase by TERT degradation.","date":"2013","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23362280","citation_count":61,"is_preprint":false},{"pmid":"18235224","id":"PMC_18235224","title":"mTORC1 signaling requires proteasomal function and the involvement of CUL4-DDB1 ubiquitin E3 ligase.","date":"2007","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/18235224","citation_count":60,"is_preprint":false},{"pmid":"18332868","id":"PMC_18332868","title":"VprBP targets Merlin to the Roc1-Cul4A-DDB1 E3 ligase complex for degradation.","date":"2008","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/18332868","citation_count":58,"is_preprint":false},{"pmid":"17301228","id":"PMC_17301228","title":"DDB1 is essential for genomic stability in developing epidermis.","date":"2007","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/17301228","citation_count":56,"is_preprint":false},{"pmid":"23062609","id":"PMC_23062609","title":"Lentivirus Vpr and Vpx accessory proteins usurp the cullin4-DDB1 (DCAF1) E3 ubiquitin ligase.","date":"2012","source":"Current opinion in virology","url":"https://pubmed.ncbi.nlm.nih.gov/23062609","citation_count":56,"is_preprint":false},{"pmid":"21389083","id":"PMC_21389083","title":"USP1 deubiquitinase maintains phosphorylated CHK1 by limiting its DDB1-dependent degradation.","date":"2011","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/21389083","citation_count":56,"is_preprint":false},{"pmid":"12151405","id":"PMC_12151405","title":"Hepatitis B virus X protein associated with UV-DDB1 induces cell death in the nucleus and is functionally antagonized by UV-DDB2.","date":"2002","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12151405","citation_count":56,"is_preprint":false},{"pmid":"26021757","id":"PMC_26021757","title":"The Cullin 4A/B-DDB1-Cereblon E3 Ubiquitin Ligase Complex Mediates the Degradation of CLC-1 Chloride Channels.","date":"2015","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/26021757","citation_count":56,"is_preprint":false},{"pmid":"19948733","id":"PMC_19948733","title":"Ubiquitin ligase components Cullin4 and DDB1 are essential for DNA methylation in Neurospora crassa.","date":"2009","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19948733","citation_count":55,"is_preprint":false},{"pmid":"28242748","id":"PMC_28242748","title":"Cep78 controls centrosome homeostasis by inhibiting EDD-DYRK2-DDB1VprBP.","date":"2017","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/28242748","citation_count":48,"is_preprint":false},{"pmid":"26032416","id":"PMC_26032416","title":"HIV-1 Vpr Protein Enhances Proteasomal Degradation of MCM10 DNA Replication Factor through the Cul4-DDB1[VprBP] E3 Ubiquitin Ligase to Induce G2/M Cell Cycle Arrest.","date":"2015","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/26032416","citation_count":48,"is_preprint":false},{"pmid":"21123655","id":"PMC_21123655","title":"Break-induced ATR and Ddb1-Cul4(Cdt)² ubiquitin ligase-dependent nucleotide synthesis promotes homologous recombination repair in fission yeast.","date":"2010","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/21123655","citation_count":45,"is_preprint":false},{"pmid":"12743284","id":"PMC_12743284","title":"Hepatitis B virus X protein and simian virus 5 V protein exhibit similar UV-DDB1 binding properties to mediate distinct activities.","date":"2003","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/12743284","citation_count":42,"is_preprint":false},{"pmid":"14701809","id":"PMC_14701809","title":"Ddb1 is required for the proteolysis of the Schizosaccharomyces pombe replication inhibitor Spd1 during S phase and after DNA damage.","date":"2003","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/14701809","citation_count":42,"is_preprint":false},{"pmid":"23612978","id":"PMC_23612978","title":"HIV-1 Vpr protein inhibits telomerase activity via the EDD-DDB1-VPRBP E3 ligase complex.","date":"2013","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23612978","citation_count":42,"is_preprint":false},{"pmid":"21135245","id":"PMC_21135245","title":"Hepatocyte-specific deletion of DDB1 induces liver regeneration and tumorigenesis.","date":"2010","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/21135245","citation_count":41,"is_preprint":false},{"pmid":"22570418","id":"PMC_22570418","title":"CRL4-DDB1-VPRBP ubiquitin ligase mediates the stress triggered proteolysis of Mcm10.","date":"2012","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/22570418","citation_count":41,"is_preprint":false},{"pmid":"36103833","id":"PMC_36103833","title":"Identification of CUL4A-DDB1-WDFY1 as an E3 ubiquitin ligase complex involved in initiation of lysophagy.","date":"2022","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/36103833","citation_count":40,"is_preprint":false},{"pmid":"12527763","id":"PMC_12527763","title":"Basal transcriptional regulation of human damage-specific DNA-binding protein genes DDB1 and DDB2 by Sp1, E2F, N-myc and NF1 elements.","date":"2003","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/12527763","citation_count":39,"is_preprint":false},{"pmid":"38192078","id":"PMC_38192078","title":"Targeted Protein Degradation through Recruitment of the CUL4 Complex Adaptor Protein DDB1.","date":"2024","source":"ACS chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/38192078","citation_count":38,"is_preprint":false},{"pmid":"26613412","id":"PMC_26613412","title":"The CUL4-DDB1 ubiquitin ligase complex controls adult and embryonic stem cell differentiation and homeostasis.","date":"2015","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/26613412","citation_count":36,"is_preprint":false},{"pmid":"34373747","id":"PMC_34373747","title":"HBx represses WDR77 to enhance HBV replication by DDB1-mediated WDR77 degradation in the liver.","date":"2021","source":"Theranostics","url":"https://pubmed.ncbi.nlm.nih.gov/34373747","citation_count":32,"is_preprint":false},{"pmid":"12181326","id":"PMC_12181326","title":"Characterization of a Schizosaccharomyces pombe strain deleted for a sequence homologue of the human damaged DNA binding 1 (DDB1) gene.","date":"2002","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12181326","citation_count":32,"is_preprint":false},{"pmid":"30598533","id":"PMC_30598533","title":"Algal photoprotection is regulated by the E3 ligase CUL4-DDB1DET1.","date":"2018","source":"Nature plants","url":"https://pubmed.ncbi.nlm.nih.gov/30598533","citation_count":31,"is_preprint":false},{"pmid":"18936169","id":"PMC_18936169","title":"Cellular concentrations of DDB2 regulate dynamic binding of DDB1 at UV-induced DNA damage.","date":"2008","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/18936169","citation_count":31,"is_preprint":false},{"pmid":"32235678","id":"PMC_32235678","title":"Hepatitis B Virus HBx Protein Mediates the Degradation of Host Restriction Factors through the Cullin 4 DDB1 E3 Ubiquitin Ligase Complex.","date":"2020","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/32235678","citation_count":31,"is_preprint":false},{"pmid":"30100344","id":"PMC_30100344","title":"Temporal Regulation of ESCO2 Degradation by the MCM Complex, the CUL4-DDB1-VPRBP Complex, and the Anaphase-Promoting Complex.","date":"2018","source":"Current biology : CB","url":"https://pubmed.ncbi.nlm.nih.gov/30100344","citation_count":30,"is_preprint":false},{"pmid":"20347598","id":"PMC_20347598","title":"The functions of the HIV1 protein Vpr and its action through the DCAF1.DDB1.Cullin4 ubiquitin ligase.","date":"2010","source":"Cytokine","url":"https://pubmed.ncbi.nlm.nih.gov/20347598","citation_count":29,"is_preprint":false},{"pmid":"32075763","id":"PMC_32075763","title":"The Human Cytomegalovirus pUL145 Isoforms Act as Viral DDB1-Cullin-Associated Factors to Instruct Host Protein Degradation to Impede Innate Immunity.","date":"2020","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/32075763","citation_count":29,"is_preprint":false},{"pmid":"28790135","id":"PMC_28790135","title":"DDB1-Mediated CRY1 Degradation Promotes FOXO1-Driven Gluconeogenesis in Liver.","date":"2017","source":"Diabetes","url":"https://pubmed.ncbi.nlm.nih.gov/28790135","citation_count":28,"is_preprint":false},{"pmid":"29930086","id":"PMC_29930086","title":"Regulation of Smoothened ubiquitylation and cell surface expression through a Cul4-DDB1-Gβ E3 ubiquitin ligase complex.","date":"2018","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/29930086","citation_count":28,"is_preprint":false},{"pmid":"25970626","id":"PMC_25970626","title":"FBXO44-Mediated Degradation of RGS2 Protein Uniquely Depends on a Cullin 4B/DDB1 Complex.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25970626","citation_count":28,"is_preprint":false},{"pmid":"27573245","id":"PMC_27573245","title":"Human DNA Ligase I Interacts with and Is Targeted for Degradation by the DCAF7 Specificity Factor of the Cul4-DDB1 Ubiquitin Ligase Complex.","date":"2016","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/27573245","citation_count":28,"is_preprint":false},{"pmid":"37679762","id":"PMC_37679762","title":"CUL4B-DDB1-COP1-mediated UTX downregulation promotes colorectal cancer progression.","date":"2023","source":"Experimental hematology & oncology","url":"https://pubmed.ncbi.nlm.nih.gov/37679762","citation_count":27,"is_preprint":false},{"pmid":"23085759","id":"PMC_23085759","title":"The Cul4A-DDB1 E3 ubiquitin ligase complex represses p73 transcriptional activity.","date":"2012","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/23085759","citation_count":27,"is_preprint":false},{"pmid":"28212551","id":"PMC_28212551","title":"NRIP/DCAF6 stabilizes the androgen receptor protein by displacing DDB2 from the CUL4A-DDB1 E3 ligase complex in prostate cancer.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/28212551","citation_count":26,"is_preprint":false},{"pmid":"22319459","id":"PMC_22319459","title":"Raf1 Is a DCAF for the Rik1 DDB1-like protein and has separable roles in siRNA generation and chromatin modification.","date":"2012","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/22319459","citation_count":26,"is_preprint":false},{"pmid":"28623141","id":"PMC_28623141","title":"Sirtuin 7-dependent deacetylation of DDB1 regulates the expression of nuclear receptor TR4.","date":"2017","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/28623141","citation_count":25,"is_preprint":false},{"pmid":"10713455","id":"PMC_10713455","title":"Studies of the murine DDB1 and DDB2 genes.","date":"2000","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/10713455","citation_count":25,"is_preprint":false},{"pmid":"10930665","id":"PMC_10930665","title":"Dissociation of DDB1-binding and transactivation properties of the hepatitis B virus X protein.","date":"2000","source":"Virus research","url":"https://pubmed.ncbi.nlm.nih.gov/10930665","citation_count":25,"is_preprint":false},{"pmid":"29907856","id":"PMC_29907856","title":"Deletion of DDB1- and CUL4- associated factor-17 (Dcaf17) gene causes spermatogenesis defects and male infertility in mice.","date":"2018","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/29907856","citation_count":24,"is_preprint":false},{"pmid":"27254819","id":"PMC_27254819","title":"DDB1 and CUL4 associated factor 11 (DCAF11) mediates degradation of Stem-loop binding protein at the end of S phase.","date":"2016","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/27254819","citation_count":23,"is_preprint":false},{"pmid":"29724823","id":"PMC_29724823","title":"HIV-1 Vpr hijacks EDD-DYRK2-DDB1DCAF1 to disrupt centrosome homeostasis.","date":"2018","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/29724823","citation_count":22,"is_preprint":false},{"pmid":"26431207","id":"PMC_26431207","title":"CUL4-DDB1-CDT2 E3 Ligase Regulates the Molecular Clock Activity by Promoting Ubiquitination-Dependent Degradation of the Mammalian CRY1.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/26431207","citation_count":22,"is_preprint":false},{"pmid":"35279029","id":"PMC_35279029","title":"Chlorogenic Acid Activates Nrf2/SKN-1 and Prolongs the Lifespan of Caenorhabditis elegans via the Akt-FOXO3/DAF16a-DDB1 Pathway and Activation of DAF16f.","date":"2022","source":"The journals of gerontology. Series A, Biological sciences and medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35279029","citation_count":21,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":47513,"output_tokens":12018,"usd":0.161405,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":22971,"output_tokens":5638,"usd":0.127903,"stage2_stop_reason":"end_turn"},"total_usd":0.289308,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2006,\n      \"finding\": \"Crystal structure of DDB1 reveals an intertwined three-propeller (BPA, BPB, BPC) architecture: two tightly coupled beta-propellers (BPA-BPB) form a double-propeller fold with a large pocket, while a third beta-propeller (BPC) is flexibly attached and docks DDB1 to the N-terminus of CUL4A. The SV5 V protein inserts a helix into the BPA-BPB double-propeller pocket to hijack the complex.\",\n      \"method\": \"X-ray crystallography of DDB1 alone and in complex with paramyxovirus SV5-V protein\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structures of apo and complex forms with functional validation, rigorous structural study\",\n      \"pmids\": [\"16413485\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"DDB1 uses its BPC beta-propeller domain for CUL4A scaffold binding and its BPA-BPB double-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 CUL4A-RBX1-DDB1 E3 ligase.\",\n      \"method\": \"X-ray crystallography of the virally-hijacked DDB1-CUL4A-ROC1 complex; tandem-affinity purification of DDB1/CUL4A complexes followed by mass spectrometry\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus proteomic validation, multiple orthogonal methods\",\n      \"pmids\": [\"16964240\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Crystal structures of the DDB1-DDB2 complex alone and bound to UV-damaged DNA (6-4PP or abasic site) show that the lesion is held exclusively by the WD40 domain of DDB2. A DDB2 hairpin inserts into the minor groove, extrudes the photodimer into a binding pocket, and kinks the duplex ~40°. DDB1 scaffolds DDB2 and the associated CUL4 ubiquitin ligase to damaged chromatin.\",\n      \"method\": \"X-ray crystallography of DDB1-DDB2 complex alone and with damaged DNA substrates\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple crystal structures with distinct DNA substrates, rigorous structural study\",\n      \"pmids\": [\"19109893\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Crystal structure of DDB1 in complex with hepatitis B virus X protein (HBx) reveals that HBx binds DDB1 through an alpha-helical motif that is also present in SV5-V protein and in cellular DCAFs, identifying a common structural element for assembly of CUL4-DDB1 E3 complexes.\",\n      \"method\": \"X-ray crystallography of DDB1-HBx complex; structure-based mutagenesis and functional analysis\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with mutagenesis and functional validation\",\n      \"pmids\": [\"19966799\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Crystal structure of DDB1-CRBN in complex with thalidomide, lenalidomide, and pomalidomide establishes that CRBN is a DCAF substrate receptor within CRL4^CRBN and enantioselectively binds IMiDs. IMiDs promote ubiquitination of IKZF1/IKZF3 while blocking endogenous substrate MEIS2 from binding, demonstrating dual modulation of E3 ligase substrate specificity.\",\n      \"method\": \"X-ray crystallography; unbiased substrate screen; functional ubiquitination assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structures with three ligands plus orthogonal functional substrate screen\",\n      \"pmids\": [\"25043012\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Crystal structure of human CRBN-DDB1-lenalidomide complex shows a hydrophobic pocket in the thalidomide-binding domain (TBD) of CRBN accommodates the glutarimide moiety of lenalidomide. Site-directed mutagenesis confirmed key drug-binding residues are critical for antiproliferative effects.\",\n      \"method\": \"X-ray crystallography; site-directed mutagenesis in lentiviral myeloma models\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus mutagenesis with functional readout\",\n      \"pmids\": [\"25108355\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Crystal structure of DDB1-DCAF1-HIV-1 Vpr-UNG2 complex reveals how Vpr engages DCAF1 to create a binding interface for UNG2 recruitment, targeting UNG2 for CRL4-mediated degradation via molecular mimicry of DNA by a Vpr variable loop.\",\n      \"method\": \"X-ray crystallography of the quaternary complex\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure of full quaternary complex with mechanistic interpretation\",\n      \"pmids\": [\"27571178\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"DDB1 associates stoichiometrically with CUL4A in vivo and binds directly to CDT1 in vitro; ectopic DDB1 bridges CDT1 to CUL4A in vivo. Silencing DDB1 prevents UV-induced CDT1 degradation in vivo and blocks CUL4A-mediated CDT1 ubiquitination in vitro, establishing DDB1 as the adaptor targeting CDT1 for CUL4A-dependent ubiquitination after UV damage.\",\n      \"method\": \"Co-immunoprecipitation; in vitro binding assay; in vitro ubiquitination assay; siRNA knockdown\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, in vitro ubiquitination reconstitution, confirmed by RNAi loss-of-function\",\n      \"pmids\": [\"15448697\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"DDB1 functions as a linker between CUL4A and substrate-recruiting WD40 proteins (DWD proteins) via a conserved DWD box motif. Fifteen DWD proteins were shown to bind DDB1-CUL4A, and the DWD box is necessary and sufficient for DDB1 binding.\",\n      \"method\": \"Yeast two-hybrid; co-immunoprecipitation; motif mutagenesis\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — systematic identification with mutagenesis of binding motif and multiple substrates tested\",\n      \"pmids\": [\"17079684\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Eighteen DDB1- and CUL4-associated factors (DCAFs) were identified, including 14 WD40 proteins. DCAFs interact with DDB1 through a conserved 'WDXR' motif. DCAF2/Cdt2 recruits Cdt1 to CUL4-DDB1 for ubiquitylation at replication forks via PCNA, and Cdt2 depletion causes rereplication.\",\n      \"method\": \"Mass spectrometry proteomics; co-immunoprecipitation; Xenopus egg extract reconstitution; siRNA knockdown\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods including biochemical reconstitution in Xenopus extracts, motif identification\",\n      \"pmids\": [\"16949367\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The DDB1-CUL4A^DDB2 ubiquitin ligase monoubiquitinates histone H2A in native chromatin at UV-damaged DNA sites. DDB2 mutations (XP-E) impair E3 ligase activity and reduce H2A monoubiquitination after UV, which is associated with decreased global genome NER.\",\n      \"method\": \"Co-immunoprecipitation of endogenous complexes from UV-irradiated cells; comparison with XP-E mutant cells; chromatin fractionation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — endogenous complex biochemistry with disease-relevant mutations confirming mechanistic role\",\n      \"pmids\": [\"16473935\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"CUL4-DDB1 complexes interact with WD40 proteins WDR5 and EED, components of histone methylation complexes. Inactivation of CUL4 or DDB1 impairs histone H3K4 and H3K27 methylation. CUL4A-DDB1 interacts with H3-methylated mononucleosomes.\",\n      \"method\": \"Co-immunoprecipitation; siRNA knockdown with histone methylation readouts; chromatin pull-down\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with orthogonal knockdown assays, single lab\",\n      \"pmids\": [\"17041588\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"DDB1 knockdown in human cells impairs repair of UV-induced cyclobutane pyrimidine dimers (CPD) but not 6-4 photoproducts. Upon UV irradiation, DDB1 translocates from loosely to tightly bound chromatin fraction in a DDB2-dependent manner. DDB1 is required for UV-induced DDB2 ubiquitylation and degradation, and bridges DDB2 to CUL4A at damage sites.\",\n      \"method\": \"siRNA knockdown; nuclear fractionation; immunofluorescence at laser-induced damage foci; repair assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple methods, single lab, loss-of-function with specific repair phenotype\",\n      \"pmids\": [\"16951172\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"DDB1 depletion causes accumulation of CDT1 protein and DNA re-replication, activates ATM/ATR checkpoints, and leads to genome-wide DNA double-strand breaks during S-phase. Co-depletion of CDT1 partially suppresses these phenotypes, placing CDT1 regulation downstream of DDB1 in genome maintenance.\",\n      \"method\": \"siRNA knockdown; flow cytometry; γH2AX immunofluorescence; epistasis by co-depletion\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis analysis with specific cellular phenotype readouts, single lab\",\n      \"pmids\": [\"16940174\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"DDB1 dynamically accumulates at UV-damaged DNA sites in living cells. Its binding to damaged DNA is transient and requires DDB2 but not CUL4A. UV-dependent degradation of DDB2 releases DDB1 from continuous association with unrepaired DNA, making DDB1 available for other functions.\",\n      \"method\": \"Live-cell fluorescence microscopy with fluorescently tagged DDB1; FRAP; cell lines with DDB2 knockdown or DDB2 mutations\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization by live imaging with FRAP, functional consequence established through DDB2 dependency\",\n      \"pmids\": [\"18936169\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Purified DDB1-DDB2 complex binds cyclobutane pyrimidine dimers with ~6-fold higher affinity than undamaged DNA, as well as 6-4 photoproducts, abasic sites, and 2-3 bp mismatches. DDB acts as a conformational sensor rather than lesion-specific detector.\",\n      \"method\": \"In vitro binding assays with highly purified DDB1-DDB2 complex and defined damaged DNA substrates; quantitative affinity measurements\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with purified proteins and quantitative affinity measurements\",\n      \"pmids\": [\"16223728\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"DDB1-CUL4 E3 ligase targets CDT1 for degradation during S phase and after DNA damage through two distinct E3 ligases: DDB1-CUL4 recognizes the N-terminal 10 amino acids of CDT1 and requires PCNA, while SCF-Skp2 recognizes a CDK-phosphorylated Cy-motif. PCNA is essential for CUL4- but not SKP2-directed CDT1 degradation.\",\n      \"method\": \"Mutational analysis of CDT1 degradation signals; siRNA co-depletion of Skp2 and Cul4; co-immunoprecipitation; cell cycle analysis\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mutational dissection of two pathways, siRNA co-depletion epistasis, replicated across groups\",\n      \"pmids\": [\"16482215\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"PCNA interacts with CDT1 and is required for CUL4-DDB1-mediated N-terminal ubiquitination of CDT1 in S phase and after UV irradiation. Overexpression of the PCNA-inhibitory domain from p21 or p57 blocks CDT1 degradation. Deletion of Ddb1 in fission yeast accumulates CDT1 even without DNA damage.\",\n      \"method\": \"In vivo ubiquitination assay; siRNA knockdown of PCNA; gel filtration co-elution; PCNA inhibitory domain overexpression; fission yeast genetics\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods, single lab, cross-species validation\",\n      \"pmids\": [\"16407242\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"CUL4A associates with Skp2 and DDB1 forms a physical complex with CUL4A, Skp2, and the COP9 signalosome. DDB1 knockdown, CSN1 knockdown, or CUL4A knockdown causes p27Kip1 accumulation. DDB1 overexpression reduces p27Kip1 stability via CUL4A and the COP9 signalosome.\",\n      \"method\": \"siRNA knockdown; co-immunoprecipitation; pulse-chase; overexpression\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and functional knockdown, single lab\",\n      \"pmids\": [\"16537899\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"DDB1 interacts with CHK1 and is part of a CUL4A/CUL4B E3 ligase complex that negatively regulates CHK1 protein stability. CHK1 ubiquitination is Cul4A/DDB1-dependent in vitro and in vivo, and CHK1 is stabilized in Cul4A/DDB1-deficient cells. CHK1 phosphorylation and replication stress enhance DDB1-CHK1 interaction.\",\n      \"method\": \"Co-immunoprecipitation; in vitro ubiquitination assay; siRNA knockdown; protein stability assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro ubiquitination reconstitution plus co-IP and knockdown, single lab\",\n      \"pmids\": [\"19276361\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"USP1 deubiquitinase counteracts DDB1-dependent degradation of phosphorylated CHK1. USP1 depletion stimulates DDB1-dependent degradation of phospho-CHK1, establishing a negative feedback circuit in the DNA damage response where activated CHK1 is downregulated via DDB1-mediated ubiquitination.\",\n      \"method\": \"siRNA knockdown of USP1; co-immunoprecipitation; CHK1 stability measurements in response to genotoxic stress\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA epistasis and co-IP, single lab\",\n      \"pmids\": [\"21389083\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"HIV-1 Vpr binds DDB1 through DCAF1/VprBP, and Vpr-mediated G2 arrest requires DDB1, CUL4A, and DCAF1. Tandem affinity purification identified DDB1, VPRBP, and CUL4A as Vpr-associated proteins. Proteasome inhibition abolishes Vpr-induced G2 arrest, consistent with ubiquitin ligase-mediated target degradation.\",\n      \"method\": \"Tandem affinity purification/mass spectrometry; co-immunoprecipitation; siRNA knockdown; cell cycle analysis by flow cytometry; proteasome inhibitor experiments\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal affinity purification, siRNA epistasis, pharmacological validation, replicated by multiple labs\",\n      \"pmids\": [\"17626091\", \"17314515\", \"17609381\", \"17630831\", \"17620334\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"HIV-1 Vpr binding to DDB1 (via DDB1-CUL4 ubiquitin ligase interaction) mediates Vpr-induced apoptosis and UNG2/SMUG1 degradation, and impairs UV-damaged DNA repair. DDB1 was identified as the predominant Vpr-interacting cellular protein by tandem affinity purification and mass spectrometry.\",\n      \"method\": \"Tandem affinity purification/mass spectrometry; co-immunoprecipitation; siRNA knockdown; functional assays for apoptosis and UNG2 degradation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — TAP-MS identification with functional knockdown validation, single lab\",\n      \"pmids\": [\"17360488\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"DDB1 (p127) is essential for SV5 V protein-mediated STAT1 degradation. V protein mutants that fail to bind DDB1 cannot block IFN signaling. siRNA depletion of DDB1 prevents STAT1 degradation and restores IFN signaling. STAT1 degradation is independent of DDB2.\",\n      \"method\": \"Protein-protein interaction assays; V protein mutagenesis; siRNA knockdown; IFN signaling assays\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis plus siRNA knockdown, functional readout, single lab\",\n      \"pmids\": [\"12388698\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"SV5 V protein acts as an adaptor linking DDB1 (via its N-terminal domain) to STAT2/STAT1 heterodimers, assembling a DDB1/CUL4A-containing ubiquitin ligase complex that ubiquitinates STAT1. V binds DDB1 and STAT2 independently; STAT1-STAT2 interaction is V-independent.\",\n      \"method\": \"Direct protein-protein interaction assays (GST pulldown, co-IP); yeast two-hybrid; ubiquitination assay with CUL4A components\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding assays for each pair plus functional ubiquitination, single lab\",\n      \"pmids\": [\"16227264\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"FBW5, a DWD-box WD40 protein, binds DDB1 and recruits TSC2 to the DDB1-CUL4-ROC1 E3 ubiquitin ligase for ubiquitination and proteasomal degradation. TSC1 co-expression with TSC2 protects TSC2 from FBW5-mediated degradation. Drosophila Cul4/Ddb1 mutations cause Gigas/TSC2 accumulation.\",\n      \"method\": \"Co-immunoprecipitation; in vitro ubiquitination; siRNA knockdown; overexpression; Drosophila genetics\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vitro ubiquitination assay, siRNA, genetic epistasis in Drosophila, multiple orthogonal methods\",\n      \"pmids\": [\"18381890\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"L2DTL/CDT2 associates with CUL4, DDB1, and PCNA in vivo. Loss of L2DTL suppresses CDT1 proteolysis after DNA damage. In vivo, inactivation of L2DTL causes dissociation of DDB1 from the CUL4 complex, and PCNA interacts with CDT1 through the same region required for CUL4-mediated degradation.\",\n      \"method\": \"Anti-CUL4 affinity chromatography/mass spectrometry; co-immunoprecipitation; siRNA knockdown in Drosophila S2 cells and human cells\",\n      \"journal\": \"Cell cycle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-based identification confirmed by co-IP and siRNA, single lab\",\n      \"pmids\": [\"16861906\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"EZH2 methylates non-histone substrate RORα, generating a monomethyl degron recognized by the DCAF1 chromo domain. The DCAF1/DDB1/CUL4 E3 complex then ubiquitinates the monomethylated substrate for degradation. Mutations in the DCAF1 chromo domain abolish binding to monomethylated substrates.\",\n      \"method\": \"In vitro methylation assay; molecular modeling; binding affinity studies; DCAF1 chromo domain mutagenesis; co-immunoprecipitation\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro assays with mutagenesis, single lab\",\n      \"pmids\": [\"23063525\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"VprBP acts as the substrate receptor that recruits Merlin (NF2 tumor suppressor) to the ROC1-CUL4A-DDB1 E3 ubiquitin ligase. Serum stimulation induces Merlin recruitment, polyubiquitination, and proteasomal degradation. VprBP depletion stabilizes Merlin and inhibits ERK/Rac activation.\",\n      \"method\": \"Co-immunoprecipitation; siRNA knockdown; in vivo ubiquitination assay; serum stimulation experiments\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, ubiquitination, siRNA knockdown, single lab\",\n      \"pmids\": [\"18332868\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"DDB1-CUL4 E3 ubiquitin ligase monoubiquitylates raptor, a component of mTORC1. UCH-L1 deubiquitinase disrupts the DDB1-CUL4/raptor complex and counteracts DDB1-CUL4-mediated raptor ubiquitination, promoting mTORC1 dissolution and secondary mTORC2 increase.\",\n      \"method\": \"Co-immunoprecipitation; ubiquitination assay; UCH-L1 transgenic and knockout mouse models; mTOR complex assembly analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, ubiquitination assay, and in vivo mouse models, single lab\",\n      \"pmids\": [\"23297343\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Conditional deletion of DDB1 in mouse brain and lens causes selective apoptosis of proliferating neuronal progenitor and lens epithelial cells, preceded by aberrant accumulation of cell cycle regulators and genomic instability. Cell death is partially rescued by co-deletion of p53, placing p53 activation downstream of DDB1 loss.\",\n      \"method\": \"Conditional knockout mouse genetics; histology; immunohistochemistry; p53 genetic epistasis\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional knockout in vivo with epistasis, multiple tissue types analyzed\",\n      \"pmids\": [\"17129780\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Tissue-specific deletion of DDB1 in mouse epidermis causes accumulation of c-Jun and p21Cip1, G2/M arrest, selective apoptosis of proliferating progenitor cells, and near-complete loss of epidermis and hair follicles. Co-deletion of p53 partially rescues progenitors but permits aneuploidy accumulation.\",\n      \"method\": \"Conditional knockout mouse genetics; immunohistochemistry; cell cycle analysis; p53 epistasis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO in vivo with specific molecular markers and genetic rescue\",\n      \"pmids\": [\"17301228\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"HBx requires DDB1 binding for both its cell-killing activity and its ability to stimulate HBV genome replication. DDB1-binding-deficient HBx point mutants fail to complement HBx-deficient HBV replication. DDB1 depletion by RNAi specifically compromises wild-type HBV replication. HBx fused directly to DDB1 rescues replication activity.\",\n      \"method\": \"HBx point mutagenesis; DDB1 fusion protein; RNAi depletion; plasmid-based HBV replication assay\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis and RNAi with viral replication readout, single lab\",\n      \"pmids\": [\"15767425\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"In fission yeast, Ddb1 is required for proteolysis of Spd1 (a ribonucleotide reductase inhibitor) in S phase and after DNA damage. Deletion of spd1 suppresses the growth defects and DNA damage sensitivity of Δddb1 cells, placing Spd1 as a key substrate downstream of Ddb1 in genome stability.\",\n      \"method\": \"Fission yeast genetics; protein stability assays; epistasis by double-mutant analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast genetics with epistasis, ortholog of mammalian DDB1\",\n      \"pmids\": [\"14701809\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Dyrk2-associated EDD-DDB1-VprBP E3 ligase mediates ubiquitin-dependent degradation of TERT (telomerase catalytic subunit). Dyrk2 phosphorylates TERT; phosphorylated TERT is then recognized by the VprBP substrate receptor of the EDD-DDB1-VprBP complex for ubiquitination and degradation at G2/M.\",\n      \"method\": \"Co-immunoprecipitation; in vivo ubiquitination assay; siRNA knockdown; kinase assay; cell cycle analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phosphorylation-ubiquitination cascade established by co-IP, ubiquitination assay, and kinase assay, single lab\",\n      \"pmids\": [\"23362280\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Ramshackle (Brwd3/BRWD3) functions as a DCAF within a CRL4 complex (CUL4-ROC1-DDB1-BRWD3) that mediates light-dependent ubiquitylation of Drosophila cryptochrome (dCRY). Light induces binding of dCRY to the complex, leading to dCRY ubiquitylation and degradation.\",\n      \"method\": \"RNAi screen in S2 cells; co-immunoprecipitation; ubiquitylation assay; light-dependent complex formation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi screen with co-IP and ubiquitylation assay, single lab\",\n      \"pmids\": [\"23479607\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CUL4A-DDB1-CDT2 E3 ligase ubiquitinates CRY1 at lysine 585 and promotes its degradation in vitro and in vivo. Depletion of DDB1, CDT2, or PCNA stabilizes CRY1 in cells and mouse liver. CRY1-K585A mutant is resistant to DDB1-mediated ubiquitination. DDB1 depletion enhances circadian Bmal1 promoter oscillatory amplitude.\",\n      \"method\": \"In vitro ubiquitination assay; siRNA knockdown; site-directed mutagenesis; circadian reporter assay; mouse liver Ddb1 deletion\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro ubiquitination with mutagenesis, in vivo genetic validation, single lab\",\n      \"pmids\": [\"26431207\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"DDB1-CUL4A ubiquitin E3 ligase degrades CRY1, thereby stabilizing FOXO1 and promoting hepatic gluconeogenesis. Hepatocyte-specific Ddb1 deletion impairs gluconeogenesis and protects from diet-induced hyperglycemia in mice. Mechanistically, DDB1 enhances FOXO1 stability by degrading CRY1, a known suppressor of FOXO1.\",\n      \"method\": \"Hepatocyte-specific conditional knockout mouse; high-fat diet experiments; gluconeogenesis assays; protein stability measurements\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO mouse with specific metabolic phenotype, mechanistic chain established, single lab\",\n      \"pmids\": [\"28790135\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SIRT7 deacetylates DDB1 at lysine 1121. The deacetylation-mimicking K1121R-DDB1 mutant shows reduced binding to DCAF1, leading to reduced CUL4B/DDB1/DCAF1 E3 ligase activity and increased TR4 nuclear receptor stability.\",\n      \"method\": \"In vitro deacetylation assay; co-immunoprecipitation; mutagenesis; target gene expression analysis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro deacetylation plus mutagenesis with binding and functional readout, single lab\",\n      \"pmids\": [\"28623141\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"WDR-23, a WD40 protein, interacts with CUL-4/DDB-1 ubiquitin ligase to repress SKN-1 protein levels, nuclear accumulation, and transcriptional activity in C. elegans, presumably by targeting SKN-1 for proteasomal degradation. WDR-23 acts downstream of p38 MAPK, GSK-3, and insulin-like receptor pathways on SKN-1.\",\n      \"method\": \"Genetic screen; co-immunoprecipitation; RNAi; fluorescence microscopy; epistasis analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, RNAi, epistasis in C. elegans, single lab\",\n      \"pmids\": [\"19273594\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"DDB1-CUL4 and MLL1 mediate oncogenic Ras-induced p16INK4a activation. DDB1 silencing blocks Ras-induced p16 induction. CUL4A directly binds the p16 locus. DDB1-CUL4 acts upstream of MLL1-mediated H3K4 methylation at the p16 locus.\",\n      \"method\": \"siRNA knockdown; ChIP; co-immunoprecipitation; Ras-induced senescence model\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and siRNA epistasis with defined pathway, single lab\",\n      \"pmids\": [\"19208841\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The CUL4A/DDB1 E3 ligase monoubiquitylates p73 through direct DDB1-p73 binding. Monoubiquitylation does not affect p73 stability but negatively regulates p73 transcriptional activity. DDB1 depletion induces p73 target gene expression in a p53-independent manner.\",\n      \"method\": \"Co-immunoprecipitation; in vivo ubiquitination assay; siRNA knockdown; transcriptional reporter assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus functional ubiquitination and transcriptional assays, single lab\",\n      \"pmids\": [\"23085759\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Molecular glue HQ461 promotes a direct interaction between CDK12 and DDB1-CUL4-RBX1 E3 ubiquitin ligase, bypassing the requirement for a substrate-specific DCAF receptor. This interaction leads to polyubiquitination and degradation of Cyclin K (CCNK), reduced CDK12 substrate phosphorylation, and cell death.\",\n      \"method\": \"High-throughput screening; loss-of-function and gain-of-function genetic screening; biochemical reconstitution; co-immunoprecipitation; SAR analysis\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — biochemical reconstitution plus genetic screening with multiple orthogonal methods\",\n      \"pmids\": [\"32804079\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CUL4A-DDB1-based E3 ligase monoubiquitinates PHGDH at lysine 146, enhancing its enzymatic activity by promoting tetrameric formation via DnaJA1 chaperone recruitment. This increases serine, glycine, and SAM levels, upregulating adhesion genes via H3K4me3, thereby promoting CRC metastasis.\",\n      \"method\": \"In vivo and in vitro ubiquitination assays; co-immunoprecipitation; mutagenesis; metabolomics; ChIP\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biochemical methods, single lab\",\n      \"pmids\": [\"34720086\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CUL4A-DDB1-WDFY1 E3 ubiquitin ligase complex initiates lysophagy by ubiquitinating LAMP2 on damaged lysosomes. WDFY1 serves as the DCAF substrate receptor. Loss of CUL4A, DDB1, or WDFY1 impairs lysophagy and clearance of damaged lysosomes.\",\n      \"method\": \"Proteomic analysis using transfection reagent-coated beads; co-immunoprecipitation; siRNA knockdown; autophagy/lysosome damage assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomics with co-IP and functional knockdown, single lab\",\n      \"pmids\": [\"36103833\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Cysteine chemoproteomic screening identified a covalent recruiter targeting C173 on DDB1. This DDB1 recruiter was exploited to develop PROTACs against BRD4 and androgen receptor. BRD4 PROTAC selectively degrades the short BRD4 isoform in a proteasome-, NEDDylation-, and DDB1-dependent manner, demonstrating DDB1 can be directly exploited for targeted protein degradation.\",\n      \"method\": \"Activity-based protein profiling; cysteine chemoproteomic screening; PROTAC development; siRNA knockdown; degradation assays\",\n      \"journal\": \"ACS chemical biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — chemoproteomic identification with functional PROTAC validation, single lab\",\n      \"pmids\": [\"38192078\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The Cul4-DDB1-Gβ E3 ubiquitin ligase complex ubiquitylates Smoothened (Smo) in Drosophila, promoting its internalization and degradation. Smo recruits Cul4-DDB1 through the β subunit of trimeric G protein. Hedgehog signaling dissociates Cul4-DDB1 from Smo by PKA-mediated phosphorylation of DDB1, disrupting its interaction with Gβ.\",\n      \"method\": \"Co-immunoprecipitation; in vivo ubiquitination assay; phosphorylation assay; genetic inactivation of Cul4-DDB1; immunofluorescence for Smo surface expression\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, ubiquitination, phosphorylation assays, Drosophila genetics, single lab\",\n      \"pmids\": [\"29930086\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"DCAF7 is a specificity factor for the CUL4-DDB1 complex that binds DNA ligase I and targets it for ubiquitylation. Three ubiquitylation sites on DNA ligase I were mapped. Knockdown of DCAF7 reduces DNA ligase I degradation upon inhibition of proliferation. Replacement of ubiquitylated lysines reduces in vitro ubiquitylation by CUL4-DDB1-DCAF7.\",\n      \"method\": \"Proteomic ubiquitylation site mapping; co-immunoprecipitation; in vitro ubiquitylation assay; siRNA knockdown; mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro ubiquitylation with site mutagenesis, confirmed by siRNA, single lab\",\n      \"pmids\": [\"27573245\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"DCAF11 (DDB1 and CUL4-associated factor 11) is the substrate receptor of CRL4 that binds phosphorylated SLBP (Stem-loop binding protein) and mediates its degradation at the end of S phase. DCAF11 cannot bind the non-phosphorylatable T61A-SLBP mutant. DCAF11 and Cul4A co-immunoprecipitate with SLBP.\",\n      \"method\": \"Pull-down with phosphorylated SLBP fragment; co-immunoprecipitation; siRNA and overexpression; cell viability assay\",\n      \"journal\": \"Cell cycle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pull-down, co-IP, and siRNA with phosphorylation-dependent binding, single lab\",\n      \"pmids\": [\"27254819\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"NTZ (nitazoxanide) inhibits the HBx-DDB1 protein-protein interaction, restoring Smc5/6 protein levels and suppressing HBV transcription and protein production in primary hepatocytes naturally infected with HBV.\",\n      \"method\": \"Split luciferase assay for HBx-DDB1 interaction; compound screening; Smc5/6 protein level measurement; viral transcription assays in primary hepatocytes and HBV minicircle system\",\n      \"journal\": \"Cellular and molecular gastroenterology and hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — target engagement assay with functional viral replication readout in primary cells, single lab\",\n      \"pmids\": [\"30704981\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DDB1 is a core adaptor/scaffolding subunit of the CUL4-RBX1-DDB1-DCAF family of cullin-RING E3 ubiquitin ligases; its three-beta-propeller architecture (BPA-BPB double-propeller + flexible BPC) enables it to bridge CUL4A/B (via BPC) to a large family of WD40-repeat substrate receptors (DCAFs, binding via the BPA-BPB pocket through a conserved alpha-helical/DWD-box motif), thereby directing ubiquitination and proteasomal degradation or activity modulation of diverse substrates including CDT1, CHK1, CRY1, p27, TSC2, Merlin, TERT, PHGDH, LAMP2, and histones H2A at UV-damaged chromatin; DDB1 is also co-opted by viral proteins (HBV HBx, SV5-V, HIV-1 Vpr, HCMV pUL145) and by small-molecule molecular glues and PROTACs that exploit the DDB1 scaffold to redirect CRL4 activity toward neo-substrates.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"DDB1 is the central adaptor subunit of the CUL4-RBX1-DDB1 family of cullin-RING E3 ubiquitin ligases (CRL4), bridging the CUL4 scaffold to interchangeable substrate-recruiting receptors and thereby directing ubiquitination of a broad set of substrates governing genome maintenance, cell-cycle control, and signaling [#1, #7]. Structurally, DDB1 adopts an intertwined three-beta-propeller architecture in which the BPA-BPB double-propeller forms a large pocket for substrate-receptor docking while the flexibly attached BPC propeller binds the N-terminus of CUL4A [#0, #1]. A large family of WD40-repeat proteins (DCAFs/DWD proteins) engages the BPA-BPB pocket through a conserved alpha-helical/DWD-box (WDxR) motif, the same structural element exploited by viral hijackers, and these receptors confer substrate specificity on the ligase [#1, #3, #8, #9]. Through distinct DCAFs, CRL4^DDB1 enforces replication licensing by degrading CDT1 in a PCNA-coupled manner via CDT2, an activity required to prevent re-replication, checkpoint activation, and genome-wide double-strand breaks [#7, #9, #16, #13], and it operates within nucleotide excision repair by scaffolding DDB2 to UV-damaged chromatin, where the complex monoubiquitinates histone H2A [#2, #10, #12]. DDB1-CUL4 additionally targets diverse regulators including CHK1, p27, TSC2, Merlin, and circadian CRY1 for degradation, and modulates substrate activity by monoubiquitination of p73 and PHGDH [#19, #18, #25, #28, #36, #41, #43]. In vivo, conditional DDB1 loss triggers aberrant accumulation of cell-cycle regulators, genomic instability, and p53-dependent apoptosis of proliferating progenitors [#30, #31]. The DDB1 scaffold is co-opted by viral proteins—paramyxovirus SV5-V, HBV HBx, and HIV-1 Vpr—to redirect CRL4 against host factors such as STAT1, Smc5/6, and UNG2 [#0, #6, #23, #32], and it is exploited pharmacologically by IMiD molecular glues acting through the DCAF CRBN and by molecular glues and covalent recruiters that engage DDB1 directly for targeted protein degradation [#4, #42, #45].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Established that DDB1 is functionally required for a viral protein to reprogram host protein degradation, the first hint that DDB1 serves as an adaptor for ubiquitin-mediated turnover.\",\n      \"evidence\": \"V protein mutagenesis and siRNA depletion of DDB1 with IFN-signaling and STAT1 degradation readouts\",\n      \"pmids\": [\"12388698\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not define the cullin/ligase machinery DDB1 recruits\", \"DDB1's endogenous cellular substrates unaddressed\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Defined DDB1 as the adaptor bridging an endogenous substrate (CDT1) to the CUL4A scaffold, establishing its core role in a cellular E3 ligase.\",\n      \"evidence\": \"Reciprocal co-IP, in vitro binding and ubiquitination reconstitution, and siRNA knockdown in human cells\",\n      \"pmids\": [\"15448697\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How DDB1 recognizes diverse substrates beyond CDT1 unknown\", \"No structural basis for adaptor function\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Resolved the three-propeller architecture of DDB1 and demonstrated a division of labor—BPC binds CUL4A while the BPA-BPB pocket receives substrate receptors—explaining how DDB1 functions as a modular adaptor and how viral helices hijack it.\",\n      \"evidence\": \"X-ray crystallography of apo DDB1 and DDB1-CUL4A-ROC1 complexes with SV5-V; TAP-MS of DDB1/CUL4A complexes\",\n      \"pmids\": [\"16413485\", \"16964240\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Conformational dynamics of BPC docking during catalysis not resolved\", \"Full DCAF repertoire not yet enumerated\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Systematically identified the DCAF/DWD family and the conserved WDxR/DWD-box motif as the universal substrate-receptor interface, explaining how one adaptor generates a combinatorial ligase family.\",\n      \"evidence\": \"Mass-spectrometry proteomics, yeast two-hybrid, and motif mutagenesis identifying ~15-18 DDB1-CUL4-associated WD40 factors\",\n      \"pmids\": [\"17079684\", \"16949367\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Substrate of most DCAFs unassigned at the time\", \"Rules governing receptor exchange on DDB1 unknown\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Established the genome-maintenance logic of CRL4^DDB1: PCNA-coupled CDT2 degradation of CDT1 prevents re-replication, with DDB1 loss causing checkpoint activation and DNA breaks.\",\n      \"evidence\": \"siRNA knockdown, Xenopus extract reconstitution, mutational dissection of CDT1 degrons, and γH2AX/epistasis assays\",\n      \"pmids\": [\"16949367\", \"16482215\", \"16407242\", \"16940174\", \"16861906\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Distinction between SCF-Skp2 and CRL4 redundancy in vivo incompletely mapped\", \"PCNA-degron coupling mechanism still being refined\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Defined DDB1's role in nucleotide excision repair, scaffolding the damage sensor DDB2 to UV lesions and enabling histone H2A monoubiquitination at damaged chromatin.\",\n      \"evidence\": \"In vitro damaged-DNA binding with purified DDB1-DDB2, endogenous complex biochemistry in UV-irradiated/XP-E cells, fractionation and repair assays\",\n      \"pmids\": [\"16223728\", \"16473935\", \"16951172\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether H2A ubiquitination directly drives repair versus chromatin remodeling unresolved\", \"CPD-versus-6-4PP repair specificity mechanism unclear\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Demonstrated that CRL4^DDB1 reaches beyond degradation into chromatin regulation by engaging histone methylation machinery (WDR5, EED) and influencing H3K4/H3K27 methylation.\",\n      \"evidence\": \"Co-IP, siRNA knockdown with methylation readouts, and methylated-nucleosome pull-down\",\n      \"pmids\": [\"17041588\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct ubiquitination substrate within the methylation complexes not defined\", \"Single-lab evidence\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Showed the structural element used by cellular DCAFs is mimicked by HBV HBx, unifying viral and host assembly of CRL4 complexes and explaining HBx-dependent viral replication.\",\n      \"evidence\": \"X-ray crystallography of DDB1-HBx with structure-based mutagenesis; HBx point-mutant complementation and RNAi in HBV replication assays\",\n      \"pmids\": [\"19966799\", \"15767425\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the host substrate degraded by HBx-DDB1 not defined here\", \"Mechanism linking degradation to replication enhancement incomplete\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Extended the substrate repertoire of CRL4^DDB1 to growth and tumor-suppressor pathways through specific DCAFs (FBW5→TSC2, VprBP→Merlin), linking DDB1 to mTOR and ERK/Rac signaling.\",\n      \"evidence\": \"Co-IP, in vitro/in vivo ubiquitination, siRNA, and Drosophila genetics\",\n      \"pmids\": [\"18381890\", \"18332868\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological signals triggering these degradation events partly defined\", \"In vivo contribution to tumor suppression untested\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Established HIV-1 Vpr as a DDB1-CUL4 hijacker acting through DCAF1/VprBP to drive G2 arrest and degrade host factors, generalizing viral exploitation of the scaffold.\",\n      \"evidence\": \"TAP-MS, reciprocal co-IP, siRNA epistasis, proteasome inhibition, and cell-cycle/apoptosis assays across multiple labs\",\n      \"pmids\": [\"17626091\", \"17314515\", \"17609381\", \"17630831\", \"17620334\", \"17360488\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full set of Vpr-redirected substrates not exhausted\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Genetic ablation in mouse tissues established the in vivo physiological requirement for DDB1 in proliferating cells, where its loss causes cell-cycle regulator accumulation, genomic instability, and p53-driven apoptosis.\",\n      \"evidence\": \"Conditional knockout in brain, lens, and epidermis with histology, marker analysis, and p53 genetic epistasis\",\n      \"pmids\": [\"17129780\", \"17301228\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which specific substrate accumulation is primary driver of apoptosis not pinpointed\", \"Tissue-specific differences in critical substrates unresolved\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identified CHK1 as a CRL4^DDB1 target, embedding DDB1 in a DNA-damage-response feedback circuit where activated CHK1 is downregulated and USP1 opposes this turnover.\",\n      \"evidence\": \"Co-IP, in vitro ubiquitination, siRNA, and stability assays; USP1 epistasis under genotoxic stress\",\n      \"pmids\": [\"19276361\", \"21389083\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the CHK1-specific DCAF not defined\", \"Quantitative impact on checkpoint timing unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Expanded CRL4^DDB1 function into circadian, metabolic, and telomere regulation, and showed it can modulate activity (monoubiquitination) rather than only trigger degradation.\",\n      \"evidence\": \"In vitro/in vivo ubiquitination, site mutagenesis, circadian reporters, conditional mouse models, and kinase assays linking DDB1 to CRY1, raptor, TERT and FOXO1/gluconeogenesis\",\n      \"pmids\": [\"23297343\", \"23362280\", \"26431207\", \"28790135\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Several substrate links rest on single-lab evidence\", \"Crosstalk between these pathways in vivo not integrated\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Revealed how small molecules exploit the DDB1 scaffold: IMiDs binding the DCAF CRBN reprogram substrate specificity, simultaneously recruiting neo-substrates (IKZF1/3) and blocking endogenous ones.\",\n      \"evidence\": \"X-ray crystallography of DDB1-CRBN with three IMiDs, unbiased substrate screen, mutagenesis, and ubiquitination assays in myeloma models\",\n      \"pmids\": [\"25043012\", \"25108355\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality of glue-induced neo-substrate recruitment beyond CRBN not yet shown here\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrated that molecular glues and covalent recruiters can engage DDB1 directly, bypassing DCAF receptors to create neo-substrate ligases, validating DDB1 itself as a targeted-degradation platform.\",\n      \"evidence\": \"HTS, genetic screens, and biochemical reconstitution for HQ461/CDK12-CCNK; cysteine chemoproteomics identifying DDB1 C173 recruiter used to build BRD4/AR PROTACs\",\n      \"pmids\": [\"32804079\", \"38192078\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of direct DDB1-glue neo-substrate ternary complexes not fully resolved\", \"Selectivity and in vivo efficacy of DDB1 recruiters early-stage\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how DDB1 dynamically selects among its many competing DCAF receptors and how this exchange is regulated by post-translational modification across distinct cellular states.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No quantitative model of DCAF competition for the BPA-BPB pocket\", \"Regulatory roles of DDB1 phosphorylation/acetylation only sketched (e.g. SIRT7, PKA in Drosophila)\", \"Substrate priority during simultaneous demands of replication, repair, and signaling unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 7, 8, 9]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [7, 10, 19, 25]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [2, 15]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [16, 36]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [14, 30]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [2, 10, 12, 14]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [2, 10, 12, 15]},\n      {\"term_id\": \"R-HSA-69306\", \"supporting_discovery_ids\": [7, 9, 16, 13]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [13, 18, 19, 30]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [1, 7, 8, 9]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [10, 11, 40]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [21, 23, 32, 49]},\n      {\"term_id\": \"R-HSA-9909396\", \"supporting_discovery_ids\": [35, 36, 37]}\n    ],\n    \"complexes\": [\n      \"CUL4A-RBX1-DDB1 (CRL4) E3 ubiquitin ligase\",\n      \"CUL4B-DDB1-DCAF1 E3 ubiquitin ligase\",\n      \"DDB1-DDB2 (UV-DDB) complex\",\n      \"EDD-DDB1-VprBP E3 ligase\"\n    ],\n    \"partners\": [\n      \"CUL4A\",\n      \"DDB2\",\n      \"DCAF1/VPRBP\",\n      \"DCAF2/CDT2\",\n      \"CRBN\",\n      \"FBW5\",\n      \"CDT1\",\n      \"RBX1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}