{"gene":"PHIP","run_date":"2026-04-28T19:45:44","timeline":{"discoveries":[{"year":2007,"finding":"A larger 1,821-aa WD40 repeat-containing isoform of PHIP (PHIP1) is expressed in pancreatic beta-cell nuclei. PHIP1 overexpression stimulates IGF-1-dependent and -independent beta-cell proliferation by transcriptionally upregulating cyclin D2. RNAi knockdown of PHIP1 abrogates IRS2-mediated DNA synthesis. PHIP1 overexpression also blocks free fatty acid-induced apoptosis via activation of PKB/AKT and inhibition of caspase-9/-3 cleavage; dominant-negative PKB attenuates this cytoprotection.","method":"Cloning/immunoblotting, RNAi knockdown, cyclin D2 promoter-reporter assay, overexpression with dominant-negative PKB, apoptosis assays (caspase cleavage)","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (KD, OE, reporter assay, dominant-negative epistasis) in single rigorous study","pmids":["17636024"],"is_preprint":false},{"year":2010,"finding":"Mice lacking PHIP1 (the full-length isoform) are born at normal size but develop a ~40% postnatal growth deficit by weaning, hypoglycemia, and die at 4–5 weeks. PHIP1-deficient mouse embryonic fibroblasts proliferate markedly slower than wild-type but show normal AKT phosphorylation and increased cell proliferation in response to IGF-1, indicating PHIP1 regulates postnatal growth in an IGF-1/AKT pathway-independent manner.","method":"Conditional knockout mouse model, MEF proliferation assays, AKT phosphorylation western blot, IGF-1 stimulation","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 2 — clean KO with defined in vivo and cellular phenotypes, multiple readouts","pmids":["20816727"],"is_preprint":false},{"year":2012,"finding":"PHIP promotes melanoma metastasis; systemic shRNA targeting of Phip inhibited metastatic progression in vivo. Stable suppression of Phip in melanoma cell lines suppressed metastatic potential and prolonged survival of tumor-bearing mice. PHIP locus is preserved (not deleted) and overexpressed in melanoma, and elevated PHIP copy number was found in a high proportion of PHIP-overexpressing melanomas.","method":"Plasmid-based shRNA in vivo, stable shRNA knockdown in melanoma cell lines, mouse xenograft survival studies, copy number analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — in vivo shRNA suppression with defined metastasis and survival phenotypes, replicated across cell lines","pmids":["22511720"],"is_preprint":false},{"year":2017,"finding":"BRWD2/PHIP colocalizes with histone H3K4 methylation genome-wide in human cells, mouse embryonic stem cells, and Drosophila. PHIP biochemically associates with the CRL4 (Cullin-4-RING ubiquitin E3 ligase) complex, nucleosomes, and chromatin remodelers. PHIP binds directly to H3K4 methylation through a previously unidentified chromatin-binding module related to Royal Family Tudor domains, named the CryptoTudor domain. COMPASS H3K4 methyltransferase family members differentially regulate BRWD2/PHIP chromatin occupancy. Depletion of the Drosophila homolog dBRWD3 results in altered gene expression and aberrant H3K27 acetylation at enhancers and promoters.","method":"ChIP-seq (genome-wide colocalization), biochemical pulldown/Co-IP (CRL4 complex, nucleosomes), direct binding assay with H3K4me peptides, CRISPR-Cas9 knockouts, Drosophila dBRWD3 depletion with gene expression and H3K27ac profiling","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods including direct binding, genome-wide chromatin localization, genetic KO, and cross-species validation","pmids":["29089422"],"is_preprint":false},{"year":2018,"finding":"PHIP's bromodomain is functional and specifically binds the histone modification H4K91ac. Suppression of PHIP significantly inhibited tumor cell proliferation and invasion in melanoma, triple-negative/basal-like breast cancer, and bronchioid NSCLC cell lines, coordinately suppressing phosphorylated AKT, cyclin D1, and talin1.","method":"Bromodomain binding assay (histone peptide array), shRNA suppression with proliferation and invasion assays, western blot for downstream effectors","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — direct bromodomain binding assay combined with loss-of-function phenotype across multiple tumor types","pmids":["29866840"],"is_preprint":false},{"year":2018,"finding":"RepID/DCAF14/PHIP recruits the CRL4 ubiquitin ligase complex to chromatin prior to DNA synthesis, playing a crucial architectural role in licensing chromosomes for replication. In the absence of RepID, cells rely on the alternative ubiquitin ligase SKP2-containing SCF complex to progress through the cell cycle. RepID depletion markedly increases cellular sensitivity to SKP2 inhibitors, triggering massive genome re-replication. RepID and SKP2 interact with distinct, non-overlapping groups of replication origins.","method":"RepID depletion (siRNA/knockout), chromatin fractionation, origin-firing assays, SKP2 inhibitor sensitivity, re-replication assays, origin mapping","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — clean KD/KO with defined replication phenotypes, epistasis with SKP2-SCF pathway, multiple orthogonal methods","pmids":["30018425"],"is_preprint":false},{"year":2020,"finding":"PHIP drives glioblastoma motility and invasion through effects on the force transduction layer of the focal adhesion complex. PHIP localizes to the leading edge of glioblastoma cells and to the force transduction layer specifically, co-localizing with talin 1 (TLN1), vinculin (VCL), integrin beta 1, paxillin (pPXN), and focal adhesion kinase (pFAK). Co-immunoprecipitation revealed a physical interaction between PHIP and VCL. PHIP silencing down-regulated these focal adhesion proteins and zyxin (ZYX), and produced disorganized stress fibers. PHIP knockdown suppressed tumor growth in intracranial implantation and reduced microvessel density and secreted VEGF levels. Migratory/invasive capacity was partially restored by TLN1 or ZYX cDNA overexpression.","method":"Immunofluorescence and confocal microscopy (localization), co-immunoprecipitation (PHIP–VCL interaction), shRNA knockdown, live-cell imaging (ZYX-GFP focal adhesion dynamics), rescue by cDNA overexpression, intracranial xenograft","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — Co-IP binding partner identification, localization with functional consequence, in vivo xenograft, epistasis rescue experiment","pmids":["32273388"],"is_preprint":false},{"year":2020,"finding":"Nuclear PHIP directly enhances transcription of pro-opiomelanocortin (POMC), a neuropeptide that suppresses appetite. Obesity-associated PHIP variants (identified by exome sequencing) repressed POMC transcription in cell-based assays, linking PHIP haploinsufficiency to disrupted central melanocortin signaling and human energy homeostasis.","method":"Exome sequencing (variant identification), cell-based POMC transcription assays with wild-type and variant PHIP constructs","journal":"Cell metabolism","confidence":"Medium","confidence_rationale":"Tier 2 — direct transcriptional assay with disease-associated variants, but single lab with limited mechanistic detail on transcriptional mechanism","pmids":["32492392"],"is_preprint":false},{"year":2020,"finding":"RepID/PHIP is required for CRL4 recruitment to chromatin. During mitosis, CRL4 dissociates from RepID and associates with RBBP7, which ubiquitinates the spindle assembly checkpoint (SAC) mediator BUB3 to enable mitotic exit. During interphase, BUB3 is protected from CRL4-mediated degradation by association with PML nuclear bodies. Deficiencies in RepID, CRL4, or RBBP7 delay mitotic exit, increase genomic instability, and enhance sensitivity to paclitaxel.","method":"Co-IP (RepID–CRL4–RBBP7 interactions), ubiquitination assay (BUB3 as substrate), RNAi/KO depletion, mitotic exit timing assays, genomic instability and drug sensitivity assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 — substrate identification with ubiquitination assay, Co-IP complex characterization, genetic depletion with defined mitotic phenotype","pmids":["31911655"],"is_preprint":false},{"year":2021,"finding":"PHIP is a chromatin-associated CRL4 ubiquitin ligase substrate receptor required for CRL4 recruitment to chromatin. PHIP binds chromatin through a trivalent reader module: a CryptoTudor domain (H3K4-methyl binding), bromodomain 1 (BD1, reader of H3K14ac), and bromodomain 2 (BD2, reader of H4K12ac). These interactions were characterized using semisynthetic nucleosomes with defined histone post-translational modifications. Human disease-associated (neurodevelopmental disorder/cancer) mutations map to each domain and the intervening linker region and likely disrupt chromatin binding.","method":"Semisynthetic nucleosome binding assays with defined PTMs, bromodomain binding characterization, disease-variant mutagenesis, CRL4 chromatin recruitment assays","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1 — reconstituted nucleosome binding assays with defined modifications, mutagenesis of disease variants, multiple domains characterized","pmids":["34819353"],"is_preprint":false},{"year":2016,"finding":"PHIP haploinsufficiency (via de novo heterozygous frameshift, nonsense, and missense variants) causes a syndrome of developmental delay, intellectual disability, obesity, anxiety, hypotonia, and dysmorphic features. The phenotype overlaps with CUL4B deficiency, suggesting PHIP mutations cause disease through disruption of the ubiquitin ligase pathway. PHIP produces multiple protein products including PHIP1/DCAF14 (a CUL4-DDB1 substrate receptor) and NDRP.","method":"Whole-exome sequencing, clinical phenotyping, genotype-phenotype correlation","journal":"Cold Spring Harbor molecular case studies","confidence":"Low","confidence_rationale":"Tier 4 — primarily genetic/clinical study; mechanistic pathway inference is indirect","pmids":["27900362"],"is_preprint":false},{"year":2006,"finding":"The DDB1-CUL4A-ROC1 ubiquitin ligase complex uses a novel family of WD40-repeat proteins as substrate-recruiting modules; PHIP/DCAF14 is among the DCAFs (DDB1- and CUL4-associated factors) identified by tandem-affinity purification of human DDB1 and CUL4A complexes followed by mass spectrometry, establishing PHIP as a substrate receptor of the CRL4 E3 ligase.","method":"Tandem affinity purification of DDB1/CUL4A complexes, mass spectrometry identification of WD40-repeat DCAFs, crystallographic analysis of DDB1 complex","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1–2 — structural and proteomic identification in a landmark study; PHIP/DCAF14 explicitly identified as CRL4 substrate receptor","pmids":["16964240"],"is_preprint":false},{"year":2012,"finding":"Large-scale structural analysis of the human bromodomain family identified PHIP as containing bromodomains. Crystal structures were determined for BRD family members and cross-family screening against histone-peptide arrays revealed acetylation-dependent substrate recognition; flanking PTMs influence bromodomain binding, suggesting BRDs recognize combinations of marks.","method":"X-ray crystallography (29 BRD structures), histone peptide array screening","journal":"Cell","confidence":"Medium","confidence_rationale":"Tier 1 — high-quality structural study; PHIP bromodomains included in family-wide analysis but individual PHIP binding specificity not deeply characterized in this paper","pmids":["22464331"],"is_preprint":false}],"current_model":"PHIP (pleckstrin homology domain-interacting protein/BRWD2/DCAF14/RepID) is a multifunctional chromatin regulator that acts as a substrate receptor for the CRL4 (CUL4-DDB1-ROC1) ubiquitin E3 ligase complex, which it recruits to chromatin through a trivalent histone reader module comprising a CryptoTudor domain (binding H3K4me), bromodomain 1 (binding H3K14ac), and bromodomain 2 (binding H4K12ac/H4K91ac); in this capacity it facilitates DNA replication origin licensing and, during mitosis, enables BUB3 ubiquitination and SAC termination via RBBP7; it also directly enhances POMC transcription to regulate energy homeostasis, promotes beta-cell proliferation and survival through cyclin D2 upregulation and PKB/AKT activation, and drives cancer cell motility/invasion by physically interacting with vinculin at the force transduction layer of the focal adhesion complex."},"narrative":{"teleology":[{"year":2006,"claim":"Identifying PHIP/DCAF14 as a WD40-repeat substrate receptor of the CRL4 ubiquitin ligase established the molecular framework through which PHIP connects to the ubiquitin–proteasome system.","evidence":"Tandem affinity purification of DDB1/CUL4A complexes followed by mass spectrometry in human cells","pmids":["16964240"],"confidence":"High","gaps":["Substrates recruited by PHIP/DCAF14 to CRL4 were unknown","How PHIP engages chromatin was uncharacterized","Physiological functions of PHIP-CRL4 were not addressed"]},{"year":2007,"claim":"Demonstrating that the full-length PHIP1 isoform transcriptionally upregulates cyclin D2 and activates PKB/AKT to promote beta-cell proliferation and survival revealed a first physiological role for PHIP in cell growth control.","evidence":"RNAi knockdown, overexpression, cyclin D2 promoter-reporter assays, dominant-negative PKB epistasis, and apoptosis assays in pancreatic beta cells","pmids":["17636024"],"confidence":"High","gaps":["Whether the proliferative function depends on CRL4 association was not tested","Mechanism of cyclin D2 transcriptional activation was not resolved","In vivo beta-cell phenotype was not assessed"]},{"year":2010,"claim":"PHIP1-knockout mice revealed an essential, IGF-1/AKT-independent role for PHIP in postnatal growth, separating its in vivo growth function from the AKT pathway previously implicated in beta cells.","evidence":"Conditional knockout mouse model with MEF proliferation assays, AKT phosphorylation, and IGF-1 stimulation","pmids":["20816727"],"confidence":"High","gaps":["The AKT-independent mechanism driving postnatal growth remained unknown","Tissue-specific contributions to the growth phenotype were not dissected"]},{"year":2012,"claim":"PHIP was shown to contain functional bromodomains recognizing acetylated histones, and its suppression inhibited melanoma metastasis in vivo, linking its chromatin-reading capacity to cancer progression.","evidence":"X-ray crystallography of bromodomain family, histone peptide arrays, shRNA knockdown in melanoma cell lines, mouse xenograft survival studies, copy number analysis","pmids":["22511720","22464331"],"confidence":"High","gaps":["Specific acetyl-histone marks read by PHIP bromodomains were not fully defined","Whether the metastatic role depended on CRL4 recruitment was untested"]},{"year":2016,"claim":"Identification of de novo loss-of-function PHIP variants in patients with intellectual disability, obesity, and dysmorphic features established PHIP haploinsufficiency as the basis of a neurodevelopmental syndrome overlapping CUL4B deficiency.","evidence":"Whole-exome sequencing and clinical phenotyping of affected individuals","pmids":["27900362"],"confidence":"Low","gaps":["Causal mechanism linking PHIP haploinsufficiency to neurodevelopmental phenotypes was not established beyond genotype–phenotype correlation","Functional impact of individual patient variants on CRL4 pathway was not tested","Independent replication cohort was limited"]},{"year":2017,"claim":"Genome-wide colocalization of PHIP with H3K4 methylation and identification of the CryptoTudor domain as a direct H3K4me reader revealed how PHIP is targeted to chromatin, connecting its CRL4 substrate receptor function to a specific epigenetic mark.","evidence":"ChIP-seq across human cells, mouse ES cells, and Drosophila; direct peptide-binding assays; CRISPR-Cas9 COMPASS knockouts; Drosophila dBRWD3 depletion with H3K27ac profiling","pmids":["29089422"],"confidence":"High","gaps":["Contributions of bromodomains to chromatin targeting were not resolved","Functional consequences of CRL4 recruitment at H3K4me-marked sites were unknown"]},{"year":2018,"claim":"Characterization of PHIP's bromodomain 2 as an H4K91ac reader and demonstration that PHIP recruits CRL4 to replication origins—where its loss forces reliance on the alternative SCF-SKP2 pathway—revealed PHIP's essential role in DNA replication licensing and a synthetic-lethal vulnerability.","evidence":"Bromodomain-histone peptide array binding, siRNA/knockout replication assays, origin mapping, SKP2 inhibitor sensitivity and re-replication assays","pmids":["29866840","30018425"],"confidence":"High","gaps":["Direct CRL4 substrates at replication origins were not identified","Structural basis for origin-specific vs. SKP2-origin targeting was unresolved"]},{"year":2020,"claim":"Three concurrent advances resolved PHIP's roles in mitotic checkpoint control (via CRL4-RBBP7–mediated BUB3 ubiquitination), POMC transcription for energy homeostasis, and focal adhesion force transduction (via vinculin interaction), greatly expanding the functional repertoire beyond replication licensing.","evidence":"Co-IP and ubiquitination assays for BUB3 substrate identification; mitotic exit timing and paclitaxel sensitivity assays; POMC transcription reporter assays with disease-associated variants; confocal microscopy, Co-IP of PHIP–VCL, shRNA with TLN1/ZYX rescue, and intracranial xenograft","pmids":["31911655","32492392","32273388"],"confidence":"High","gaps":["How CRL4 switches from RepID-dependent chromatin tethering to RBBP7-dependent mitotic activity is mechanistically unclear","Direct transcriptional mechanism of POMC activation by PHIP is unresolved","Whether the focal adhesion function requires CRL4 activity or is CRL4-independent is unknown"]},{"year":2021,"claim":"Reconstitution with semisynthetic nucleosomes defined PHIP's trivalent chromatin-reading module (CryptoTudor for H3K4me, BD1 for H3K14ac, BD2 for H4K12ac) and showed that neurodevelopmental and cancer-associated mutations disrupt these interactions, unifying the chromatin-targeting mechanism with human disease.","evidence":"Semisynthetic nucleosome binding assays with defined histone PTMs, disease-variant mutagenesis, CRL4 chromatin recruitment assays","pmids":["34819353"],"confidence":"High","gaps":["No high-resolution structure of full-length PHIP on a nucleosome exists","Quantitative contribution of each reader domain to in vivo chromatin occupancy is not established","Whether all three marks must co-occur on the same nucleosome or can be read in trans is unresolved"]},{"year":null,"claim":"The direct CRL4 substrates at replication origins, the structural basis for PHIP's chromatin-to-focal-adhesion shuttling, and the mechanism by which PHIP activates POMC transcription remain major open questions.","evidence":"","pmids":[],"confidence":"Low","gaps":["CRL4 substrates at replication origins have not been identified","No structural model of full-length PHIP exists","Mechanism of POMC transcriptional activation is undefined","Relationship between CRL4-dependent and CRL4-independent PHIP functions is unexplored"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[3,4,9,12]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,7]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[5,8,11]}],"localization":[{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[3,5,9]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,7]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[6]}],"pathway":[{"term_id":"R-HSA-69306","term_label":"DNA Replication","supporting_discovery_ids":[5]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[5,8]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[3,9]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[8,11]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,7]}],"complexes":["CRL4 (CUL4-DDB1-ROC1)"],"partners":["DDB1","CUL4A","VCL","RBBP7","BUB3","TLN1"],"other_free_text":[]},"mechanistic_narrative":"PHIP (PH-interacting protein/BRWD2/DCAF14/RepID) is a chromatin-associated substrate receptor for the CRL4 (CUL4–DDB1–ROC1) ubiquitin E3 ligase complex that couples multivalent histone mark recognition to diverse downstream processes including DNA replication origin licensing, mitotic checkpoint termination, transcriptional regulation, and cell motility [PMID:16964240, PMID:29089422, PMID:34819353]. PHIP engages chromatin through a trivalent reader module—a CryptoTudor domain binding H3K4 methylation, bromodomain 1 reading H3K14ac, and bromodomain 2 reading H4K12ac—and recruits CRL4 to chromatin to facilitate replication licensing at a subset of origins that are non-redundant with SCF-SKP2–dependent origins; during mitosis, CRL4 dissociates from PHIP and partners with RBBP7 to ubiquitinate BUB3, enabling spindle assembly checkpoint silencing and mitotic exit [PMID:30018425, PMID:31911655, PMID:34819353]. Beyond ubiquitin ligase functions, PHIP directly enhances POMC transcription to regulate energy homeostasis, promotes pancreatic beta-cell proliferation through cyclin D2 upregulation and PKB/AKT activation, and drives cancer cell invasion by physically interacting with vinculin at the force transduction layer of focal adhesions [PMID:17636024, PMID:32492392, PMID:32273388]. De novo heterozygous loss-of-function PHIP variants cause a neurodevelopmental syndrome featuring intellectual disability, obesity, and dysmorphic features that phenotypically overlaps with CUL4B deficiency [PMID:27900362]."},"prefetch_data":{"uniprot":{"accession":"Q8WWQ0","full_name":"PH-interacting protein","aliases":["DDB1- and CUL4-associated factor 14","IRS-1 PH domain-binding protein","WD repeat-containing protein 11"],"length_aa":1821,"mass_kda":206.7,"function":"Probable regulator of the insulin and insulin-like growth factor signaling pathways. Stimulates cell proliferation through regulation of cyclin transcription and has an anti-apoptotic activity through AKT1 phosphorylation and activation. Plays a role in the regulation of cell morphology and cytoskeletal organization","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q8WWQ0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PHIP","classification":"Not Classified","n_dependent_lines":72,"n_total_lines":1208,"dependency_fraction":0.059602649006622516},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"NUCKS1","stoichiometry":10.0},{"gene":"NUMA1","stoichiometry":4.0},{"gene":"HIST2H2BE","stoichiometry":0.2},{"gene":"HMGA1","stoichiometry":0.2},{"gene":"HMGN5","stoichiometry":0.2},{"gene":"NCK1","stoichiometry":0.2},{"gene":"NECAP1","stoichiometry":0.2},{"gene":"SSRP1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/PHIP","total_profiled":1310},"omim":[{"mim_id":"617991","title":"CHUNG-JANSEN SYNDROME; CHUJANS","url":"https://www.omim.org/entry/617991"},{"mim_id":"617824","title":"BROMODOMAIN AND WD REPEAT DOMAIN-CONTAINING PROTEIN 1; BRWD1","url":"https://www.omim.org/entry/617824"},{"mim_id":"612870","title":"PLECKSTRIN HOMOLOGY DOMAIN-INTERACTING PROTEIN; PHIP","url":"https://www.omim.org/entry/612870"},{"mim_id":"603756","title":"ATP-BINDING CASSETTE, SUBFAMILY G, MEMBER 2; ABCG2","url":"https://www.omim.org/entry/603756"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Nucleoli rim","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PHIP"},"hgnc":{"alias_symbol":["ndrp","BRWD2","RepID","DCAF14","FLJ20705"],"prev_symbol":["WDR11"]},"alphafold":{"accession":"Q8WWQ0","domains":[{"cath_id":"-","chopping":"2-121","consensus_level":"medium","plddt":81.6739,"start":2,"end":121},{"cath_id":"2.130.10.10","chopping":"165-410_423-604_724-732","consensus_level":"medium","plddt":92.6936,"start":165,"end":732},{"cath_id":"-","chopping":"953-1062","consensus_level":"medium","plddt":86.2257,"start":953,"end":1062},{"cath_id":"2.30.30.1040","chopping":"1066-1148","consensus_level":"medium","plddt":87.0736,"start":1066,"end":1148},{"cath_id":"1.20.920.10","chopping":"1158-1280","consensus_level":"medium","plddt":90.1076,"start":1158,"end":1280},{"cath_id":"1.20.920.10","chopping":"1320-1433","consensus_level":"medium","plddt":89.1552,"start":1320,"end":1433}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8WWQ0","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8WWQ0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8WWQ0-F1-predicted_aligned_error_v6.png","plddt_mean":66.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PHIP","jax_strain_url":"https://www.jax.org/strain/search?query=PHIP"},"sequence":{"accession":"Q8WWQ0","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8WWQ0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8WWQ0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8WWQ0"}},"corpus_meta":[{"pmid":"9000552","id":"PMC_9000552","title":"The prostate: a target for carcinogenicity of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) derived from cooked foods.","date":"1997","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/9000552","citation_count":323,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30190553","id":"PMC_30190553","title":"PhIP-Seq characterization of serum antibodies using oligonucleotide-encoded peptidomes.","date":"2018","source":"Nature protocols","url":"https://pubmed.ncbi.nlm.nih.gov/30190553","citation_count":147,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8055652","id":"PMC_8055652","title":"Metabolic activation pathway for the formation of DNA adducts of the carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in rat extrahepatic tissues.","date":"1994","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/8055652","citation_count":147,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"2665964","id":"PMC_2665964","title":"Genotoxicity of the food mutagen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP): formation of 2-hydroxamino-PhIP, a directly acting genotoxic metabolite.","date":"1989","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/2665964","citation_count":121,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"21538638","id":"PMC_21538638","title":"Parahydrogen-induced polarization (PHIP) hyperpolarized MR receptor imaging in vivo: a pilot study of 13C imaging of atheroma in mice.","date":"2011","source":"NMR in biomedicine","url":"https://pubmed.ncbi.nlm.nih.gov/21538638","citation_count":98,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"1483260","id":"PMC_1483260","title":"Formation of DNA adducts of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in male Fischer-344 rats.","date":"1992","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/1483260","citation_count":87,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9202746","id":"PMC_9202746","title":"Chemoprotection against the formation of colon DNA adducts from the food-borne carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in the rat.","date":"1997","source":"Mutation research","url":"https://pubmed.ncbi.nlm.nih.gov/9202746","citation_count":85,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8222059","id":"PMC_8222059","title":"Enzymatic phase II activation of the N-hydroxylamines of IQ, MeIQx and PhIP by various organs of monkeys and rats.","date":"1993","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/8222059","citation_count":82,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"11535243","id":"PMC_11535243","title":"The role of human glutathione S-transferases (hGSTs) in the detoxification of the food-derived carcinogen metabolite N-acetoxy-PhIP, and the effect of a polymorphism in hGSTA1 on colorectal cancer risk.","date":"2001","source":"Mutation research","url":"https://pubmed.ncbi.nlm.nih.gov/11535243","citation_count":79,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"2197012","id":"PMC_2197012","title":"Activation of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) to mutagenic metabolites.","date":"1990","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/2197012","citation_count":78,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16167840","id":"PMC_16167840","title":"Differential metabolism of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in mice humanized for CYP1A1 and CYP1A2.","date":"2005","source":"Chemical research in toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/16167840","citation_count":76,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9202745","id":"PMC_9202745","title":"Carcinogenicity of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in the rat.","date":"1997","source":"Mutation research","url":"https://pubmed.ncbi.nlm.nih.gov/9202745","citation_count":75,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"14690798","id":"PMC_14690798","title":"Effect of dietary constituents with chemopreventive potential on adduct formation of a low dose of the heterocyclic amines PhIP and IQ and phase II hepatic enzymes.","date":"2003","source":"Nutrition and cancer","url":"https://pubmed.ncbi.nlm.nih.gov/14690798","citation_count":72,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8625468","id":"PMC_8625468","title":"Mutational spectra of the dietary carcinogen 2-amino-1-methyl-6- phenylimidazo[4,5-b]pyridine(PhIP) at the Chinese hamsters hprt locus.","date":"1996","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/8625468","citation_count":65,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"11408353","id":"PMC_11408353","title":"N-glucuronidation of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and N_hydroxy-PhIP by specific human UDP-glucuronosyltransferases.","date":"2001","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/11408353","citation_count":63,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32492392","id":"PMC_32492392","title":"Exome Sequencing Identifies Genes and Gene Sets Contributing to Severe Childhood Obesity, Linking PHIP Variants to Repressed POMC Transcription.","date":"2020","source":"Cell metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/32492392","citation_count":62,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29089422","id":"PMC_29089422","title":"A cryptic Tudor domain links BRWD2/PHIP to COMPASS-mediated histone H3K4 methylation.","date":"2017","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/29089422","citation_count":58,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"20715105","id":"PMC_20715105","title":"NADPH oxidase overexpression in human colon cancers and rat colon tumors induced by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP).","date":"2010","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/20715105","citation_count":58,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17416774","id":"PMC_17416774","title":"Grilled meat consumption and PhIP-DNA adducts in prostate carcinogenesis.","date":"2007","source":"Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/17416774","citation_count":57,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9328177","id":"PMC_9328177","title":"Metabolism of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) by human cytochrome P4501B1.","date":"1997","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/9328177","citation_count":56,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"27900362","id":"PMC_27900362","title":"De novo PHIP-predicted deleterious variants are associated with developmental delay, intellectual disability, obesity, and dysmorphic features.","date":"2016","source":"Cold Spring Harbor molecular case studies","url":"https://pubmed.ncbi.nlm.nih.gov/27900362","citation_count":55,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32410729","id":"PMC_32410729","title":"Identification of novel, clinically correlated autoantigens in the monogenic autoimmune syndrome APS1 by proteome-wide PhIP-Seq.","date":"2020","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/32410729","citation_count":55,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"15680679","id":"PMC_15680679","title":"Coffee diterpenes prevent the genotoxic effects of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and N-nitrosodimethylamine in a human derived liver cell line (HepG2).","date":"2005","source":"Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association","url":"https://pubmed.ncbi.nlm.nih.gov/15680679","citation_count":55,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"18680760","id":"PMC_18680760","title":"ABCG2/BCRP decreases the transfer of a food-born chemical carcinogen, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in perfused term human placenta.","date":"2008","source":"Toxicology and applied pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/18680760","citation_count":55,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"12351148","id":"PMC_12351148","title":"Molecular and genetic toxicology of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP).","date":"2002","source":"Mutation research","url":"https://pubmed.ncbi.nlm.nih.gov/12351148","citation_count":54,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"12438004","id":"PMC_12438004","title":"Protection by beverages, fruits, vegetables, herbs, and flavonoids against genotoxicity of 2-acetylaminofluorene and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in metabolically competent V79 cells.","date":"2002","source":"Mutation research","url":"https://pubmed.ncbi.nlm.nih.gov/12438004","citation_count":54,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17638922","id":"PMC_17638922","title":"Glucuronidation of PhIP and N-OH-PhIP by UDP-glucuronosyltransferase 1A10.","date":"2007","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/17638922","citation_count":51,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"7586192","id":"PMC_7586192","title":"Possible mechanisms for PhIP-DNA adduct formation in the mammary gland of female Sprague-Dawley rats.","date":"1995","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/7586192","citation_count":51,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17279779","id":"PMC_17279779","title":"A comprehensive investigation of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) metabolism in the mouse using a multivariate data analysis approach.","date":"2007","source":"Chemical research in toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/17279779","citation_count":51,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16232193","id":"PMC_16232193","title":"Modeling human colon cancer in rodents using a food-borne carcinogen, PhIP.","date":"2005","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/16232193","citation_count":49,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24594156","id":"PMC_24594156","title":"Ammonia and formaldehyde participate in the formation of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in addition to creati(ni)ne and phenylacetaldehyde.","date":"2014","source":"Food chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24594156","citation_count":49,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30248218","id":"PMC_30248218","title":"Metabolic Studies of Tumor Cells Using [1-13 C] Pyruvate Hyperpolarized by Means of PHIP-Side Arm Hydrogenation.","date":"2018","source":"Chemphyschem : a European journal of chemical physics and physical chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/30248218","citation_count":46,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29209020","id":"PMC_29209020","title":"A genotype-first approach identifies an intellectual disability-overweight syndrome caused by PHIP haploinsufficiency.","date":"2017","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/29209020","citation_count":44,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17636024","id":"PMC_17636024","title":"Identification of a WD40 repeat-containing isoform of PHIP as a novel regulator of beta-cell growth and survival.","date":"2007","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/17636024","citation_count":44,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"15310245","id":"PMC_15310245","title":"Human UDP-glucuronosyltransferase 1A1 is the primary enzyme responsible for the N-glucuronidation of N-hydroxy-PhIP in vitro.","date":"2004","source":"Chemical research in toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/15310245","citation_count":44,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9766658","id":"PMC_9766658","title":"Immunohistochemical demonstration of carcinogen-DNA adducts in tissues of rats given 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP): detection in paraffin-embedded sections and tissue distribution.","date":"1998","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/9766658","citation_count":43,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"12351151","id":"PMC_12351151","title":"Response of Apc(min) and A33 (delta N beta-cat) mutant mice to treatment with tea, sulindac, and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP).","date":"2002","source":"Mutation research","url":"https://pubmed.ncbi.nlm.nih.gov/12351151","citation_count":42,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"10962432","id":"PMC_10962432","title":"Effect of diet on serum albumin and hemoglobin adducts of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in humans.","date":"2000","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/10962432","citation_count":42,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23484039","id":"PMC_23484039","title":"Combined genotoxic effects of a polycyclic aromatic hydrocarbon (B(a)P) and an heterocyclic amine (PhIP) in relation to colorectal carcinogenesis.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23484039","citation_count":41,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30018425","id":"PMC_30018425","title":"The replication initiation determinant protein (RepID) modulates replication by recruiting CUL4 to chromatin.","date":"2018","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/30018425","citation_count":40,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22511720","id":"PMC_22511720","title":"Pleckstrin homology domain-interacting protein (PHIP) as a marker and mediator of melanoma metastasis.","date":"2012","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/22511720","citation_count":40,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"12351154","id":"PMC_12351154","title":"Mammary gland carcinogenesis by food-derived heterocyclic amines and studies on the mechanisms of carcinogenesis of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP).","date":"2002","source":"Mutation research","url":"https://pubmed.ncbi.nlm.nih.gov/12351154","citation_count":40,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"36300623","id":"PMC_36300623","title":"Autoantibody discovery across monogenic, acquired, and COVID-19-associated autoimmunity with scalable PhIP-seq.","date":"2022","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/36300623","citation_count":39,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"7955104","id":"PMC_7955104","title":"In vitro formation and degradation of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) protein adducts.","date":"1994","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/7955104","citation_count":37,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"1747929","id":"PMC_1747929","title":"The effect of dose and enzyme inducers on the metabolism of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in rats.","date":"1991","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/1747929","citation_count":35,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"18293303","id":"PMC_18293303","title":"Consumption of Brussels sprouts protects peripheral human lymphocytes against 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and oxidative DNA-damage: results of a controlled human intervention trial.","date":"2008","source":"Molecular nutrition & food research","url":"https://pubmed.ncbi.nlm.nih.gov/18293303","citation_count":35,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"12663521","id":"PMC_12663521","title":"Carcinogenesis of the food mutagen PhIP in mice is independent of CYP1A2.","date":"2003","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/12663521","citation_count":34,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9862191","id":"PMC_9862191","title":"Genetic analysis of PHIP intestinal mutations in MutaMouse.","date":"1998","source":"Mutagenesis","url":"https://pubmed.ncbi.nlm.nih.gov/9862191","citation_count":34,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"12351153","id":"PMC_12351153","title":"A rat colon cancer model induced by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine, PhIP.","date":"2002","source":"Mutation research","url":"https://pubmed.ncbi.nlm.nih.gov/12351153","citation_count":33,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"27599846","id":"PMC_27599846","title":"DNA damage response curtails detrimental replication stress and chromosomal instability induced by the dietary carcinogen PhIP.","date":"2016","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/27599846","citation_count":33,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17156947","id":"PMC_17156947","title":"Mechanisms of action of the carcinogenic heterocyclic amine PhIP.","date":"2006","source":"Toxicology letters","url":"https://pubmed.ncbi.nlm.nih.gov/17156947","citation_count":33,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32273388","id":"PMC_32273388","title":"PHIP drives glioblastoma motility and invasion by regulating the focal adhesion complex.","date":"2020","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/32273388","citation_count":32,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"14601045","id":"PMC_14601045","title":"Genetic polymorphisms and modulation of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-DNA adducts in human lymphocytes.","date":"2003","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/14601045","citation_count":32,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26004342","id":"PMC_26004342","title":"Curcumin inhibits PhIP induced cytotoxicity in breast epithelial cells through multiple molecular targets.","date":"2015","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/26004342","citation_count":32,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"11867197","id":"PMC_11867197","title":"Inhibition of conjugated fatty acids derived from safflower or perilla oil of induction and development of mammary tumors in rats induced by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP).","date":"2002","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/11867197","citation_count":32,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"7955116","id":"PMC_7955116","title":"Removal of DNA adducts of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in the male Fischer-344 rat.","date":"1994","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/7955116","citation_count":32,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31911655","id":"PMC_31911655","title":"The RepID-CRL4 ubiquitin ligase complex regulates metaphase to anaphase transition via BUB3 degradation.","date":"2020","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/31911655","citation_count":31,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"1576715","id":"PMC_1576715","title":"Metabolism of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in mice.","date":"1992","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/1576715","citation_count":31,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"34819353","id":"PMC_34819353","title":"A trivalent nucleosome interaction by PHIP/BRWD2 is disrupted in neurodevelopmental disorders and cancer.","date":"2021","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/34819353","citation_count":30,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8001231","id":"PMC_8001231","title":"DNA adduct levels of 2-amino-1-methyl-6-phenylimidazo-[4,5-b]pyridine (PhIP) in tissues of cynomolgus monkeys after single or multiple dosing.","date":"1994","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/8001231","citation_count":30,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"10503897","id":"PMC_10503897","title":"Comparative biotransformation studies of MeIQx and PhIP in animal models and humans.","date":"1999","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/10503897","citation_count":29,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"12856103","id":"PMC_12856103","title":"Effect of chrysin, a flavonoid compound, on the mutagenic activity of 2-amino-1-methyl-6-phenylimidazo[4,5- b]pyridine (PhIP) and benzo(a)pyrene (B(a)P) in bacterial and human hepatoma (HepG2) cells.","date":"2003","source":"Archives of toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/12856103","citation_count":29,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8657203","id":"PMC_8657203","title":"Effects of phenethyl isothiocyanate on metabolism and on genotoxicity of dimethylnitrosamine and 2-amino-1-methyl-6-phenylimidazo[4, 5-beta]pyridine (PhIP).","date":"1996","source":"Mutation research","url":"https://pubmed.ncbi.nlm.nih.gov/8657203","citation_count":28,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"11285198","id":"PMC_11285198","title":"Intestinal toxicity and carcinogenic potential of the food mutagen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in DNA repair deficient XPA-/- mice.","date":"2001","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/11285198","citation_count":28,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30698310","id":"PMC_30698310","title":"Ultrafast Single-Scan 2D NMR Spectroscopic Detection of a PHIP-Hyperpolarized Protease Inhibitor.","date":"2019","source":"Chemistry (Weinheim an der Bergstrasse, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/30698310","citation_count":26,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16527260","id":"PMC_16527260","title":"Cytochrome P450 expression and metabolic activation of cooked food mutagen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in MCF10A breast epithelial cells.","date":"2006","source":"Chemico-biological interactions","url":"https://pubmed.ncbi.nlm.nih.gov/16527260","citation_count":26,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9364003","id":"PMC_9364003","title":"Reduction in formation of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-induced aberrant crypt foci in the rat colon by docosahexaenoic acid (DHA).","date":"1997","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/9364003","citation_count":26,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16533016","id":"PMC_16533016","title":"PhIP carcinogenicity in breast cancer: computational and experimental evidence for competitive interactions with human estrogen receptor.","date":"2005","source":"Chemical research in toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/16533016","citation_count":25,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29866840","id":"PMC_29866840","title":"PHIP as a therapeutic target for driver-negative subtypes of melanoma, breast, and lung cancer.","date":"2018","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/29866840","citation_count":25,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17052995","id":"PMC_17052995","title":"Mouse lung CYP1A1 catalyzes the metabolic activation of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP).","date":"2006","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/17052995","citation_count":25,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"12067574","id":"PMC_12067574","title":"2-Amino-1-methyl-6-(5-hydroxy-)phenylimidazo[4,5-b]pyridine (5-OH-PhIP), a biomarker for the genotoxic dose of the heterocyclic amine, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP).","date":"2002","source":"Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association","url":"https://pubmed.ncbi.nlm.nih.gov/12067574","citation_count":25,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32363160","id":"PMC_32363160","title":"In-vitro NMR Studies of Prostate Tumor Cell Metabolism by Means of Hyperpolarized [1-13C]Pyruvate Obtained Using the PHIP-SAH Method.","date":"2020","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/32363160","citation_count":24,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8269621","id":"PMC_8269621","title":"Metabolism of the food-derived mutagen/carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in nonhuman primates.","date":"1993","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/8269621","citation_count":24,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8895492","id":"PMC_8895492","title":"Short-term carcinogenicity testing of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) in E(mu)-pim-1 transgenic mice.","date":"1996","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/8895492","citation_count":24,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"10965019","id":"PMC_10965019","title":"More frequent beta-catenin gene mutations in adenomas than in aberrant crypt foci or adenocarcinomas in the large intestines of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-treated rats.","date":"2000","source":"Japanese journal of cancer research : Gann","url":"https://pubmed.ncbi.nlm.nih.gov/10965019","citation_count":23,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31167805","id":"PMC_31167805","title":"Clinical and genetic characterization of individuals with predicted deleterious PHIP variants.","date":"2019","source":"Cold Spring Harbor molecular case studies","url":"https://pubmed.ncbi.nlm.nih.gov/31167805","citation_count":22,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"7767987","id":"PMC_7767987","title":"Identification of aprt gene mutations induced in repair-deficient and P450-expressing CHO cells by the food-related mutagen/carcinogen, PhIP.","date":"1995","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/7767987","citation_count":22,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"34582963","id":"PMC_34582963","title":"Cyanidin-3-O-glucoside and its metabolite protocatechuic acid ameliorate 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) induced cytotoxicity in HepG2 cells by regulating apoptotic and Nrf2/p62 pathways.","date":"2021","source":"Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association","url":"https://pubmed.ncbi.nlm.nih.gov/34582963","citation_count":21,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16908439","id":"PMC_16908439","title":"Detection of 2-amino-1-methyl-6-phenylimidazo [4,5-b]-pyridine (PhIP)-DNA adducts in human pancreatic tissues.","date":"2006","source":"Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals","url":"https://pubmed.ncbi.nlm.nih.gov/16908439","citation_count":21,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22138251","id":"PMC_22138251","title":"Protective effects of xanthohumol against the genotoxicity of heterocyclic aromatic amines MeIQx and PhIP in bacteria and in human hepatoma (HepG2) cells.","date":"2011","source":"Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association","url":"https://pubmed.ncbi.nlm.nih.gov/22138251","citation_count":20,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"10985566","id":"PMC_10985566","title":"Mass spectrometric detection and measurement of N2-(2'-deoxyguanosin-8-yl)PhIP adducts in DNA.","date":"2000","source":"Journal of chromatography. B, Biomedical sciences and applications","url":"https://pubmed.ncbi.nlm.nih.gov/10985566","citation_count":20,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24877718","id":"PMC_24877718","title":"The cooked meat-derived mammary carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) elicits estrogenic-like microRNA responses in breast cancer cells.","date":"2014","source":"Toxicology letters","url":"https://pubmed.ncbi.nlm.nih.gov/24877718","citation_count":20,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"20816727","id":"PMC_20816727","title":"The full-length isoform of the mouse pleckstrin homology domain-interacting protein (PHIP) is required for postnatal growth.","date":"2010","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/20816727","citation_count":20,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"15066585","id":"PMC_15066585","title":"Inhibitory effects of beer on heterocyclic amine-induced mutagenesis and PhIP-induced aberrant crypt foci in rat colon.","date":"2004","source":"Mutation research","url":"https://pubmed.ncbi.nlm.nih.gov/15066585","citation_count":20,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8921513","id":"PMC_8921513","title":"Organ distinctive mutagenicity in MutaMouse after short-term exposure to PhIP.","date":"1996","source":"Mutagenesis","url":"https://pubmed.ncbi.nlm.nih.gov/8921513","citation_count":20,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"36726590","id":"PMC_36726590","title":"PHIP-associated Chung-Jansen syndrome: Report of 23 new individuals.","date":"2023","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/36726590","citation_count":19,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35631089","id":"PMC_35631089","title":"Phage ImmunoPrecipitation Sequencing (PhIP-Seq): The Promise of High Throughput Serology.","date":"2022","source":"Pathogens (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/35631089","citation_count":19,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"7586200","id":"PMC_7586200","title":"DNA-binding and disposition of 2-amino-1-methyl-6-phenylimidazo[4,5-b] pyridine (PhIP) in the rat.","date":"1995","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/7586200","citation_count":19,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24334255","id":"PMC_24334255","title":"Bcrp1;Mdr1a/b;Mrp2 combination knockout mice: altered disposition of the dietary carcinogen PhIP (2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine) and its genotoxic metabolites.","date":"2013","source":"Molecular pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/24334255","citation_count":19,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9760588","id":"PMC_9760588","title":"Bioactivation of the proximal food mutagen 2-hydroxyamino-1-methyl-6-phenylimidazo[4,5-b]pyridine (N-OH-PhIP) to DNA-binding species by human mammary gland enzymes.","date":"1998","source":"Nutrition (Burbank, Los Angeles County, Calif.)","url":"https://pubmed.ncbi.nlm.nih.gov/9760588","citation_count":19,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"15635146","id":"PMC_15635146","title":"Induction of colon tumors in C57BL/6J mice fed MeIQx, IQ, or PhIP followed by dextran sulfate sodium treatment.","date":"2005","source":"Toxicological sciences : an official journal of the Society of Toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/15635146","citation_count":19,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17487839","id":"PMC_17487839","title":"Racial differences in clinical and pathological associations with PhIP-DNA adducts in prostate.","date":"2007","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/17487839","citation_count":18,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"10050262","id":"PMC_10050262","title":"Inhibition of DNA adduct formation of PhIP in female F344 rats by dietary conjugated linoleic acid.","date":"1998","source":"Nutrition and cancer","url":"https://pubmed.ncbi.nlm.nih.gov/10050262","citation_count":18,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26295367","id":"PMC_26295367","title":"Protective activity of probiotic bacteria against 2-amino-3-methyl-3H-imidazo[4,5-f]quinoline (IQ) and 2-amino-1-methyl-6-phenyl-1H-imidazo[4,5-b]pyridine (PhIP) - an in vitro study.","date":"2015","source":"Food additives & contaminants. Part A, Chemistry, analysis, control, exposure & risk assessment","url":"https://pubmed.ncbi.nlm.nih.gov/26295367","citation_count":18,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"12507937","id":"PMC_12507937","title":"H-ras oncogene mutations during development of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-induced rat mammary gland cancer.","date":"2002","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/12507937","citation_count":18,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"10383905","id":"PMC_10383905","title":"2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) retards mammary gland involution in lactating Sprague-Dawley rats.","date":"1999","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/10383905","citation_count":18,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"36857108","id":"PMC_36857108","title":"Real-Time Pyruvate Chemical Conversion Monitoring Enabled by PHIP.","date":"2023","source":"Journal of the American Chemical Society","url":"https://pubmed.ncbi.nlm.nih.gov/36857108","citation_count":17,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23400709","id":"PMC_23400709","title":"2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-DNA adducts in benign prostate and subsequent risk for prostate cancer.","date":"2013","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/23400709","citation_count":17,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"10050263","id":"PMC_10050263","title":"Effects of dietary conjugated linoleic acid on DNA adduct formation of PhIP and IQ after bolus administration to female F344 rats.","date":"1998","source":"Nutrition and cancer","url":"https://pubmed.ncbi.nlm.nih.gov/10050263","citation_count":17,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17936011","id":"PMC_17936011","title":"New insights in the formation of deoxynucleoside adducts with the heterocyclic aromatic amines PhIP and IQ by means of ion trap MSn and accurate mass measurement of fragment ions.","date":"2007","source":"Journal of the American Society for Mass Spectrometry","url":"https://pubmed.ncbi.nlm.nih.gov/17936011","citation_count":17,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16169070","id":"PMC_16169070","title":"A human protein-protein interaction network: a resource for annotating the proteome.","date":"2005","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/16169070","citation_count":1704,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12477932","id":"PMC_12477932","title":"Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.","date":"2002","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/12477932","citation_count":1479,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"22464331","id":"PMC_22464331","title":"Histone recognition and large-scale structural analysis of the human bromodomain family.","date":"2012","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/22464331","citation_count":1328,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"23033978","id":"PMC_23033978","title":"Diagnostic exome sequencing in persons with severe intellectual disability.","date":"2012","source":"The New England journal of medicine","url":"https://pubmed.ncbi.nlm.nih.gov/23033978","citation_count":1245,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26496610","id":"PMC_26496610","title":"A human interactome in three quantitative dimensions organized by stoichiometries and abundances.","date":"2015","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/26496610","citation_count":1015,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"29507755","id":"PMC_29507755","title":"VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation.","date":"2018","source":"Cell discovery","url":"https://pubmed.ncbi.nlm.nih.gov/29507755","citation_count":829,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"14702039","id":"PMC_14702039","title":"Complete sequencing and characterization of 21,243 full-length human cDNAs.","date":"2003","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/14702039","citation_count":754,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21873635","id":"PMC_21873635","title":"Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium.","date":"2011","source":"Briefings in bioinformatics","url":"https://pubmed.ncbi.nlm.nih.gov/21873635","citation_count":656,"is_preprint":false,"source_track":"gene2pubmed"},{"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":585,"is_preprint":false,"source_track":"gene2pubmed"},{"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":538,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26638075","id":"PMC_26638075","title":"A Dynamic Protein Interaction Landscape of the Human Centrosome-Cilium Interface.","date":"2015","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/26638075","citation_count":433,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"35271311","id":"PMC_35271311","title":"OpenCell: Endogenous tagging for the cartography of human cellular organization.","date":"2022","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/35271311","citation_count":432,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"16344560","id":"PMC_16344560","title":"Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes.","date":"2005","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/16344560","citation_count":409,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26344197","id":"PMC_26344197","title":"Panorama of ancient metazoan macromolecular complexes.","date":"2015","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/26344197","citation_count":407,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"34079125","id":"PMC_34079125","title":"A proximity-dependent biotinylation map of a human cell.","date":"2021","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/34079125","citation_count":339,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21145461","id":"PMC_21145461","title":"Dynamics of cullin-RING ubiquitin ligase network revealed by systematic quantitative proteomics.","date":"2010","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/21145461","citation_count":318,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"23752268","id":"PMC_23752268","title":"The functional interactome landscape of the human histone deacetylase family.","date":"2013","source":"Molecular systems biology","url":"https://pubmed.ncbi.nlm.nih.gov/23752268","citation_count":235,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"25281560","id":"PMC_25281560","title":"Proximity biotinylation and affinity purification are complementary approaches for the interactome mapping of chromatin-associated protein complexes.","date":"2014","source":"Journal of proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/25281560","citation_count":215,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"25593309","id":"PMC_25593309","title":"Screen identifies bromodomain protein ZMYND8 in chromatin recognition of transcription-associated DNA damage that promotes homologous recombination.","date":"2015","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/25593309","citation_count":203,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21834987","id":"PMC_21834987","title":"Identification and characterization of a set of conserved and new regulators of cytoskeletal organization, cell morphology and migration.","date":"2011","source":"BMC biology","url":"https://pubmed.ncbi.nlm.nih.gov/21834987","citation_count":164,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"33004838","id":"PMC_33004838","title":"Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders.","date":"2020","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/33004838","citation_count":161,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15009096","id":"PMC_15009096","title":"Proteomics analysis of the centromere complex from HeLa interphase cells: UV-damaged DNA binding protein 1 (DDB-1) is a component of the CEN-complex, while BMI-1 is transiently co-localized with the centromeric region in interphase.","date":"2004","source":"Genes to cells : devoted to molecular & cellular mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/15009096","citation_count":151,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"32877691","id":"PMC_32877691","title":"A High-Density Human Mitochondrial Proximity Interaction Network.","date":"2020","source":"Cell metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/32877691","citation_count":148,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"22586326","id":"PMC_22586326","title":"Functional proteomics establishes the interaction of SIRT7 with chromatin remodeling complexes and expands its role in regulation of RNA polymerase I transcription.","date":"2012","source":"Molecular & cellular proteomics : MCP","url":"https://pubmed.ncbi.nlm.nih.gov/22586326","citation_count":145,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"31871319","id":"PMC_31871319","title":"Mapping the proximity interaction network of the Rho-family GTPases reveals signalling pathways and regulatory mechanisms.","date":"2019","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/31871319","citation_count":137,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"30554943","id":"PMC_30554943","title":"Interactome Rewiring Following Pharmacological Targeting of BET Bromodomains.","date":"2018","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/30554943","citation_count":136,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"10737800","id":"PMC_10737800","title":"Shotgun sequencing of the human transcriptome with ORF expressed sequence tags.","date":"2000","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/10737800","citation_count":135,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"24457600","id":"PMC_24457600","title":"The central role of EED in the orchestration of polycomb group complexes.","date":"2014","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/24457600","citation_count":131,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"23376485","id":"PMC_23376485","title":"Proteomic analysis of podocyte exosome-enriched fraction from normal human urine.","date":"2013","source":"Journal of proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/23376485","citation_count":126,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"31753913","id":"PMC_31753913","title":"Systematic bromodomain protein screens identify homologous recombination and R-loop suppression pathways involved in genome integrity.","date":"2019","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/31753913","citation_count":110,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":58520,"output_tokens":3743,"usd":0.115852},"stage2":{"model":"claude-opus-4-6","input_tokens":6958,"output_tokens":3075,"usd":0.167497},"total_usd":0.5965,"stage1_batch_id":"msgbatch_01SUR8NDzVrNmyszWyJeCct7","stage2_batch_id":"msgbatch_01G7Yfutko3cDWzejrwH5AMx","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":71197,"output_tokens":4473,"usd":0.140343},"round2_rules_fired":"R2","round2_stage2":{"model":"claude-opus-4-6","input_tokens":7581,"output_tokens":3092,"usd":0.172808}},"stage1_raw":"Looking through the abstracts, I need to identify papers about the PHIP gene (pleckstrin homology domain-interacting protein), not the chemical carcinogen PhIP (2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine). The relevant papers are #16, #17, #21, #33, #34, #40, #41, #52, #57, #59, #69, #76, #83, and #86.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2007,\n      \"finding\": \"A larger, 1,821-amino-acid WD40 repeat-containing isoform of PHIP (PHIP1/DCAF14) is predominantly expressed in the nucleus of pancreatic beta-cells. PHIP1 overexpression stimulates IGF-1-dependent and -independent beta-cell proliferation by transcriptionally upregulating the cyclin D2 promoter and increasing cyclin D2 protein levels. RNAi knockdown of PHIP1 abrogates IRS2-mediated DNA synthesis. PHIP1 overexpression also blocks free fatty acid-induced apoptosis via activation of PKB/AKT and inhibition of caspase-9 and caspase-3 cleavage, an effect attenuated by dominant-negative PKB.\",\n      \"method\": \"Molecular cloning, immunoblotting, immunohistochemistry, RNAi knockdown, overexpression with proliferation assays, cyclin D2 promoter reporter assay, dominant-negative PKB overexpression, caspase activity assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (cloning, RNAi, OE, reporter assay, signaling readouts) in single study with rigorous controls\",\n      \"pmids\": [\"17636024\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Mice lacking PHIP1 (the full-length isoform of PHIP) are born at normal size but develop a ~40% growth deficit by weaning, hypoglycemia, and die within 4-5 weeks postnatally. PHIP1-deficient mouse embryonic fibroblasts grow markedly slower than wild-type but exhibit normal AKT phosphorylation and increased cell proliferation in response to IGF-1, indicating PHIP1 regulates postnatal growth in an IGF-1/AKT pathway-independent manner.\",\n      \"method\": \"Genetic knockout mouse model, growth measurements, blood glucose assays, MEF proliferation assays, AKT phosphorylation western blotting, IGF-1 stimulation\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined phenotypic readouts and epistasis placing PHIP1 outside the IGF-1/AKT axis\",\n      \"pmids\": [\"20816727\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PHIP promotes melanoma metastasis. Systemic shRNA-mediated suppression of Phip inhibited metastatic progression of melanoma in vivo, and stable Phip suppression in melanoma cell lines suppressed metastatic potential and prolonged survival of tumor-bearing mice. The PHIP locus was preserved (not deleted) in melanoma, and PHIP overexpression was associated with increased PHIP copy number.\",\n      \"method\": \"Plasmid-based shRNA in vivo, stable shRNA knockdown in cell lines, tumor progression assays, survival analysis, copy number analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo shRNA knockdown with defined metastatic phenotype, replicated across cell lines and in vivo models\",\n      \"pmids\": [\"22511720\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"BRWD2/PHIP colocalizes with histone H3K4 methylation genome-wide in human cells, mouse embryonic stem cells, and Drosophila. PHIP binds directly to H3K4 methylation through a novel chromatin-binding module called the CryptoTudor domain. PHIP also associates biochemically with the CRL4 (Cullin-4-RING ubiquitin E3 ligase-4) complex, nucleosomes, and chromatin remodelers. CRISPR-Cas9 knockout of COMPASS H3K4 methyltransferase family members differentially regulates BRWD2/PHIP chromatin occupancy. Depletion of the Drosophila homolog dBRWD3 results in altered gene expression and aberrant H3K27 acetylation at enhancers and promoters.\",\n      \"method\": \"ChIP-seq (genome-wide colocalization), biochemical pulldown/co-IP with CRL4 complex and nucleosomes, direct binding assay to H3K4me, CRISPR-Cas9 KO of COMPASS members, Drosophila genetic depletion with RNA-seq and ChIP-seq\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct binding demonstrated, CRISPR epistasis, genome-wide occupancy, multiple organisms and orthogonal methods in single study\",\n      \"pmids\": [\"29089422\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"RepID (DCAF14/PHIP) recruits the CRL4 ubiquitin ligase complex to chromatin prior to DNA synthesis, playing a crucial architectural role in licensing chromosomes for replication. In the absence of RepID, cells rely on the alternative ubiquitin ligase SKP2-containing SCF complex to progress through the cell cycle. RepID depletion markedly increases cellular sensitivity to SKP2 inhibitors, triggering genome re-replication. RepID and SKP2 interact with distinct, non-overlapping groups of replication origins.\",\n      \"method\": \"RepID depletion (knockdown/KO), origin binding assays, SKP2 inhibitor sensitivity assays, re-replication assays, ChIP for origin binding, genetic epistasis with SKP2\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods, genetic epistasis, defined mechanistic phenotype in single rigorous study\",\n      \"pmids\": [\"30018425\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PHIP's bromodomain is functional and specifically binds the histone modification H4K91ac. Suppression of PHIP expression in triple-negative breast cancer, bronchioid lung cancer, and melanoma significantly inhibited tumor cell proliferation and invasion, coordinately suppressing phosphorylated AKT, cyclin D1, and talin1 expression across all three tumor types.\",\n      \"method\": \"Bromodomain binding assay (H4K91ac), shRNA knockdown in multiple tumor cell lines, proliferation and invasion assays, western blotting for AKT/cyclin D1/talin1, TCGA expression analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — bromodomain binding assay plus functional KD phenotypes across multiple tumor types, moderate evidence for downstream signaling pathway placement\",\n      \"pmids\": [\"29866840\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Nuclear PHIP directly enhances transcription of pro-opiomelanocortin (POMC), a neuropeptide that suppresses appetite. Obesity-associated PHIP variants identified by exome sequencing repress POMC transcription in cell-based assays, implicating PHIP in energy homeostasis through transcriptional regulation of central melanocortin signaling.\",\n      \"method\": \"Exome sequencing for variant identification, cell-based POMC transcription assays with wild-type and variant PHIP, nuclear localization determination\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct transcription assay in cells linking specific variants to POMC regulation; single lab with limited mechanistic depth on the transcriptional mechanism\",\n      \"pmids\": [\"32492392\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PHIP localizes to the leading edge of glioblastoma cells at the force transduction layer of the focal adhesion complex, co-localizing with vinculin (VCL), talin 1 (TLN1), integrin beta 1 (ITGB1), paxillin (pPXN), and focal adhesion kinase (pFAK). Immunoprecipitation demonstrated a direct physical interaction between PHIP and VCL. PHIP silencing downregulated these focal adhesion proteins and zyxin (ZYX), caused disorganized stress fibers, and suppressed migratory and invasive capacity. Overexpression of TLN1 or ZYX partially restored migration after PHIP knockdown. PHIP knockdown also suppressed tumor growth in vivo and reduced microvessel density and secreted VEGF.\",\n      \"method\": \"Immunofluorescence/confocal microscopy for subcellular localization, co-immunoprecipitation (PHIP-VCL), shRNA knockdown, migration/invasion assays, live-cell imaging with ZYX-GFP, TLN1/ZYX rescue overexpression, intracranial tumor implantation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, defined subcellular localization with functional consequence, epistatic rescue experiments, in vivo validation\",\n      \"pmids\": [\"32273388\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The CRL4 ubiquitin ligase complex, recruited to chromatin by RepID/DCAF14/PHIP during interphase, dissociates from RepID during mitosis and instead associates with RBBP7, which then ubiquitinates the spindle assembly checkpoint (SAC) mediator BUB3 to enable mitotic exit (metaphase to anaphase transition). During interphase, BUB3 is protected from CRL4-mediated degradation by associating with PML nuclear bodies. Deficiencies in RepID, CRL4, or RBBP7 delay mitotic exit, increase genomic instability, and enhance sensitivity to paclitaxel.\",\n      \"method\": \"Co-IP (CRL4-RBBP7 interaction), ubiquitination assay (BUB3), genetic KD/KO of RepID/CRL4/RBBP7, mitotic exit timing assays, cell fractionation, paclitaxel sensitivity assays, PML body association assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — ubiquitination substrate identified, multiple Co-IPs, KO phenotypes with defined molecular mechanism across multiple components\",\n      \"pmids\": [\"31911655\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PHIP/BRWD2 is a chromatin-associated CRL4 ubiquitin ligase substrate receptor required for CRL4 recruitment to chromatin. PHIP binds chromatin through a trivalent reader domain: a CryptoTudor domain (H3K4-methyl binding) and two bromodomains—BD1 reads H3K14ac and BD2 reads H4K12ac—characterized using semisynthetic nucleosomes with defined histone PTMs. Human neurodevelopmental disease-associated mutations map to each domain and the linker region and likely disrupt chromatin binding.\",\n      \"method\": \"Semisynthetic nucleosome binding assays with defined histone PTMs (H3K14ac, H4K12ac), CRL4 co-IP/recruitment assay, domain mutagenesis mapping disease variants, bromodomain binding characterization\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted semisynthetic nucleosome binding assays with defined PTMs, mutagenesis of disease variants, mechanistic validation of trivalent chromatin reading\",\n      \"pmids\": [\"34819353\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PHIP haploinsufficiency causes an intellectual disability-overweight syndrome. Genotype-first sequencing in 3,275 ID individuals identified enrichment of disruptive PHIP mutations; 23 individuals with PHIP mutations all had developmental delay/ID and the majority were overweight or obese. Phenotype analysis pointed to haploinsufficiency of the PHIP/DCAF14 isoform (not NDRP) as the causative mechanism, implicating PHIP's role in E3 ubiquitination and neurodevelopmental processes.\",\n      \"method\": \"MIP-based targeted re-sequencing, genotype-first approach with reverse phenotyping, genotype-phenotype correlation across 23 individuals\",\n      \"journal\": \"European journal of human genetics : EJHG\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — large-scale sequencing with phenotype correlation; mechanistic inference from isoform specificity but no direct functional experiment in this paper\",\n      \"pmids\": [\"29209020\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PHIP/BRWD2 (pleckstrin homology domain-interacting protein) is a multifunctional chromatin regulator that acts as a substrate receptor for the CRL4 ubiquitin ligase complex, which it recruits to chromatin via a trivalent reader module comprising a CryptoTudor domain (binding H3K4me) and two bromodomains (BD1 binding H3K14ac, BD2 binding H4K12ac); during mitosis CRL4 switches from RepID/PHIP to RBBP7 to ubiquitinate BUB3 and enable SAC termination, while during interphase PHIP regulates replication origin licensing, beta-cell growth and survival through cyclin D2 upregulation and AKT signaling, POMC transcription for energy homeostasis, and tumor cell motility/invasion through physical interaction with focal adhesion proteins including vinculin and talin1.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll classify each paper first, then extract discoveries only from KEEP papers.\n\n**Classification:**\n\nPapers about PHIP (pleckstrin homology domain-interacting protein, the canonical gene):\n- KEEP: [16], [17], [21], [33], [34], [40], [41], [52], [57], [59], [69], [76], [83], [86]\n- KEEP from additional: [3], [4], [9], [10]\n\nPapers about PhIP (2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine, food carcinogen): EXCLUDE [1],[3],[4],[6],[7],[8],[9],[10],[11],[12],[13],[14],[15],[18],[19],[20],[23],[24],[25],[26],[27],[28],[29],[30],[31],[36],[37],[38],[39],[42],[44],[45],[46],[47],[48],[49],[50],[51],[53],[54],[55],[56],[58],[60],[61],[62],[63],[64],[65 is PHIP-NMR not protein],[66],[67],[68],[70],[71],[73],[74],[75],[77],[78],[79],[80],[81],[82],[84],[85],[88],[89],[90],[91],[92],[93],[94],[95],[96],[98],[99],[100]\n\nPapers about PhIP-Seq (phage immunoprecipitation sequencing): EXCLUDE [2],[22],[43],[87]\n\nPapers about PHIP (NMR hyperpolarization method): EXCLUDE [5],[32],[65],[72],[97]\n\nAdditional curated papers:\n- KEEP: [3] Filippakopoulos bromodomain paper (relevant to PHIP bromodomains), [4] DDB1-CUL4 paper (relevant to PHIP/DCAF14 function), [9] Jin et al DCAF paper (PHIP is DCAF14), [10] Bennett et al CRL network\n- Many others are large-scale proteomics/interactome papers that tangentially mention PHIP — I'll include those where PHIP function is specifically addressed\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2007,\n      \"finding\": \"A larger 1,821-aa WD40 repeat-containing isoform of PHIP (PHIP1) is expressed in pancreatic beta-cell nuclei. PHIP1 overexpression stimulates IGF-1-dependent and -independent beta-cell proliferation by transcriptionally upregulating cyclin D2. RNAi knockdown of PHIP1 abrogates IRS2-mediated DNA synthesis. PHIP1 overexpression also blocks free fatty acid-induced apoptosis via activation of PKB/AKT and inhibition of caspase-9/-3 cleavage; dominant-negative PKB attenuates this cytoprotection.\",\n      \"method\": \"Cloning/immunoblotting, RNAi knockdown, cyclin D2 promoter-reporter assay, overexpression with dominant-negative PKB, apoptosis assays (caspase cleavage)\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (KD, OE, reporter assay, dominant-negative epistasis) in single rigorous study\",\n      \"pmids\": [\"17636024\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Mice lacking PHIP1 (the full-length isoform) are born at normal size but develop a ~40% postnatal growth deficit by weaning, hypoglycemia, and die at 4–5 weeks. PHIP1-deficient mouse embryonic fibroblasts proliferate markedly slower than wild-type but show normal AKT phosphorylation and increased cell proliferation in response to IGF-1, indicating PHIP1 regulates postnatal growth in an IGF-1/AKT pathway-independent manner.\",\n      \"method\": \"Conditional knockout mouse model, MEF proliferation assays, AKT phosphorylation western blot, IGF-1 stimulation\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined in vivo and cellular phenotypes, multiple readouts\",\n      \"pmids\": [\"20816727\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PHIP promotes melanoma metastasis; systemic shRNA targeting of Phip inhibited metastatic progression in vivo. Stable suppression of Phip in melanoma cell lines suppressed metastatic potential and prolonged survival of tumor-bearing mice. PHIP locus is preserved (not deleted) and overexpressed in melanoma, and elevated PHIP copy number was found in a high proportion of PHIP-overexpressing melanomas.\",\n      \"method\": \"Plasmid-based shRNA in vivo, stable shRNA knockdown in melanoma cell lines, mouse xenograft survival studies, copy number analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo shRNA suppression with defined metastasis and survival phenotypes, replicated across cell lines\",\n      \"pmids\": [\"22511720\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"BRWD2/PHIP colocalizes with histone H3K4 methylation genome-wide in human cells, mouse embryonic stem cells, and Drosophila. PHIP biochemically associates with the CRL4 (Cullin-4-RING ubiquitin E3 ligase) complex, nucleosomes, and chromatin remodelers. PHIP binds directly to H3K4 methylation through a previously unidentified chromatin-binding module related to Royal Family Tudor domains, named the CryptoTudor domain. COMPASS H3K4 methyltransferase family members differentially regulate BRWD2/PHIP chromatin occupancy. Depletion of the Drosophila homolog dBRWD3 results in altered gene expression and aberrant H3K27 acetylation at enhancers and promoters.\",\n      \"method\": \"ChIP-seq (genome-wide colocalization), biochemical pulldown/Co-IP (CRL4 complex, nucleosomes), direct binding assay with H3K4me peptides, CRISPR-Cas9 knockouts, Drosophila dBRWD3 depletion with gene expression and H3K27ac profiling\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods including direct binding, genome-wide chromatin localization, genetic KO, and cross-species validation\",\n      \"pmids\": [\"29089422\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PHIP's bromodomain is functional and specifically binds the histone modification H4K91ac. Suppression of PHIP significantly inhibited tumor cell proliferation and invasion in melanoma, triple-negative/basal-like breast cancer, and bronchioid NSCLC cell lines, coordinately suppressing phosphorylated AKT, cyclin D1, and talin1.\",\n      \"method\": \"Bromodomain binding assay (histone peptide array), shRNA suppression with proliferation and invasion assays, western blot for downstream effectors\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct bromodomain binding assay combined with loss-of-function phenotype across multiple tumor types\",\n      \"pmids\": [\"29866840\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"RepID/DCAF14/PHIP recruits the CRL4 ubiquitin ligase complex to chromatin prior to DNA synthesis, playing a crucial architectural role in licensing chromosomes for replication. In the absence of RepID, cells rely on the alternative ubiquitin ligase SKP2-containing SCF complex to progress through the cell cycle. RepID depletion markedly increases cellular sensitivity to SKP2 inhibitors, triggering massive genome re-replication. RepID and SKP2 interact with distinct, non-overlapping groups of replication origins.\",\n      \"method\": \"RepID depletion (siRNA/knockout), chromatin fractionation, origin-firing assays, SKP2 inhibitor sensitivity, re-replication assays, origin mapping\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KD/KO with defined replication phenotypes, epistasis with SKP2-SCF pathway, multiple orthogonal methods\",\n      \"pmids\": [\"30018425\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PHIP drives glioblastoma motility and invasion through effects on the force transduction layer of the focal adhesion complex. PHIP localizes to the leading edge of glioblastoma cells and to the force transduction layer specifically, co-localizing with talin 1 (TLN1), vinculin (VCL), integrin beta 1, paxillin (pPXN), and focal adhesion kinase (pFAK). Co-immunoprecipitation revealed a physical interaction between PHIP and VCL. PHIP silencing down-regulated these focal adhesion proteins and zyxin (ZYX), and produced disorganized stress fibers. PHIP knockdown suppressed tumor growth in intracranial implantation and reduced microvessel density and secreted VEGF levels. Migratory/invasive capacity was partially restored by TLN1 or ZYX cDNA overexpression.\",\n      \"method\": \"Immunofluorescence and confocal microscopy (localization), co-immunoprecipitation (PHIP–VCL interaction), shRNA knockdown, live-cell imaging (ZYX-GFP focal adhesion dynamics), rescue by cDNA overexpression, intracranial xenograft\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP binding partner identification, localization with functional consequence, in vivo xenograft, epistasis rescue experiment\",\n      \"pmids\": [\"32273388\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Nuclear PHIP directly enhances transcription of pro-opiomelanocortin (POMC), a neuropeptide that suppresses appetite. Obesity-associated PHIP variants (identified by exome sequencing) repressed POMC transcription in cell-based assays, linking PHIP haploinsufficiency to disrupted central melanocortin signaling and human energy homeostasis.\",\n      \"method\": \"Exome sequencing (variant identification), cell-based POMC transcription assays with wild-type and variant PHIP constructs\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct transcriptional assay with disease-associated variants, but single lab with limited mechanistic detail on transcriptional mechanism\",\n      \"pmids\": [\"32492392\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"RepID/PHIP is required for CRL4 recruitment to chromatin. During mitosis, CRL4 dissociates from RepID and associates with RBBP7, which ubiquitinates the spindle assembly checkpoint (SAC) mediator BUB3 to enable mitotic exit. During interphase, BUB3 is protected from CRL4-mediated degradation by association with PML nuclear bodies. Deficiencies in RepID, CRL4, or RBBP7 delay mitotic exit, increase genomic instability, and enhance sensitivity to paclitaxel.\",\n      \"method\": \"Co-IP (RepID–CRL4–RBBP7 interactions), ubiquitination assay (BUB3 as substrate), RNAi/KO depletion, mitotic exit timing assays, genomic instability and drug sensitivity assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — substrate identification with ubiquitination assay, Co-IP complex characterization, genetic depletion with defined mitotic phenotype\",\n      \"pmids\": [\"31911655\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PHIP is a chromatin-associated CRL4 ubiquitin ligase substrate receptor required for CRL4 recruitment to chromatin. PHIP binds chromatin through a trivalent reader module: a CryptoTudor domain (H3K4-methyl binding), bromodomain 1 (BD1, reader of H3K14ac), and bromodomain 2 (BD2, reader of H4K12ac). These interactions were characterized using semisynthetic nucleosomes with defined histone post-translational modifications. Human disease-associated (neurodevelopmental disorder/cancer) mutations map to each domain and the intervening linker region and likely disrupt chromatin binding.\",\n      \"method\": \"Semisynthetic nucleosome binding assays with defined PTMs, bromodomain binding characterization, disease-variant mutagenesis, CRL4 chromatin recruitment assays\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted nucleosome binding assays with defined modifications, mutagenesis of disease variants, multiple domains characterized\",\n      \"pmids\": [\"34819353\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PHIP haploinsufficiency (via de novo heterozygous frameshift, nonsense, and missense variants) causes a syndrome of developmental delay, intellectual disability, obesity, anxiety, hypotonia, and dysmorphic features. The phenotype overlaps with CUL4B deficiency, suggesting PHIP mutations cause disease through disruption of the ubiquitin ligase pathway. PHIP produces multiple protein products including PHIP1/DCAF14 (a CUL4-DDB1 substrate receptor) and NDRP.\",\n      \"method\": \"Whole-exome sequencing, clinical phenotyping, genotype-phenotype correlation\",\n      \"journal\": \"Cold Spring Harbor molecular case studies\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 — primarily genetic/clinical study; mechanistic pathway inference is indirect\",\n      \"pmids\": [\"27900362\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The DDB1-CUL4A-ROC1 ubiquitin ligase complex uses a novel family of WD40-repeat proteins as substrate-recruiting modules; PHIP/DCAF14 is among the DCAFs (DDB1- and CUL4-associated factors) identified by tandem-affinity purification of human DDB1 and CUL4A complexes followed by mass spectrometry, establishing PHIP as a substrate receptor of the CRL4 E3 ligase.\",\n      \"method\": \"Tandem affinity purification of DDB1/CUL4A complexes, mass spectrometry identification of WD40-repeat DCAFs, crystallographic analysis of DDB1 complex\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — structural and proteomic identification in a landmark study; PHIP/DCAF14 explicitly identified as CRL4 substrate receptor\",\n      \"pmids\": [\"16964240\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Large-scale structural analysis of the human bromodomain family identified PHIP as containing bromodomains. Crystal structures were determined for BRD family members and cross-family screening against histone-peptide arrays revealed acetylation-dependent substrate recognition; flanking PTMs influence bromodomain binding, suggesting BRDs recognize combinations of marks.\",\n      \"method\": \"X-ray crystallography (29 BRD structures), histone peptide array screening\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — high-quality structural study; PHIP bromodomains included in family-wide analysis but individual PHIP binding specificity not deeply characterized in this paper\",\n      \"pmids\": [\"22464331\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PHIP (pleckstrin homology domain-interacting protein/BRWD2/DCAF14/RepID) is a multifunctional chromatin regulator that acts as a substrate receptor for the CRL4 (CUL4-DDB1-ROC1) ubiquitin E3 ligase complex, which it recruits to chromatin through a trivalent histone reader module comprising a CryptoTudor domain (binding H3K4me), bromodomain 1 (binding H3K14ac), and bromodomain 2 (binding H4K12ac/H4K91ac); in this capacity it facilitates DNA replication origin licensing and, during mitosis, enables BUB3 ubiquitination and SAC termination via RBBP7; it also directly enhances POMC transcription to regulate energy homeostasis, promotes beta-cell proliferation and survival through cyclin D2 upregulation and PKB/AKT activation, and drives cancer cell motility/invasion by physically interacting with vinculin at the force transduction layer of the focal adhesion complex.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"PHIP (also known as BRWD2/DCAF14/RepID) is a multivalent chromatin reader and CRL4 ubiquitin ligase substrate receptor that integrates histone mark recognition with ubiquitin-dependent signaling to regulate DNA replication licensing, mitotic progression, transcription, and cell motility. PHIP engages chromatin through a trivalent reader module—a CryptoTudor domain binding H3K4 methylation and two bromodomains reading H3K14ac (BD1) and H4K12ac (BD2)—and recruits the CRL4 E3 ligase complex to chromatin during interphase, where it licenses replication origins in a pathway parallel to the SCF-SKP2 complex; during mitosis, CRL4 switches from PHIP to RBBP7 to ubiquitinate BUB3 and enable spindle assembly checkpoint termination [PMID:29089422, PMID:34819353, PMID:30018425, PMID:31911655]. Beyond replication and mitosis, PHIP activates transcription of cyclin D2 to drive beta-cell proliferation and survival via AKT signaling, transcriptionally enhances POMC expression for energy homeostasis, and localizes to focal adhesions where it physically interacts with vinculin and talin1 to promote tumor cell migration and invasion [PMID:17636024, PMID:32492392, PMID:32273388]. PHIP haploinsufficiency causes an intellectual disability–overweight syndrome, with neurodevelopmental disease-associated mutations mapping to each of its chromatin-reading domains [PMID:29209020, PMID:34819353].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"The identification of a full-length nuclear PHIP isoform and its ability to upregulate cyclin D2 and activate AKT established PHIP as a transcriptional regulator of beta-cell proliferation and survival, answering how IRS2 signaling drives beta-cell expansion.\",\n      \"evidence\": \"Molecular cloning, RNAi, overexpression, cyclin D2 promoter reporter, and caspase assays in pancreatic beta-cell lines\",\n      \"pmids\": [\"17636024\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Chromatin-level mechanism of cyclin D2 promoter activation unknown\",\n        \"Whether PHIP's proliferative role extends beyond beta-cells was not tested\",\n        \"Physiological relevance in vivo not yet established\"\n      ]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Knockout mice revealed that PHIP1 is essential for postnatal growth and survival but, surprisingly, this function is independent of the IGF-1/AKT axis previously implicated in vitro, refining the pathway placement of PHIP.\",\n      \"evidence\": \"PHIP1 knockout mouse with growth measurements, blood glucose, MEF proliferation, AKT phosphorylation, and IGF-1 stimulation assays\",\n      \"pmids\": [\"20816727\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The IGF-1/AKT-independent growth pathway controlled by PHIP remains unidentified\",\n        \"Cause of postnatal lethality not molecularly defined\",\n        \"Tissue-specific contributions not dissected\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstration that PHIP suppression inhibits melanoma metastasis in vivo established PHIP as a pro-metastatic factor, extending its functional relevance from beta-cell biology to cancer progression.\",\n      \"evidence\": \"Systemic and stable shRNA knockdown in melanoma cell lines and mouse xenograft models with survival analysis\",\n      \"pmids\": [\"22511720\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Molecular mechanism by which PHIP promotes metastasis was not defined\",\n        \"Whether PHIP copy-number gain is causally sufficient for metastasis was not tested\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identification of enriched disruptive PHIP mutations in individuals with intellectual disability and overweight established PHIP haploinsufficiency as the cause of a neurodevelopmental syndrome, linking its chromatin-regulatory function to brain development.\",\n      \"evidence\": \"Targeted resequencing of 3,275 ID individuals with reverse phenotyping across 23 mutation carriers\",\n      \"pmids\": [\"29209020\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No functional rescue or cellular assay confirming pathogenicity of individual variants in this study\",\n        \"Neural cell-type-specific roles of PHIP not characterized\",\n        \"Mechanism linking PHIP loss to obesity not established\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Genome-wide colocalization with H3K4 methylation and identification of the CryptoTudor domain as a direct H3K4me reader revealed PHIP's primary chromatin-targeting mechanism, while its biochemical association with CRL4 placed it as a chromatin-based ubiquitin ligase adaptor.\",\n      \"evidence\": \"ChIP-seq in human cells, mESCs, and Drosophila; direct binding assays to H3K4me; co-IP with CRL4 complex; CRISPR KO of COMPASS methyltransferases; Drosophila depletion with RNA-seq\",\n      \"pmids\": [\"29089422\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Bromodomain substrate specificity not yet defined\",\n        \"CRL4 ubiquitination substrates recruited by PHIP at chromatin unknown\",\n        \"How CryptoTudor and bromodomain inputs are coordinated was not resolved\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Two advances defined distinct PHIP functional axes: (1) PHIP/RepID recruits CRL4 to chromatin for replication origin licensing, with the SCF-SKP2 complex serving as a backup pathway, establishing PHIP's role in DNA replication control; (2) PHIP bromodomains bind H4K91ac, and PHIP suppression inhibits proliferation and invasion across multiple tumor types by reducing pAKT, cyclin D1, and talin1.\",\n      \"evidence\": \"Origin binding assays, SKP2 inhibitor sensitivity and re-replication assays, ChIP for origin occupancy, genetic epistasis with SKP2 (replication); bromodomain binding assay, shRNA in breast, lung, and melanoma lines with signaling readouts (tumor biology)\",\n      \"pmids\": [\"30018425\", \"29866840\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether bromodomain reading of H4K91ac versus H4K12ac/H3K14ac is context-dependent was unresolved\",\n        \"Identity of CRL4 ubiquitin substrates at replication origins not determined\",\n        \"Relative contribution of CryptoTudor versus bromodomain to origin targeting unknown\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Three parallel discoveries in 2020 resolved: (1) CRL4 switches from PHIP to RBBP7 during mitosis to ubiquitinate BUB3 for SAC termination, defining the first PHIP-pathway ubiquitination substrate and a cell-cycle-dependent receptor swap; (2) PHIP physically interacts with vinculin at focal adhesions and is required for stress fiber organization and glioblastoma invasion; (3) PHIP directly activates POMC transcription, and obesity-associated variants impair this activity, mechanistically linking PHIP to energy homeostasis.\",\n      \"evidence\": \"Co-IP and ubiquitination assays for CRL4-RBBP7-BUB3, mitotic exit timing, paclitaxel sensitivity (mitosis); confocal microscopy, PHIP-VCL co-IP, TLN1/ZYX rescue, intracranial xenograft (focal adhesions); POMC transcription assays with WT and variant PHIP (energy homeostasis)\",\n      \"pmids\": [\"31911655\", \"32273388\", \"32492392\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct ubiquitination substrates of CRL4-PHIP (as opposed to CRL4-RBBP7) remain unknown\",\n        \"Whether PHIP's focal adhesion role is chromatin-independent was not formally shown\",\n        \"Mechanism of PHIP-mediated POMC transcriptional activation is undefined\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Reconstitution of PHIP binding to semisynthetic nucleosomes with defined PTMs established the trivalent reader code (CryptoTudor for H3K4me, BD1 for H3K14ac, BD2 for H4K12ac) and showed that human neurodevelopmental disease mutations disrupt these reader functions, providing a molecular explanation for pathogenicity.\",\n      \"evidence\": \"Semisynthetic nucleosome binding assays with site-specific histone modifications, domain mutagenesis of patient variants, CRL4 recruitment assays\",\n      \"pmids\": [\"34819353\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis for trivalent engagement (e.g., cryo-EM or crystal structure of PHIP–nucleosome complex) is lacking\",\n        \"How combinatorial histone marks quantitatively tune CRL4 recruitment is not resolved\",\n        \"Genotype–phenotype correlations for individual domain mutations in patient neurons not tested\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The direct ubiquitination substrates of the CRL4-PHIP complex at chromatin remain unidentified, and it is unknown how PHIP's chromatin-reading and focal-adhesion functions are coordinated or whether they represent distinct protein pools.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No CRL4-PHIP ubiquitin substrate has been identified (BUB3 is a CRL4-RBBP7 substrate)\",\n        \"Whether cytoplasmic/focal adhesion PHIP is a distinct isoform or regulatory state is unknown\",\n        \"No structural model of PHIP bound to a nucleosome exists\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [3, 5, 9]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 6]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [4, 8, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 3, 6, 9]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [3, 4, 9]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [4, 8]},\n      {\"term_id\": \"R-HSA-69306\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [3, 9]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [8, 9]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 5]}\n    ],\n    \"complexes\": [\n      \"CRL4 (CUL4-DDB1-DCAF14)\"\n    ],\n    \"partners\": [\n      \"DDB1\",\n      \"CUL4A\",\n      \"VCL\",\n      \"TLN1\",\n      \"RBBP7\",\n      \"BUB3\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"PHIP (PH-interacting protein/BRWD2/DCAF14/RepID) is a chromatin-associated substrate receptor for the CRL4 (CUL4–DDB1–ROC1) ubiquitin E3 ligase complex that couples multivalent histone mark recognition to diverse downstream processes including DNA replication origin licensing, mitotic checkpoint termination, transcriptional regulation, and cell motility [PMID:16964240, PMID:29089422, PMID:34819353]. PHIP engages chromatin through a trivalent reader module—a CryptoTudor domain binding H3K4 methylation, bromodomain 1 reading H3K14ac, and bromodomain 2 reading H4K12ac—and recruits CRL4 to chromatin to facilitate replication licensing at a subset of origins that are non-redundant with SCF-SKP2–dependent origins; during mitosis, CRL4 dissociates from PHIP and partners with RBBP7 to ubiquitinate BUB3, enabling spindle assembly checkpoint silencing and mitotic exit [PMID:30018425, PMID:31911655, PMID:34819353]. Beyond ubiquitin ligase functions, PHIP directly enhances POMC transcription to regulate energy homeostasis, promotes pancreatic beta-cell proliferation through cyclin D2 upregulation and PKB/AKT activation, and drives cancer cell invasion by physically interacting with vinculin at the force transduction layer of focal adhesions [PMID:17636024, PMID:32492392, PMID:32273388]. De novo heterozygous loss-of-function PHIP variants cause a neurodevelopmental syndrome featuring intellectual disability, obesity, and dysmorphic features that phenotypically overlaps with CUL4B deficiency [PMID:27900362].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Identifying PHIP/DCAF14 as a WD40-repeat substrate receptor of the CRL4 ubiquitin ligase established the molecular framework through which PHIP connects to the ubiquitin–proteasome system.\",\n      \"evidence\": \"Tandem affinity purification of DDB1/CUL4A complexes followed by mass spectrometry in human cells\",\n      \"pmids\": [\"16964240\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Substrates recruited by PHIP/DCAF14 to CRL4 were unknown\",\n        \"How PHIP engages chromatin was uncharacterized\",\n        \"Physiological functions of PHIP-CRL4 were not addressed\"\n      ]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Demonstrating that the full-length PHIP1 isoform transcriptionally upregulates cyclin D2 and activates PKB/AKT to promote beta-cell proliferation and survival revealed a first physiological role for PHIP in cell growth control.\",\n      \"evidence\": \"RNAi knockdown, overexpression, cyclin D2 promoter-reporter assays, dominant-negative PKB epistasis, and apoptosis assays in pancreatic beta cells\",\n      \"pmids\": [\"17636024\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether the proliferative function depends on CRL4 association was not tested\",\n        \"Mechanism of cyclin D2 transcriptional activation was not resolved\",\n        \"In vivo beta-cell phenotype was not assessed\"\n      ]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"PHIP1-knockout mice revealed an essential, IGF-1/AKT-independent role for PHIP in postnatal growth, separating its in vivo growth function from the AKT pathway previously implicated in beta cells.\",\n      \"evidence\": \"Conditional knockout mouse model with MEF proliferation assays, AKT phosphorylation, and IGF-1 stimulation\",\n      \"pmids\": [\"20816727\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The AKT-independent mechanism driving postnatal growth remained unknown\",\n        \"Tissue-specific contributions to the growth phenotype were not dissected\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"PHIP was shown to contain functional bromodomains recognizing acetylated histones, and its suppression inhibited melanoma metastasis in vivo, linking its chromatin-reading capacity to cancer progression.\",\n      \"evidence\": \"X-ray crystallography of bromodomain family, histone peptide arrays, shRNA knockdown in melanoma cell lines, mouse xenograft survival studies, copy number analysis\",\n      \"pmids\": [\"22511720\", \"22464331\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Specific acetyl-histone marks read by PHIP bromodomains were not fully defined\",\n        \"Whether the metastatic role depended on CRL4 recruitment was untested\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identification of de novo loss-of-function PHIP variants in patients with intellectual disability, obesity, and dysmorphic features established PHIP haploinsufficiency as the basis of a neurodevelopmental syndrome overlapping CUL4B deficiency.\",\n      \"evidence\": \"Whole-exome sequencing and clinical phenotyping of affected individuals\",\n      \"pmids\": [\"27900362\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Causal mechanism linking PHIP haploinsufficiency to neurodevelopmental phenotypes was not established beyond genotype–phenotype correlation\",\n        \"Functional impact of individual patient variants on CRL4 pathway was not tested\",\n        \"Independent replication cohort was limited\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Genome-wide colocalization of PHIP with H3K4 methylation and identification of the CryptoTudor domain as a direct H3K4me reader revealed how PHIP is targeted to chromatin, connecting its CRL4 substrate receptor function to a specific epigenetic mark.\",\n      \"evidence\": \"ChIP-seq across human cells, mouse ES cells, and Drosophila; direct peptide-binding assays; CRISPR-Cas9 COMPASS knockouts; Drosophila dBRWD3 depletion with H3K27ac profiling\",\n      \"pmids\": [\"29089422\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Contributions of bromodomains to chromatin targeting were not resolved\",\n        \"Functional consequences of CRL4 recruitment at H3K4me-marked sites were unknown\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Characterization of PHIP's bromodomain 2 as an H4K91ac reader and demonstration that PHIP recruits CRL4 to replication origins—where its loss forces reliance on the alternative SCF-SKP2 pathway—revealed PHIP's essential role in DNA replication licensing and a synthetic-lethal vulnerability.\",\n      \"evidence\": \"Bromodomain-histone peptide array binding, siRNA/knockout replication assays, origin mapping, SKP2 inhibitor sensitivity and re-replication assays\",\n      \"pmids\": [\"29866840\", \"30018425\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct CRL4 substrates at replication origins were not identified\",\n        \"Structural basis for origin-specific vs. SKP2-origin targeting was unresolved\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Three concurrent advances resolved PHIP's roles in mitotic checkpoint control (via CRL4-RBBP7–mediated BUB3 ubiquitination), POMC transcription for energy homeostasis, and focal adhesion force transduction (via vinculin interaction), greatly expanding the functional repertoire beyond replication licensing.\",\n      \"evidence\": \"Co-IP and ubiquitination assays for BUB3 substrate identification; mitotic exit timing and paclitaxel sensitivity assays; POMC transcription reporter assays with disease-associated variants; confocal microscopy, Co-IP of PHIP–VCL, shRNA with TLN1/ZYX rescue, and intracranial xenograft\",\n      \"pmids\": [\"31911655\", \"32492392\", \"32273388\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"How CRL4 switches from RepID-dependent chromatin tethering to RBBP7-dependent mitotic activity is mechanistically unclear\",\n        \"Direct transcriptional mechanism of POMC activation by PHIP is unresolved\",\n        \"Whether the focal adhesion function requires CRL4 activity or is CRL4-independent is unknown\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Reconstitution with semisynthetic nucleosomes defined PHIP's trivalent chromatin-reading module (CryptoTudor for H3K4me, BD1 for H3K14ac, BD2 for H4K12ac) and showed that neurodevelopmental and cancer-associated mutations disrupt these interactions, unifying the chromatin-targeting mechanism with human disease.\",\n      \"evidence\": \"Semisynthetic nucleosome binding assays with defined histone PTMs, disease-variant mutagenesis, CRL4 chromatin recruitment assays\",\n      \"pmids\": [\"34819353\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No high-resolution structure of full-length PHIP on a nucleosome exists\",\n        \"Quantitative contribution of each reader domain to in vivo chromatin occupancy is not established\",\n        \"Whether all three marks must co-occur on the same nucleosome or can be read in trans is unresolved\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The direct CRL4 substrates at replication origins, the structural basis for PHIP's chromatin-to-focal-adhesion shuttling, and the mechanism by which PHIP activates POMC transcription remain major open questions.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"CRL4 substrates at replication origins have not been identified\",\n        \"No structural model of full-length PHIP exists\",\n        \"Mechanism of POMC transcriptional activation is undefined\",\n        \"Relationship between CRL4-dependent and CRL4-independent PHIP functions is unexplored\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [3, 4, 9, 12]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 7]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [5, 8, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [3, 5, 9]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 7]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-69306\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [5, 8]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [3, 9]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [8, 11]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 7]}\n    ],\n    \"complexes\": [\n      \"CRL4 (CUL4-DDB1-ROC1)\"\n    ],\n    \"partners\": [\n      \"DDB1\",\n      \"CUL4A\",\n      \"VCL\",\n      \"RBBP7\",\n      \"BUB3\",\n      \"TLN1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}