{"gene":"WDR48","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2007,"finding":"WDR48 (UAF1) is a stoichiometric subunit of the USP1 deubiquitinating enzyme complex; UAF1 activates USP1 by increasing its catalytic turnover (kcat) without altering substrate affinity (KM), as demonstrated by in vitro reconstitution with Ub-AMC and purified monoubiquitinated FANCD2 as substrates.","method":"Affinity purification from HeLa cells, in vitro reconstitution of DUB activity, kinetic analysis (kcat and KM measurements)","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with two distinct substrates, kinetic characterization, stoichiometric complex purification; foundational mechanistic study","pmids":["18082604"],"is_preprint":false},{"year":2008,"finding":"UAF1 (WDR48) is a shared activating subunit of at least three distinct deubiquitinating enzyme complexes—USP1/UAF1, USP12/UAF1, and USP46/UAF1—functioning as a bona fide regulatory subunit that stimulates enzymatic activity in each complex.","method":"Immunoprecipitation, complex purification, in vitro DUB activity assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — reciprocal co-IP, in vitro activity assays across three separate complexes, replicated by subsequent studies","pmids":["19075014"],"is_preprint":false},{"year":2010,"finding":"WDR20, a second WD40-repeat protein, associates exclusively with the USP12/UAF1 and USP46/UAF1 complexes (not USP1/UAF1) to form a ternary complex; WDR20 further stimulates USP12 enzymatic activity beyond that provided by UAF1 alone.","method":"Affinity purification, co-immunoprecipitation, in vitro DUB activity assays, siRNA knockdown","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — ternary complex purified and reconstituted, activity measured with and without WDR20, selectivity for USP12/46 over USP1 demonstrated","pmids":["20147737"],"is_preprint":false},{"year":2011,"finding":"The USP1/UAF1 complex promotes homologous recombination (HR)-mediated double-strand break repair; UAF1-deficient cells are hypersensitive to camptothecin and PARP inhibitors, and disruption of NHEJ in UAF1-deficient cells restores resistance, indicating UAF1 promotes HR at least partly by suppressing NHEJ.","method":"Gene knockout in chicken DT40 cells, chemical sensitivity assays, epistasis with NHEJ-deficient mutants","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO cells, genetic epistasis, multiple DNA damaging agents, replicated phenotypes across USP1-/- and UAF1-/- cells","pmids":["21482670"],"is_preprint":false},{"year":2013,"finding":"WDR48 (UAF1) in complex with USP12 deubiquitinates PHLPP1, stabilizing it and thereby suppressing PI3K/Akt signaling and promoting apoptosis; a cancer-associated WDR48 somatic mutation (L580F) is defective in stabilizing PHLPP1.","method":"Tandem affinity purification, co-immunoprecipitation, ubiquitination assays, cell viability and apoptosis assays, mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — TAP-MS identification, functional validation by DUB assay, multiple orthogonal methods, somatic mutation analysis","pmids":["24145035"],"is_preprint":false},{"year":2013,"finding":"C. elegans WDR-48 (orthologue of WDR48/UAF1) binds and stimulates USP-46 catalytic activity in vitro; in vivo, WDR-48 and WDR-20 overexpression increases GLR-1 glutamate receptor abundance in the ventral nerve cord by reducing its ubiquitination, and loss-of-function wdr-48 mutants show decreased GLR-1 and altered locomotion.","method":"In vitro DUB activity assays, in vivo receptor abundance measurements (fluorescence microscopy), genetic loss-of-function mutants, ubiquitin conjugate analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro reconstitution plus in vivo genetic analysis with defined phenotypic readout; multiple orthogonal methods","pmids":["24356955"],"is_preprint":false},{"year":2016,"finding":"Crystal structures of the USP12–UAF1 complex reveal that UAF1 binds the distal end of the USP12 Fingers domain and allosterically activates the enzyme via a cascade of structural changes reaching a ubiquitin-contacting loop near the catalytic cleft, without increasing substrate affinity.","method":"X-ray crystallography, biochemical activity assays, mutagenesis","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with mutagenesis and biochemical validation; allosteric mechanism defined at atomic resolution","pmids":["27373336"],"is_preprint":false},{"year":2016,"finding":"UAF1 (WDR48) binds DNA and forms a dimeric complex with RAD51AP1 via SUMO-like domains in UAF1 engaging a SUMO-interacting motif in RAD51AP1; UAF1 enhances RAD51-mediated homologous DNA pairing through this complex in a manner independent of USP1.","method":"Biochemical reconstitution, co-immunoprecipitation, DNA binding assays, RAD51-mediated strand exchange assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro reconstitution, defined protein–protein interaction domains, functional HR assay, USP1-independent mechanism established","pmids":["27239033"],"is_preprint":false},{"year":2019,"finding":"Efficient FANCD2 deubiquitination by the USP1-UAF1 complex requires DNA binding by UAF1; RAD51AP1, whose DNA binding activity can substitute for that of UAF1, forms a UAF1-RAD51AP1-USP1 trimeric complex that enables DNA-dependent FANCD2 deubiquitination.","method":"Reconstituted biochemical system, DNA binding assays, deubiquitination assays, cell-based FANCD2 deubiquitination experiments","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — fully reconstituted biochemical system with defined mutants, complemented by cellular validation","pmids":["31253762"],"is_preprint":false},{"year":2021,"finding":"Crystal structures of USP1-UAF1 and cryo-EM reconstruction of USP1-UAF1 bound to monoubiquitinated FANCI-FANCD2 reveal that an extensive UAF1–FANCI interface (not direct UAF1 catalytic involvement) is required for FANCD2 deubiquitination, and USP1-UAF1 induces conformational changes in the FANCI-FANCD2 substrate.","method":"X-ray crystallography, cryo-EM, mutagenesis, biochemical deubiquitination assays","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure + cryo-EM + mutagenesis + biochemical assays in a single study","pmids":["33795880"],"is_preprint":false},{"year":2012,"finding":"Serine 313 phosphorylation of USP1 by CDK1 is required for USP1 interaction with UAF1; an inserted domain (amino acids 235–408) in USP1 mediates the UAF1 interaction in a pSer313-dependent manner; protein phosphatase treatment of USP1 inactivates the USP1/UAF1 complex.","method":"Mutagenesis, phosphomimetic substitution, co-immunoprecipitation, in vitro kinase/phosphatase assays, DUB activity assays","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (mutagenesis, kinase assay, phosphatase treatment, activity reconstitution) in one study","pmids":["23116119"],"is_preprint":false},{"year":2013,"finding":"Homozygous Uaf1 knockout mice die at embryonic day 7.5; Uaf1+/- cells show increased FANCD2-Ub and PCNA-Ub levels, chromosome instability, genotoxin hypersensitivity, and defective homologous recombination repair, establishing UAF1 as essential for embryonic development and HR-mediated DNA repair in vivo.","method":"Mouse knockout, MEF characterization, comet assay, HR reporter assays, flow cytometry for DNA damage markers","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean mouse KO with multiple cellular readouts; embryonic lethality and HR defect independently confirmed","pmids":["24001775"],"is_preprint":false},{"year":2017,"finding":"USP1-UAF1 complex stabilizes TBK1 by removing its K48-linked polyubiquitination, preventing proteasomal degradation; this enhances IRF3 activation and IFN-β secretion during viral infection, and the USP1-UAF1 inhibitor ML323 attenuates IFN-β expression and enhances viral replication.","method":"Co-immunoprecipitation, ubiquitination assays, siRNA knockdown, IFN-β reporter assays, pharmacological inhibition","journal":"The Journal of experimental medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP and deubiquitination assay in single lab, multiple cellular readouts but not in vitro reconstitution","pmids":["29138248"],"is_preprint":false},{"year":2020,"finding":"The UAF1/USP1 complex selectively removes K48-linked polyubiquitination from NLRP3 to suppress its degradation; UAF1/USP12 and UAF1/USP46 complexes remove K48-linked polyubiquitination from p65 NF-κB to promote NLRP3 and pro-IL-1β transcription; Uaf1 deficiency in vivo attenuates NLRP3 inflammasome activation and IL-1β secretion.","method":"Co-immunoprecipitation, ubiquitination assays, siRNA knockdown, Uaf1-deficient mice, NLRP3 inflammasome activation assays","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple substrates identified, in vivo genetic validation, single lab study","pmids":["33247121"],"is_preprint":false},{"year":2007,"finding":"WDR48 (p80) interacts with the N-terminal 40 amino acids of HPV E1 helicase; this interaction is conserved among anogenital HPV types; E1 redistributes WDR48 from the cytoplasm to the nucleus via E1's nuclear localization signal; mutations in E1 that abrogate p80 binding prevent maintenance of HPV episomes in keratinocytes.","method":"Tandem affinity purification/mass spectrometry, co-immunoprecipitation, colocalization microscopy, mutagenesis, HPV episome maintenance assay in keratinocytes","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — TAP-MS identification with mutagenesis validation, functional episome assay, single lab","pmids":["18032488"],"is_preprint":false},{"year":2012,"finding":"USP1 nuclear localization signals (NLSs) mediate nuclear import of the USP1/UAF1 complex; UAF1 alone localizes to the cytoplasm but is carried into the nucleus by USP1; a conserved 100 amino acid motif in USP1 mediates the UAF1-binding interaction.","method":"Cellular relocation assay, deletion/mutagenesis analysis, immunofluorescence microscopy","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — mutagenesis and cellular localization assay, defined interacting domain, single lab","pmids":["22701671"],"is_preprint":false},{"year":2016,"finding":"Crystal structure of USP12-Ub/UAF1 reveals two UAF1 binding sites on USP12 (stoichiometry 1:2 in solution); the high-affinity site (Kd ~4 nM) at the Fingers subdomain is required for activation, while the second lower-affinity site (Kd ~325 nM) does not affect activation; this two-step binding is conserved in USP1.","method":"X-ray crystallography, isothermal titration calorimetry, mutagenesis, in vitro DUB activity assays","journal":"Journal of structural biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with mutagenesis, biophysical binding measurements, and activity assays; allosteric mechanism defined","pmids":["27650958"],"is_preprint":false},{"year":2016,"finding":"UAF1 mediates interaction between USP1 and RAD51AP1; depletion of USP1 or UAF1 decreases RAD51AP1 stability; cells expressing a UAF1-interaction-deficient RAD51AP1 mutant show increased chromosomal aberrations and persistent RAD51 foci after DNA damage, indicating the USP1-UAF1 complex promotes a later step of HR repair through RAD51AP1.","method":"Co-immunoprecipitation, protein interaction mapping, siRNA knockdown, chromosomal aberration assay, RAD51 focus analysis","journal":"Cell cycle","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP, mutagenesis of interaction interface, multiple cellular readouts, single lab","pmids":["27463890"],"is_preprint":false}],"current_model":"WDR48 (UAF1) functions as a shared allosteric activator subunit for a subfamily of deubiquitinating enzymes—USP1, USP12, and USP46—binding via their Fingers domains and stimulating catalytic turnover without affecting substrate affinity; the USP1/UAF1 complex is recruited to the nucleus via USP1 NLSs and, upon CDK1-mediated phosphorylation of USP1-Ser313, deubiquitinates key DNA repair substrates (FANCD2-Ub, PCNA-Ub) to regulate the Fanconi anemia pathway and promote homologous recombination repair, while also stabilizing TBK1 and NLRP3 through K48-deubiquitination and interacting with RAD51AP1 to support HR in a USP1-independent manner; WDR48 also forms a USP12-containing complex that stabilizes the tumor suppressor PHLPP1 to suppress Akt signaling, and it is recruited by HPV E1 helicase to the nucleus to maintain viral episomes."},"narrative":{"mechanistic_narrative":"WDR48 (UAF1) is a WD40-repeat protein that functions as a shared allosteric activator subunit for a subfamily of deubiquitinating enzymes—USP1, USP12, and USP46—stimulating their catalytic turnover (kcat) without altering substrate affinity (KM) [PMID:18082604, PMID:19075014]. Structural studies define the mechanism: UAF1 docks onto the distal end of the substrate USP Fingers domain via a high-affinity site, triggering a cascade of conformational changes that reach a ubiquitin-contacting loop near the catalytic cleft [PMID:27373336, PMID:27650958]. In the USP12/USP46 complexes a second WD40 protein, WDR20, joins to form a ternary assembly that further stimulates activity, whereas USP1/UAF1 lacks WDR20 [PMID:20147737]. The USP1/UAF1 complex is the central effector in DNA repair: it is imported to the nucleus via USP1 nuclear localization signals, its activity is gated by CDK1 phosphorylation of USP1-Ser313, and it deubiquitinates the Fanconi anemia and replication substrates FANCD2-Ub and PCNA-Ub to support homologous recombination repair [PMID:23116119, PMID:24001775, PMID:22701671]. Efficient FANCD2 deubiquitination depends on UAF1 DNA binding and an extensive UAF1–FANCI interface that remodels the FANCI-FANCD2 substrate [PMID:31253762, PMID:33795880]. UAF1 also acts through SUMO-like domains to recruit RAD51AP1, enhancing RAD51-mediated DNA pairing and promoting a later step of HR—a function that can proceed independently of USP1 [PMID:27239033, PMID:27463890]. Beyond genome maintenance, the USP12/UAF1 complex deubiquitinates and stabilizes the tumor suppressor PHLPP1 to suppress PI3K/Akt signaling, and UAF1-containing complexes remove K48-linked ubiquitin from immune regulators TBK1 and NLRP3 to control interferon and inflammasome responses [PMID:24145035, PMID:29138248, PMID:33247121]. WDR48 is also targeted by HPV E1 helicase, which relocalizes it to the nucleus to maintain viral episomes [PMID:18032488].","teleology":[{"year":2007,"claim":"Established that WDR48/UAF1 is not a passive scaffold but a catalytic activator, answering how USP1 achieves physiological deubiquitinase activity.","evidence":"Affinity purification from HeLa cells with in vitro reconstitution and kinetic analysis using Ub-AMC and monoubiquitinated FANCD2","pmids":["18082604"],"confidence":"High","gaps":["Structural basis of activation unresolved at this stage","Did not address whether other USPs share this regulation"]},{"year":2007,"claim":"Identified WDR48 as a host factor hijacked by HPV E1 helicase, linking it to viral genome persistence.","evidence":"TAP-MS, co-IP, colocalization, and HPV episome maintenance assay in keratinocytes","pmids":["18032488"],"confidence":"Medium","gaps":["Mechanism by which WDR48 supports episome maintenance not defined","Single lab; whether DUB activity is required is unaddressed"]},{"year":2008,"claim":"Generalized UAF1's role by showing it is a shared activating subunit of three distinct DUB complexes (USP1, USP12, USP46), defining a regulated DUB subfamily.","evidence":"Reciprocal co-IP, complex purification, and in vitro DUB activity assays across three complexes","pmids":["19075014"],"confidence":"High","gaps":["Substrates of USP12/UAF1 and USP46/UAF1 not yet identified","Did not explain selectivity of partner usage"]},{"year":2010,"claim":"Resolved complex-specific composition by showing WDR20 selectively joins USP12/USP46—but not USP1—complexes and provides additional activation.","evidence":"Affinity purification, co-IP, siRNA, and in vitro DUB assays with and without WDR20","pmids":["20147737"],"confidence":"High","gaps":["Structural basis of WDR20 contribution not determined here","Functional consequence of WDR20 absence in USP1 complex unclear"]},{"year":2011,"claim":"Placed the USP1/UAF1 complex functionally within DNA double-strand break repair by showing it promotes HR partly by suppressing NHEJ.","evidence":"Gene knockout in chicken DT40 cells, chemical sensitivity assays, and epistasis with NHEJ-deficient mutants","pmids":["21482670"],"confidence":"High","gaps":["Molecular mechanism linking DUB activity to NHEJ suppression not defined","Relevant substrate driving the HR phenotype not pinpointed"]},{"year":2012,"claim":"Defined how the complex is spatially and temporally controlled: USP1 NLSs import UAF1 into the nucleus, and CDK1 phosphorylation of USP1-Ser313 gates complex formation and activity.","evidence":"Cellular relocation assays, deletion mutagenesis, immunofluorescence, kinase/phosphatase and DUB activity assays","pmids":["22701671","23116119"],"confidence":"High","gaps":["Cell-cycle dynamics of activation in vivo not fully mapped","Phosphatase responsible for inactivation in cells not identified"]},{"year":2013,"claim":"Demonstrated UAF1 is essential in vivo and confirmed FANCD2-Ub and PCNA-Ub as physiological substrates underlying genome stability.","evidence":"Uaf1 knockout mice, MEF characterization, comet and HR reporter assays, flow cytometry for ubiquitinated DNA repair markers","pmids":["24001775"],"confidence":"High","gaps":["Cause of E7.5 embryonic lethality not mechanistically dissected","Did not separate USP1-dependent from USP1-independent contributions"]},{"year":2013,"claim":"Extended UAF1 function beyond DNA repair by showing the USP12/UAF1 complex stabilizes PHLPP1 to suppress Akt signaling, with a cancer mutation defective in this role.","evidence":"TAP-MS, co-IP, ubiquitination, viability/apoptosis assays, and L580F mutagenesis","pmids":["24145035"],"confidence":"High","gaps":["WDR20 contribution to PHLPP1 regulation not addressed","Tumor relevance of L580F beyond cell models untested"]},{"year":2013,"claim":"Confirmed evolutionary conservation and a neuronal role by showing C. elegans WDR-48 activates USP-46 to control GLR-1 glutamate receptor abundance and behavior.","evidence":"In vitro DUB assays plus in vivo genetic loss-of-function and receptor abundance microscopy in worms","pmids":["24356955"],"confidence":"High","gaps":["Mammalian neuronal relevance not established here","Direct deubiquitination of the receptor not shown biochemically"]},{"year":2016,"claim":"Solved the structural basis of allosteric activation, showing UAF1 binds the Fingers domain and transmits conformational changes to the catalytic cleft via a high-affinity site.","evidence":"X-ray crystallography of USP12–UAF1, ITC, mutagenesis, and DUB activity assays","pmids":["27373336","27650958"],"confidence":"High","gaps":["Function of the second low-affinity UAF1 site undefined","Structures of full-length substrate-engaged complexes still lacking at this point"]},{"year":2016,"claim":"Uncovered a USP1-independent UAF1 function in HR through DNA binding and SUMO-like-domain-mediated recruitment of RAD51AP1 to enhance RAD51 strand pairing.","evidence":"Biochemical reconstitution, co-IP, DNA binding assays, RAD51 strand-exchange assays, and cellular RAD51 focus/chromosomal aberration analysis","pmids":["27239033","27463890"],"confidence":"High","gaps":["Interplay between USP1-dependent and RAD51AP1-dependent HR roles not fully resolved","Regulation of UAF1 DNA binding in cells unknown"]},{"year":2017,"claim":"Expanded the substrate repertoire to innate immunity, showing USP1-UAF1 stabilizes TBK1 by removing K48 ubiquitin to promote interferon responses.","evidence":"Co-IP, ubiquitination assays, siRNA, IFN-β reporter assays, and ML323 pharmacological inhibition","pmids":["29138248"],"confidence":"Medium","gaps":["No in vitro reconstitution of TBK1 deubiquitination","Single lab; in vivo immune phenotype not tested here"]},{"year":2019,"claim":"Mechanistically explained why UAF1 DNA binding matters, showing it is required for efficient FANCD2 deubiquitination and that RAD51AP1 can substitute for this function in a trimeric complex.","evidence":"Fully reconstituted biochemical system with DNA binding and deubiquitination assays plus cellular validation","pmids":["31253762"],"confidence":"High","gaps":["How DNA binding positions the substrate not visualized at this stage","Physiological switch between UAF1- and RAD51AP1-dependent modes unclear"]},{"year":2020,"claim":"Defined opposing UAF1 complex roles in inflammasome signaling: USP1/UAF1 stabilizes NLRP3 while USP12/46 complexes stabilize p65 to drive transcription.","evidence":"Co-IP, ubiquitination assays, siRNA, Uaf1-deficient mice, and NLRP3 inflammasome activation assays","pmids":["33247121"],"confidence":"Medium","gaps":["No in vitro reconstitution of NLRP3 or p65 deubiquitination","Single lab; substrate specificity across complexes not biochemically separated"]},{"year":2021,"claim":"Provided the substrate-engaged structure, revealing that an extensive UAF1–FANCI interface, not direct catalysis by UAF1, drives FANCD2 deubiquitination through substrate remodeling.","evidence":"X-ray crystallography of USP1-UAF1 and cryo-EM of the complex bound to monoubiquitinated FANCI-FANCD2, with mutagenesis and biochemical assays","pmids":["33795880"],"confidence":"High","gaps":["Structural basis of the RAD51AP1-substituted pathway not resolved","How CDK1 phosphorylation alters this assembly structurally unknown"]},{"year":null,"claim":"How UAF1 complex composition and substrate selection are coordinated across its diverse roles—DNA repair, Akt suppression, innate immunity, and viral episome maintenance—within a single cell remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying model for context-specific substrate routing among USP1/12/46 complexes","Immune substrate deubiquitination lacks in vitro reconstitution","Regulation balancing USP1-dependent vs USP1-independent HR functions undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,2,6,16]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[7,8,9,17]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[7,8]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[14,15]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[14,15]}],"pathway":[{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[3,9,11]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[12,13]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,1]}],"complexes":["USP1/UAF1 complex","USP12/UAF1 complex","USP46/UAF1 complex","USP12-UAF1-WDR20 ternary complex"],"partners":["USP1","USP12","USP46","WDR20","RAD51AP1","FANCI","PHLPP1","HPV E1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8TAF3","full_name":"WD repeat-containing protein 48","aliases":["USP1-associated factor 1","WD repeat endosomal protein","p80"],"length_aa":677,"mass_kda":76.2,"function":"Regulator of deubiquitinating complexes, which acts as a strong activator of USP1, USP12 and USP46 (PubMed:18082604, PubMed:19075014, PubMed:26388029, PubMed:31253762). Enhances the USP1-mediated deubiquitination of FANCD2; USP1 being almost inactive by itself (PubMed:18082604, PubMed:31253762). Activates deubiquitination by increasing the catalytic turnover without increasing the affinity of deubiquitinating enzymes for the substrate (PubMed:19075014, PubMed:27373336). Also activates deubiquitinating activity of complexes containing USP12 (PubMed:19075014, PubMed:27373336, PubMed:27650958). In complex with USP12, acts as a potential tumor suppressor by positively regulating PHLPP1 stability (PubMed:24145035). Docks at the distal end of the USP12 fingers domain and induces a cascade of structural changes leading to the activation of the enzyme (PubMed:27373336, PubMed:27650958). Together with RAD51AP1, promotes DNA repair by stimulating RAD51-mediated homologous recombination (PubMed:27239033, PubMed:27463890, PubMed:32350107). Binds single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA) (PubMed:27239033, PubMed:31253762, PubMed:32350107). DNA-binding is required both for USP1-mediated deubiquitination of FANCD2 and stimulation of RAD51-mediated homologous recombination: both WDR48/UAF1 and RAD51AP1 have coordinated role in DNA-binding during these processes (PubMed:31253762, PubMed:32350107). Together with ATAD5 and by regulating USP1 activity, has a role in PCNA-mediated translesion synthesis (TLS) by deubiquitinating monoubiquitinated PCNA (PubMed:20147293). Together with ATAD5, has a role in recruiting RAD51 to stalled forks during replication stress (PubMed:31844045) (Microbial infection) In case of infection by Herpesvirus saimiri, may play a role in vesicular transport or membrane fusion events necessary for transport to lysosomes. Induces lysosomal vesicle formation via interaction with Herpesvirus saimiri tyrosine kinase-interacting protein (TIP). Subsequently, TIP recruits tyrosine-protein kinase LCK, resulting in down-regulation of T-cell antigen receptor TCR. May play a role in generation of enlarged endosomal vesicles via interaction with TIP (PubMed:12196293). In case of infection by papillomavirus HPV11, promotes the maintenance of the viral genome via its interaction with HPV11 helicase E1 (PubMed:18032488)","subcellular_location":"Nucleus; Cytoplasm; Lysosome; Late endosome","url":"https://www.uniprot.org/uniprotkb/Q8TAF3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/WDR48","classification":"Not Classified","n_dependent_lines":516,"n_total_lines":1208,"dependency_fraction":0.4271523178807947},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"USP1","stoichiometry":10.0},{"gene":"CLASP2","stoichiometry":0.2},{"gene":"H2AFZ","stoichiometry":0.2},{"gene":"HIST2H2BE","stoichiometry":0.2},{"gene":"KPNB1","stoichiometry":0.2},{"gene":"RABIF","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/WDR48","total_profiled":1310},"omim":[{"mim_id":"617741","title":"WD REPEAT-CONTAINING PROTEIN 20; WDR20","url":"https://www.omim.org/entry/617741"},{"mim_id":"612167","title":"WD REPEAT-CONTAINING PROTEIN 48; WDR48","url":"https://www.omim.org/entry/612167"},{"mim_id":"609534","title":"ATPase FAMILY, AAA DOMAIN-CONTAINING, MEMBER 5; ATAD5","url":"https://www.omim.org/entry/609534"},{"mim_id":"603478","title":"UBIQUITIN-SPECIFIC PROTEASE 1; USP1","url":"https://www.omim.org/entry/603478"},{"mim_id":"603091","title":"UBIQUITIN-SPECIFIC PROTEASE 12; USP12","url":"https://www.omim.org/entry/603091"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Vesicles","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/WDR48"},"hgnc":{"alias_symbol":["UAF1","KIAA1449","P80","SPG60","Bun62"],"prev_symbol":[]},"alphafold":{"accession":"Q8TAF3","domains":[{"cath_id":"-","chopping":"362-479_503-554","consensus_level":"high","plddt":95.6671,"start":362,"end":554},{"cath_id":"3.10.20.90","chopping":"563-608_626-673","consensus_level":"high","plddt":83.5044,"start":563,"end":673}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8TAF3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8TAF3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8TAF3-F1-predicted_aligned_error_v6.png","plddt_mean":88.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=WDR48","jax_strain_url":"https://www.jax.org/strain/search?query=WDR48"},"sequence":{"accession":"Q8TAF3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8TAF3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8TAF3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8TAF3"}},"corpus_meta":[{"pmid":"11406658","id":"PMC_11406658","title":"ALK1 and p80 expression and chromosomal rearrangements involving 2p23 in inflammatory myofibroblastic tumor.","date":"2001","source":"Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc","url":"https://pubmed.ncbi.nlm.nih.gov/11406658","citation_count":443,"is_preprint":false},{"pmid":"2033369","id":"PMC_2033369","title":"Human autoantibody to a novel protein of the nuclear coiled body: immunological characterization and cDNA cloning of p80-coilin.","date":"1991","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/2033369","citation_count":329,"is_preprint":false},{"pmid":"18082604","id":"PMC_18082604","title":"A UAF1-containing multisubunit protein complex regulates the Fanconi anemia pathway.","date":"2007","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/18082604","citation_count":306,"is_preprint":false},{"pmid":"12218210","id":"PMC_12218210","title":"Expression of ALK1 and p80 in inflammatory myofibroblastic tumor and its mesenchymal mimics: a study of 135 cases.","date":"2002","source":"Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc","url":"https://pubmed.ncbi.nlm.nih.gov/12218210","citation_count":268,"is_preprint":false},{"pmid":"8633037","id":"PMC_8633037","title":"Characterization of the transforming activity of p80, a hyperphosphorylated protein in a Ki-1 lymphoma cell line with chromosomal translocation t(2;5).","date":"1996","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/8633037","citation_count":249,"is_preprint":false},{"pmid":"1967267","id":"PMC_1967267","title":"Antibodies against the CD44 p80, lymphocyte homing receptor molecule augment human peripheral blood T cell activation.","date":"1990","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/1967267","citation_count":238,"is_preprint":false},{"pmid":"24531842","id":"PMC_24531842","title":"A selective USP1-UAF1 inhibitor links deubiquitination to DNA damage responses.","date":"2014","source":"Nature chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/24531842","citation_count":227,"is_preprint":false},{"pmid":"2646376","id":"PMC_2646376","title":"Monoclonal antibodies against the CD44 [In(Lu)-related p80], and Pgp-1 antigens in man recognize the Hermes class of lymphocyte homing receptors.","date":"1989","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/2646376","citation_count":196,"is_preprint":false},{"pmid":"22118673","id":"PMC_22118673","title":"Selective and cell-active inhibitors of the USP1/ UAF1 deubiquitinase complex reverse cisplatin resistance in non-small cell lung cancer cells.","date":"2011","source":"Chemistry & biology","url":"https://pubmed.ncbi.nlm.nih.gov/22118673","citation_count":194,"is_preprint":false},{"pmid":"8547653","id":"PMC_8547653","title":"High incidence of the t(2;5)(p23;q35) translocation in anaplastic large cell lymphoma and its lack of detection in Hodgkin's disease. Comparison of cytogenetic analysis, reverse transcriptase-polymerase chain reaction, and P-80 immunostaining.","date":"1996","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/8547653","citation_count":193,"is_preprint":false},{"pmid":"9032102","id":"PMC_9032102","title":"Differential regulation of the p80 tumor necrosis factor receptor in human obesity and insulin resistance.","date":"1997","source":"Diabetes","url":"https://pubmed.ncbi.nlm.nih.gov/9032102","citation_count":187,"is_preprint":false},{"pmid":"9036990","id":"PMC_9036990","title":"Enhancement of TNF receptor p60-mediated cytotoxicity by TNF receptor p80: requirement of the TNF receptor-associated factor-2 binding site.","date":"1997","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/9036990","citation_count":163,"is_preprint":false},{"pmid":"19075014","id":"PMC_19075014","title":"UAF1 is a subunit of multiple deubiquitinating enzyme complexes.","date":"2008","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19075014","citation_count":159,"is_preprint":false},{"pmid":"8144934","id":"PMC_8144934","title":"TNF induces internalization of the p60 receptor and shedding of the p80 receptor.","date":"1994","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/8144934","citation_count":156,"is_preprint":false},{"pmid":"7853509","id":"PMC_7853509","title":"Pestivirus NS3 (p80) protein possesses RNA helicase activity.","date":"1995","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/7853509","citation_count":151,"is_preprint":false},{"pmid":"8923355","id":"PMC_8923355","title":"Recombinant soluble tumor necrosis factor receptor (p80) fusion protein: toxicity and dose finding trial in refractory rheumatoid arthritis.","date":"1996","source":"The Journal of rheumatology","url":"https://pubmed.ncbi.nlm.nih.gov/8923355","citation_count":143,"is_preprint":false},{"pmid":"9531270","id":"PMC_9531270","title":"Overexpression of the p80 TNF receptor leads to TNF-dependent apoptosis, nuclear factor-kappa B activation, and c-Jun kinase activation.","date":"1998","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/9531270","citation_count":139,"is_preprint":false},{"pmid":"7490287","id":"PMC_7490287","title":"Mutational analysis of p80 coilin indicates a functional interaction between coiled bodies and the nucleolus.","date":"1995","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/7490287","citation_count":137,"is_preprint":false},{"pmid":"2308937","id":"PMC_2308937","title":"Isolation and characterization of cDNA encoding the 80-kDa subunit protein of the human autoantigen Ku (p70/p80) recognized by autoantibodies from patients with scleroderma-polymyositis overlap syndrome.","date":"1990","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/2308937","citation_count":137,"is_preprint":false},{"pmid":"10751153","id":"PMC_10751153","title":"Two domains of p80 katanin regulate microtubule severing and spindle pole targeting by p60 katanin.","date":"2000","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/10751153","citation_count":127,"is_preprint":false},{"pmid":"10671223","id":"PMC_10671223","title":"A crucial role for p80 TNF-R2 in amplifying p60 TNF-R1 apoptosis signals in T lymphocytes.","date":"2000","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/10671223","citation_count":125,"is_preprint":false},{"pmid":"6224850","id":"PMC_6224850","title":"Differentiation of human T lymphocytes. I. Acquisition of a novel human cell surface protein (p80) during normal intrathymic T cell maturation.","date":"1983","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/6224850","citation_count":120,"is_preprint":false},{"pmid":"9414185","id":"PMC_9414185","title":"Anaplastic large cell lymphoma: a distinct molecular pathologic entity: a reappraisal with special reference to p80(NPM/ALK) expression.","date":"1997","source":"The American journal of surgical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/9414185","citation_count":118,"is_preprint":false},{"pmid":"33247121","id":"PMC_33247121","title":"UAF1 deubiquitinase complexes facilitate NLRP3 inflammasome activation by promoting NLRP3 expression.","date":"2020","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/33247121","citation_count":112,"is_preprint":false},{"pmid":"21482670","id":"PMC_21482670","title":"The USP1/UAF1 complex promotes double-strand break repair through homologous recombination.","date":"2011","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/21482670","citation_count":107,"is_preprint":false},{"pmid":"7592885","id":"PMC_7592885","title":"p80/85 cortactin associates with the Src SH2 domain and colocalizes with v-Src in transformed cells.","date":"1995","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/7592885","citation_count":106,"is_preprint":false},{"pmid":"8382392","id":"PMC_8382392","title":"RNA-stimulated NTPase activity associated with the p80 protein of the pestivirus bovine viral diarrhea virus.","date":"1993","source":"Virology","url":"https://pubmed.ncbi.nlm.nih.gov/8382392","citation_count":103,"is_preprint":false},{"pmid":"2419410","id":"PMC_2419410","title":"Identification of Ki (Ku, p70/p80) autoantigens and analysis of anti-Ki autoantibody reactivity.","date":"1986","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/2419410","citation_count":102,"is_preprint":false},{"pmid":"10378883","id":"PMC_10378883","title":"Expression and localization of p80 and p68 interleukin-1 receptor proteins in the brain of adult mice.","date":"1999","source":"Journal of neuroimmunology","url":"https://pubmed.ncbi.nlm.nih.gov/10378883","citation_count":88,"is_preprint":false},{"pmid":"25521379","id":"PMC_25521379","title":"Katanin p80 regulates human cortical development by limiting centriole and cilia number.","date":"2014","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/25521379","citation_count":86,"is_preprint":false},{"pmid":"8258294","id":"PMC_8258294","title":"Chromosomal location and expression of the genes coding for Ku p70 and p80 in human cell lines and normal tissues.","date":"1994","source":"Cytogenetics and cell genetics","url":"https://pubmed.ncbi.nlm.nih.gov/8258294","citation_count":86,"is_preprint":false},{"pmid":"14739293","id":"PMC_14739293","title":"Adhesion or plasmin regulates tyrosine phosphorylation of a novel membrane glycoprotein p80/gp140/CUB domain-containing protein 1 in epithelia.","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/14739293","citation_count":84,"is_preprint":false},{"pmid":"20147737","id":"PMC_20147737","title":"WDR20 regulates activity of the USP12 x UAF1 deubiquitinating enzyme complex.","date":"2010","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20147737","citation_count":81,"is_preprint":false},{"pmid":"22654669","id":"PMC_22654669","title":"An essential role for katanin p80 and microtubule severing in male gamete production.","date":"2012","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/22654669","citation_count":81,"is_preprint":false},{"pmid":"15176475","id":"PMC_15176475","title":"The effects of ketamine vary among inbred mouse strains and mimic schizophrenia for the P80, but not P20 or N40 auditory ERP components.","date":"2004","source":"Neurochemical research","url":"https://pubmed.ncbi.nlm.nih.gov/15176475","citation_count":79,"is_preprint":false},{"pmid":"1626075","id":"PMC_1626075","title":"Antibodies to the p70/p80 (Ku) antigens in systemic lupus erythematosus.","date":"1992","source":"Rheumatic diseases clinics of North America","url":"https://pubmed.ncbi.nlm.nih.gov/1626075","citation_count":74,"is_preprint":false},{"pmid":"29138248","id":"PMC_29138248","title":"USP1-UAF1 deubiquitinase complex stabilizes TBK1 and enhances antiviral responses.","date":"2017","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/29138248","citation_count":69,"is_preprint":false},{"pmid":"18164266","id":"PMC_18164266","title":"Differential roles of p80- and p130-angiomotin in the switch between migration and stabilization of endothelial cells.","date":"2007","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/18164266","citation_count":69,"is_preprint":false},{"pmid":"9422740","id":"PMC_9422740","title":"Identification of two domains of the p70 Ku protein mediating dimerization with p80 and DNA binding.","date":"1998","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9422740","citation_count":67,"is_preprint":false},{"pmid":"8214007","id":"PMC_8214007","title":"Analysis of p60 and p80 tumor necrosis factor-alpha receptor messenger RNA and protein in human placentas.","date":"1993","source":"The American journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/8214007","citation_count":64,"is_preprint":false},{"pmid":"24145035","id":"PMC_24145035","title":"WD repeat protein WDR48 in complex with deubiquitinase USP12 suppresses Akt-dependent cell survival signaling by stabilizing PH domain leucine-rich repeat protein phosphatase 1 (PHLPP1).","date":"2013","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24145035","citation_count":62,"is_preprint":false},{"pmid":"2480381","id":"PMC_2480381","title":"CD44 antibody against In(Lu)-related p80, lymphocyte-homing receptor molecule inhibits the binding of human erythrocytes to T cells.","date":"1989","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/2480381","citation_count":62,"is_preprint":false},{"pmid":"21921206","id":"PMC_21921206","title":"Preclinical prophylactic efficacy testing of Sm-p80-based vaccine in a nonhuman primate model of Schistosoma mansoni infection and immunoglobulin G and E responses to Sm-p80 in human serum samples from an area where schistosomiasis is endemic.","date":"2011","source":"The Journal of infectious diseases","url":"https://pubmed.ncbi.nlm.nih.gov/21921206","citation_count":61,"is_preprint":false},{"pmid":"15302820","id":"PMC_15302820","title":"PF15p is the chlamydomonas homologue of the Katanin p80 subunit and is required for assembly of flagellar central microtubules.","date":"2004","source":"Eukaryotic cell","url":"https://pubmed.ncbi.nlm.nih.gov/15302820","citation_count":61,"is_preprint":false},{"pmid":"27373336","id":"PMC_27373336","title":"Allosteric Activation of Ubiquitin-Specific Proteases by β-Propeller Proteins UAF1 and WDR20.","date":"2016","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/27373336","citation_count":60,"is_preprint":false},{"pmid":"12798631","id":"PMC_12798631","title":"Enhancement of Sm-p80 (large subunit of calpain) induced protective immunity against Schistosoma mansoni through co-delivery of interleukin-2 and interleukin-12 in a DNA vaccine formulation.","date":"2003","source":"Vaccine","url":"https://pubmed.ncbi.nlm.nih.gov/12798631","citation_count":58,"is_preprint":false},{"pmid":"27430014","id":"PMC_27430014","title":"Food Additive P-80 Impacts Mouse Gut Microbiota Promoting Intestinal Inflammation, Obesity and Liver Dysfunction.","date":"2016","source":"SOJ microbiology & infectious diseases","url":"https://pubmed.ncbi.nlm.nih.gov/27430014","citation_count":58,"is_preprint":false},{"pmid":"25229643","id":"PMC_25229643","title":"Synthesis and structure-activity relationship studies of N-benzyl-2-phenylpyrimidin-4-amine derivatives as potent USP1/UAF1 deubiquitinase inhibitors with anticancer activity against nonsmall cell lung cancer.","date":"2014","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25229643","citation_count":57,"is_preprint":false},{"pmid":"8020186","id":"PMC_8020186","title":"Intratracheal administration of endotoxin and cytokines. VII. The soluble interleukin-1 receptor and the soluble tumor necrosis factor receptor II (p80) inhibit acute inflammation.","date":"1994","source":"Clinical immunology and immunopathology","url":"https://pubmed.ncbi.nlm.nih.gov/8020186","citation_count":56,"is_preprint":false},{"pmid":"31253762","id":"PMC_31253762","title":"DNA requirement in FANCD2 deubiquitination by USP1-UAF1-RAD51AP1 in the Fanconi anemia DNA damage response.","date":"2019","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/31253762","citation_count":55,"is_preprint":false},{"pmid":"9499406","id":"PMC_9499406","title":"Interaction of recombinant Tetrahymena telomerase proteins p80 and p95 with telomerase RNA and telomeric DNA substrates.","date":"1998","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/9499406","citation_count":55,"is_preprint":false},{"pmid":"7532471","id":"PMC_7532471","title":"Human p80-coilin is targeted to sphere organelles in the amphibian germinal vesicle.","date":"1994","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/7532471","citation_count":54,"is_preprint":false},{"pmid":"19809833","id":"PMC_19809833","title":"Prime-boost and recombinant protein vaccination strategies using Sm-p80 protects against Schistosoma mansoni infection in the mouse model to levels previously attainable only by the irradiated cercarial vaccine.","date":"2009","source":"Parasitology research","url":"https://pubmed.ncbi.nlm.nih.gov/19809833","citation_count":54,"is_preprint":false},{"pmid":"1701785","id":"PMC_1701785","title":"Antigenic determinants of the Ku (p70/p80) autoantigen are poorly conserved between species.","date":"1990","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/1701785","citation_count":54,"is_preprint":false},{"pmid":"12819068","id":"PMC_12819068","title":"Induction of protective immunity against Schistosoma mansoni via DNA priming and boosting with the large subunit of calpain (Sm-p80): adjuvant effects of granulocyte-macrophage colony-stimulating factor and interleukin-4.","date":"2003","source":"Infection and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/12819068","citation_count":53,"is_preprint":false},{"pmid":"1707916","id":"PMC_1707916","title":"Epitopes of the p70 and p80 (Ku) lupus autoantigens.","date":"1991","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/1707916","citation_count":53,"is_preprint":false},{"pmid":"2142008","id":"PMC_2142008","title":"In vivo modulation with anti-interleukin-1 (IL-1) receptor (p80) antibody 35F5 of the response to IL-1. The relationship of radioprotection, colony-stimulating factor, and IL-6.","date":"1990","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/2142008","citation_count":53,"is_preprint":false},{"pmid":"19366570","id":"PMC_19366570","title":"Protective and antifecundity effects of Sm-p80-based DNA vaccine formulation against Schistosoma mansoni in a nonhuman primate model.","date":"2009","source":"Vaccine","url":"https://pubmed.ncbi.nlm.nih.gov/19366570","citation_count":52,"is_preprint":false},{"pmid":"27239033","id":"PMC_27239033","title":"Promotion of RAD51-Mediated Homologous DNA Pairing by the RAD51AP1-UAF1 Complex.","date":"2016","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/27239033","citation_count":51,"is_preprint":false},{"pmid":"30133707","id":"PMC_30133707","title":"Sm-p80-based schistosomiasis vaccine: double-blind preclinical trial in baboons demonstrates comprehensive prophylactic and parasite transmission-blocking efficacy.","date":"2018","source":"Annals of the New York Academy of Sciences","url":"https://pubmed.ncbi.nlm.nih.gov/30133707","citation_count":51,"is_preprint":false},{"pmid":"11438547","id":"PMC_11438547","title":"Genetic deletion of the tumor necrosis factor receptor p60 or p80 abrogates ligand-mediated activation of nuclear factor-kappa B and of mitogen-activated protein kinases in macrophages.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11438547","citation_count":50,"is_preprint":false},{"pmid":"1309861","id":"PMC_1309861","title":"Heterogeneous expression of the non-structural protein p80/p125 in cells infected with different pestiviruses.","date":"1992","source":"The Journal of general virology","url":"https://pubmed.ncbi.nlm.nih.gov/1309861","citation_count":48,"is_preprint":false},{"pmid":"1639139","id":"PMC_1639139","title":"Immunolocalization of Ku-proteins (p80/p70): localization of p70 to nucleoli and periphery of both interphase nuclei and metaphase chromosomes.","date":"1992","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/1639139","citation_count":48,"is_preprint":false},{"pmid":"7971277","id":"PMC_7971277","title":"Structure, expression and chromosomal localization of human p80-coilin gene.","date":"1994","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/7971277","citation_count":47,"is_preprint":false},{"pmid":"33795880","id":"PMC_33795880","title":"Structural basis of FANCD2 deubiquitination by USP1-UAF1.","date":"2021","source":"Nature structural & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/33795880","citation_count":45,"is_preprint":false},{"pmid":"1310388","id":"PMC_1310388","title":"Inhibition of ligand binding and antiproliferative effects of tumor necrosis factor and lymphotoxin by soluble forms of recombinant P60 and P80 receptors.","date":"1992","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/1310388","citation_count":44,"is_preprint":false},{"pmid":"19222788","id":"PMC_19222788","title":"Sm-p80-based DNA vaccine formulation induces potent protective immunity against Schistosoma mansoni.","date":"2009","source":"Parasite immunology","url":"https://pubmed.ncbi.nlm.nih.gov/19222788","citation_count":42,"is_preprint":false},{"pmid":"12482610","id":"PMC_12482610","title":"p80 ROKalpha binding protein is a novel splice variant of CRMP-1 which associates with CRMP-2 and modulates RhoA-induced neuronal morphology.","date":"2002","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/12482610","citation_count":42,"is_preprint":false},{"pmid":"24436452","id":"PMC_24436452","title":"Use of an Sm-p80-based therapeutic vaccine to kill established adult schistosome parasites in chronically infected baboons.","date":"2014","source":"The Journal of infectious diseases","url":"https://pubmed.ncbi.nlm.nih.gov/24436452","citation_count":42,"is_preprint":false},{"pmid":"26929214","id":"PMC_26929214","title":"Proteomic Analysis of the Mammalian Katanin Family of Microtubule-severing Enzymes Defines Katanin p80 subunit B-like 1 (KATNBL1) as a Regulator of Mammalian Katanin Microtubule-severing.","date":"2016","source":"Molecular & cellular proteomics : MCP","url":"https://pubmed.ncbi.nlm.nih.gov/26929214","citation_count":42,"is_preprint":false},{"pmid":"7699019","id":"PMC_7699019","title":"Assembly and DNA binding of recombinant Ku (p70/p80) autoantigen defined by a novel monoclonal antibody specific for p70/p80 heterodimers.","date":"1994","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/7699019","citation_count":41,"is_preprint":false},{"pmid":"20187746","id":"PMC_20187746","title":"Sm-p80-based DNA vaccine provides baboons with levels of protection against Schistosoma mansoni infection comparable to those achieved by the irradiated cercarial vaccine.","date":"2010","source":"The Journal of infectious diseases","url":"https://pubmed.ncbi.nlm.nih.gov/20187746","citation_count":41,"is_preprint":false},{"pmid":"24356955","id":"PMC_24356955","title":"The WD40-repeat proteins WDR-20 and WDR-48 bind and activate the deubiquitinating enzyme USP-46 to promote the abundance of the glutamate receptor GLR-1 in the ventral nerve cord of Caenorhabditis elegans.","date":"2013","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24356955","citation_count":39,"is_preprint":false},{"pmid":"17351128","id":"PMC_17351128","title":"LAPSER1 is a putative cytokinetic tumor suppressor that shows the same centrosome and midbody subcellular localization pattern as p80 katanin.","date":"2007","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/17351128","citation_count":39,"is_preprint":false},{"pmid":"18032488","id":"PMC_18032488","title":"Human papillomavirus E1 helicase interacts with the WD repeat protein p80 to promote maintenance of the viral genome in keratinocytes.","date":"2007","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/18032488","citation_count":38,"is_preprint":false},{"pmid":"7622600","id":"PMC_7622600","title":"p80-coilin: a component of coiled bodies and interchromatin granule-associated zones.","date":"1995","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/7622600","citation_count":38,"is_preprint":false},{"pmid":"1529529","id":"PMC_1529529","title":"Nucleotide sequence and transcriptional analysis of the p80 gene of Autographa californica nuclear polyhedrosis virus: a homologue of the Orgyia pseudotsugata nuclear polyhedrosis virus capsid-associated gene.","date":"1992","source":"Virology","url":"https://pubmed.ncbi.nlm.nih.gov/1529529","citation_count":38,"is_preprint":false},{"pmid":"1335762","id":"PMC_1335762","title":"Down-modulation of cell surface expression of p80 form of the tumor necrosis factor receptor by human immunodeficiency virus-1 tat gene.","date":"1992","source":"Lymphokine and cytokine research","url":"https://pubmed.ncbi.nlm.nih.gov/1335762","citation_count":37,"is_preprint":false},{"pmid":"8911263","id":"PMC_8911263","title":"Differential sensitivity to Escherichia coli infection in mice lacking tumor necrosis factor p55 or interleukin-1 p80 receptors.","date":"1996","source":"Archives of surgery (Chicago, Ill. : 1960)","url":"https://pubmed.ncbi.nlm.nih.gov/8911263","citation_count":37,"is_preprint":false},{"pmid":"24001775","id":"PMC_24001775","title":"Inactivation of Uaf1 causes defective homologous recombination and early embryonic lethality in mice.","date":"2013","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/24001775","citation_count":35,"is_preprint":false},{"pmid":"23116119","id":"PMC_23116119","title":"Serine phosphorylation is critical for the activation of ubiquitin-specific protease 1 and its interaction with WD40-repeat protein UAF1.","date":"2012","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23116119","citation_count":35,"is_preprint":false},{"pmid":"28079116","id":"PMC_28079116","title":"Katanin p80, NuMA and cytoplasmic dynein cooperate to control microtubule dynamics.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28079116","citation_count":35,"is_preprint":false},{"pmid":"9449486","id":"PMC_9449486","title":"The t(2;5)-associated p80 NPM/ALK fusion protein in nodal and cutaneous CD30+ lymphoproliferative disorders.","date":"1997","source":"Journal of cutaneous pathology","url":"https://pubmed.ncbi.nlm.nih.gov/9449486","citation_count":34,"is_preprint":false},{"pmid":"7774599","id":"PMC_7774599","title":"Role of free p70 (Ku) subunit in posttranslational stabilization of newly synthesized p80 during DNA-dependent protein kinase assembly.","date":"1995","source":"European journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/7774599","citation_count":34,"is_preprint":false},{"pmid":"8176381","id":"PMC_8176381","title":"Detection of bovine viral diarrhoea virus p80 protein in subpopulations of bovine leukocytes.","date":"1994","source":"The Journal of general virology","url":"https://pubmed.ncbi.nlm.nih.gov/8176381","citation_count":34,"is_preprint":false},{"pmid":"24728521","id":"PMC_24728521","title":"Longevity of Sm-p80-specific antibody responses following vaccination with Sm-p80 vaccine in mice and baboons and transplacental transfer of Sm-p80-specific antibodies in a baboon.","date":"2014","source":"Parasitology research","url":"https://pubmed.ncbi.nlm.nih.gov/24728521","citation_count":32,"is_preprint":false},{"pmid":"20630783","id":"PMC_20630783","title":"Protective effects of Sm-p80 in the presence of resiquimod as an adjuvant against challenge infection with Schistosoma mansoni in mice.","date":"2010","source":"International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases","url":"https://pubmed.ncbi.nlm.nih.gov/20630783","citation_count":32,"is_preprint":false},{"pmid":"12695514","id":"PMC_12695514","title":"Genetic deletion of the tumor necrosis factor receptor p60 or p80 sensitizes macrophages to lipopolysaccharide-induced nuclear factor-kappa B, mitogen-activated protein kinases, and apoptosis.","date":"2003","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12695514","citation_count":32,"is_preprint":false},{"pmid":"27463890","id":"PMC_27463890","title":"The USP1-UAF1 complex interacts with RAD51AP1 to promote homologous recombination repair.","date":"2016","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/27463890","citation_count":31,"is_preprint":false},{"pmid":"15701761","id":"PMC_15701761","title":"The p80 homology region of TEP1 is sufficient for its association with the telomerase and vault RNAs, and the vault particle.","date":"2005","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/15701761","citation_count":31,"is_preprint":false},{"pmid":"19546164","id":"PMC_19546164","title":"Angiomotin p80/p130 ratio: a new indicator of exercise-induced angiogenic activity in skeletal muscles from obese and non-obese rats?","date":"2009","source":"The Journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/19546164","citation_count":31,"is_preprint":false},{"pmid":"21277404","id":"PMC_21277404","title":"Role of antibodies in Sm-p80-mediated protection against Schistosoma mansoni challenge infection in murine and nonhuman primate models.","date":"2011","source":"Vaccine","url":"https://pubmed.ncbi.nlm.nih.gov/21277404","citation_count":31,"is_preprint":false},{"pmid":"22701671","id":"PMC_22701671","title":"Two nuclear localization signals in USP1 mediate nuclear import of the USP1/UAF1 complex.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22701671","citation_count":30,"is_preprint":false},{"pmid":"29026995","id":"PMC_29026995","title":"Cross-species prophylactic efficacy of Sm-p80-based vaccine and intracellular localization of Sm-p80/Sm-p80 ortholog proteins during development in Schistosoma mansoni, Schistosoma japonicum, and Schistosoma haematobium.","date":"2017","source":"Parasitology research","url":"https://pubmed.ncbi.nlm.nih.gov/29026995","citation_count":30,"is_preprint":false},{"pmid":"27650958","id":"PMC_27650958","title":"A conserved two-step binding for the UAF1 regulator to the USP12 deubiquitinating enzyme.","date":"2016","source":"Journal of structural biology","url":"https://pubmed.ncbi.nlm.nih.gov/27650958","citation_count":29,"is_preprint":false},{"pmid":"8756580","id":"PMC_8756580","title":"Dual expression of p80 type I and p68 type II interleukin-I receptors on anterior pituitary cells synthesizing growth hormone.","date":"1996","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/8756580","citation_count":29,"is_preprint":false},{"pmid":"10571209","id":"PMC_10571209","title":"The immunohistochemical expression of DNA-PKCS and Ku (p70/p80) in head and neck cancers: relationships with radiosensitivity.","date":"1999","source":"International journal of radiation oncology, biology, physics","url":"https://pubmed.ncbi.nlm.nih.gov/10571209","citation_count":29,"is_preprint":false},{"pmid":"29888790","id":"PMC_29888790","title":"Sm-p80-based vaccine trial in baboons: efficacy when mimicking natural conditions of chronic disease, praziquantel therapy, immunization, and Schistosoma mansoni re-encounter.","date":"2018","source":"Annals of the New York Academy of Sciences","url":"https://pubmed.ncbi.nlm.nih.gov/29888790","citation_count":29,"is_preprint":false},{"pmid":"23000221","id":"PMC_23000221","title":"Role of antibody dependent cell mediated cytotoxicity (ADCC) in Sm-p80-mediated protection against Schistosoma mansoni.","date":"2012","source":"Vaccine","url":"https://pubmed.ncbi.nlm.nih.gov/23000221","citation_count":29,"is_preprint":false},{"pmid":"15670880","id":"PMC_15670880","title":"Characterization of the immune response to DNA vaccination strategies for schistosomiasis candidate antigen, Sm-p80 in the baboon.","date":"2005","source":"Vaccine","url":"https://pubmed.ncbi.nlm.nih.gov/15670880","citation_count":29,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":51694,"output_tokens":4491,"usd":0.111224,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12469,"output_tokens":4850,"usd":0.091798,"stage2_stop_reason":"end_turn"},"total_usd":0.203022,"stage1_batch_id":"msgbatch_01UT1AahFPCAyn2uVweS7A9z","stage2_batch_id":"msgbatch_01HuKWtKNT4Pqj1bc8eEP5RV","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2007,\n      \"finding\": \"WDR48 (UAF1) is a stoichiometric subunit of the USP1 deubiquitinating enzyme complex; UAF1 activates USP1 by increasing its catalytic turnover (kcat) without altering substrate affinity (KM), as demonstrated by in vitro reconstitution with Ub-AMC and purified monoubiquitinated FANCD2 as substrates.\",\n      \"method\": \"Affinity purification from HeLa cells, in vitro reconstitution of DUB activity, kinetic analysis (kcat and KM measurements)\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with two distinct substrates, kinetic characterization, stoichiometric complex purification; foundational mechanistic study\",\n      \"pmids\": [\"18082604\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"UAF1 (WDR48) is a shared activating subunit of at least three distinct deubiquitinating enzyme complexes—USP1/UAF1, USP12/UAF1, and USP46/UAF1—functioning as a bona fide regulatory subunit that stimulates enzymatic activity in each complex.\",\n      \"method\": \"Immunoprecipitation, complex purification, in vitro DUB activity assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — reciprocal co-IP, in vitro activity assays across three separate complexes, replicated by subsequent studies\",\n      \"pmids\": [\"19075014\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"WDR20, a second WD40-repeat protein, associates exclusively with the USP12/UAF1 and USP46/UAF1 complexes (not USP1/UAF1) to form a ternary complex; WDR20 further stimulates USP12 enzymatic activity beyond that provided by UAF1 alone.\",\n      \"method\": \"Affinity purification, co-immunoprecipitation, in vitro DUB activity assays, siRNA knockdown\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — ternary complex purified and reconstituted, activity measured with and without WDR20, selectivity for USP12/46 over USP1 demonstrated\",\n      \"pmids\": [\"20147737\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The USP1/UAF1 complex promotes homologous recombination (HR)-mediated double-strand break repair; UAF1-deficient cells are hypersensitive to camptothecin and PARP inhibitors, and disruption of NHEJ in UAF1-deficient cells restores resistance, indicating UAF1 promotes HR at least partly by suppressing NHEJ.\",\n      \"method\": \"Gene knockout in chicken DT40 cells, chemical sensitivity assays, epistasis with NHEJ-deficient mutants\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO cells, genetic epistasis, multiple DNA damaging agents, replicated phenotypes across USP1-/- and UAF1-/- cells\",\n      \"pmids\": [\"21482670\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"WDR48 (UAF1) in complex with USP12 deubiquitinates PHLPP1, stabilizing it and thereby suppressing PI3K/Akt signaling and promoting apoptosis; a cancer-associated WDR48 somatic mutation (L580F) is defective in stabilizing PHLPP1.\",\n      \"method\": \"Tandem affinity purification, co-immunoprecipitation, ubiquitination assays, cell viability and apoptosis assays, mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — TAP-MS identification, functional validation by DUB assay, multiple orthogonal methods, somatic mutation analysis\",\n      \"pmids\": [\"24145035\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"C. elegans WDR-48 (orthologue of WDR48/UAF1) binds and stimulates USP-46 catalytic activity in vitro; in vivo, WDR-48 and WDR-20 overexpression increases GLR-1 glutamate receptor abundance in the ventral nerve cord by reducing its ubiquitination, and loss-of-function wdr-48 mutants show decreased GLR-1 and altered locomotion.\",\n      \"method\": \"In vitro DUB activity assays, in vivo receptor abundance measurements (fluorescence microscopy), genetic loss-of-function mutants, ubiquitin conjugate analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro reconstitution plus in vivo genetic analysis with defined phenotypic readout; multiple orthogonal methods\",\n      \"pmids\": [\"24356955\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Crystal structures of the USP12–UAF1 complex reveal that UAF1 binds the distal end of the USP12 Fingers domain and allosterically activates the enzyme via a cascade of structural changes reaching a ubiquitin-contacting loop near the catalytic cleft, without increasing substrate affinity.\",\n      \"method\": \"X-ray crystallography, biochemical activity assays, mutagenesis\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with mutagenesis and biochemical validation; allosteric mechanism defined at atomic resolution\",\n      \"pmids\": [\"27373336\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"UAF1 (WDR48) binds DNA and forms a dimeric complex with RAD51AP1 via SUMO-like domains in UAF1 engaging a SUMO-interacting motif in RAD51AP1; UAF1 enhances RAD51-mediated homologous DNA pairing through this complex in a manner independent of USP1.\",\n      \"method\": \"Biochemical reconstitution, co-immunoprecipitation, DNA binding assays, RAD51-mediated strand exchange assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro reconstitution, defined protein–protein interaction domains, functional HR assay, USP1-independent mechanism established\",\n      \"pmids\": [\"27239033\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Efficient FANCD2 deubiquitination by the USP1-UAF1 complex requires DNA binding by UAF1; RAD51AP1, whose DNA binding activity can substitute for that of UAF1, forms a UAF1-RAD51AP1-USP1 trimeric complex that enables DNA-dependent FANCD2 deubiquitination.\",\n      \"method\": \"Reconstituted biochemical system, DNA binding assays, deubiquitination assays, cell-based FANCD2 deubiquitination experiments\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — fully reconstituted biochemical system with defined mutants, complemented by cellular validation\",\n      \"pmids\": [\"31253762\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Crystal structures of USP1-UAF1 and cryo-EM reconstruction of USP1-UAF1 bound to monoubiquitinated FANCI-FANCD2 reveal that an extensive UAF1–FANCI interface (not direct UAF1 catalytic involvement) is required for FANCD2 deubiquitination, and USP1-UAF1 induces conformational changes in the FANCI-FANCD2 substrate.\",\n      \"method\": \"X-ray crystallography, cryo-EM, mutagenesis, biochemical deubiquitination assays\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure + cryo-EM + mutagenesis + biochemical assays in a single study\",\n      \"pmids\": [\"33795880\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Serine 313 phosphorylation of USP1 by CDK1 is required for USP1 interaction with UAF1; an inserted domain (amino acids 235–408) in USP1 mediates the UAF1 interaction in a pSer313-dependent manner; protein phosphatase treatment of USP1 inactivates the USP1/UAF1 complex.\",\n      \"method\": \"Mutagenesis, phosphomimetic substitution, co-immunoprecipitation, in vitro kinase/phosphatase assays, DUB activity assays\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (mutagenesis, kinase assay, phosphatase treatment, activity reconstitution) in one study\",\n      \"pmids\": [\"23116119\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Homozygous Uaf1 knockout mice die at embryonic day 7.5; Uaf1+/- cells show increased FANCD2-Ub and PCNA-Ub levels, chromosome instability, genotoxin hypersensitivity, and defective homologous recombination repair, establishing UAF1 as essential for embryonic development and HR-mediated DNA repair in vivo.\",\n      \"method\": \"Mouse knockout, MEF characterization, comet assay, HR reporter assays, flow cytometry for DNA damage markers\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean mouse KO with multiple cellular readouts; embryonic lethality and HR defect independently confirmed\",\n      \"pmids\": [\"24001775\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"USP1-UAF1 complex stabilizes TBK1 by removing its K48-linked polyubiquitination, preventing proteasomal degradation; this enhances IRF3 activation and IFN-β secretion during viral infection, and the USP1-UAF1 inhibitor ML323 attenuates IFN-β expression and enhances viral replication.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, siRNA knockdown, IFN-β reporter assays, pharmacological inhibition\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP and deubiquitination assay in single lab, multiple cellular readouts but not in vitro reconstitution\",\n      \"pmids\": [\"29138248\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The UAF1/USP1 complex selectively removes K48-linked polyubiquitination from NLRP3 to suppress its degradation; UAF1/USP12 and UAF1/USP46 complexes remove K48-linked polyubiquitination from p65 NF-κB to promote NLRP3 and pro-IL-1β transcription; Uaf1 deficiency in vivo attenuates NLRP3 inflammasome activation and IL-1β secretion.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, siRNA knockdown, Uaf1-deficient mice, NLRP3 inflammasome activation assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple substrates identified, in vivo genetic validation, single lab study\",\n      \"pmids\": [\"33247121\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"WDR48 (p80) interacts with the N-terminal 40 amino acids of HPV E1 helicase; this interaction is conserved among anogenital HPV types; E1 redistributes WDR48 from the cytoplasm to the nucleus via E1's nuclear localization signal; mutations in E1 that abrogate p80 binding prevent maintenance of HPV episomes in keratinocytes.\",\n      \"method\": \"Tandem affinity purification/mass spectrometry, co-immunoprecipitation, colocalization microscopy, mutagenesis, HPV episome maintenance assay in keratinocytes\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — TAP-MS identification with mutagenesis validation, functional episome assay, single lab\",\n      \"pmids\": [\"18032488\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"USP1 nuclear localization signals (NLSs) mediate nuclear import of the USP1/UAF1 complex; UAF1 alone localizes to the cytoplasm but is carried into the nucleus by USP1; a conserved 100 amino acid motif in USP1 mediates the UAF1-binding interaction.\",\n      \"method\": \"Cellular relocation assay, deletion/mutagenesis analysis, immunofluorescence microscopy\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — mutagenesis and cellular localization assay, defined interacting domain, single lab\",\n      \"pmids\": [\"22701671\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Crystal structure of USP12-Ub/UAF1 reveals two UAF1 binding sites on USP12 (stoichiometry 1:2 in solution); the high-affinity site (Kd ~4 nM) at the Fingers subdomain is required for activation, while the second lower-affinity site (Kd ~325 nM) does not affect activation; this two-step binding is conserved in USP1.\",\n      \"method\": \"X-ray crystallography, isothermal titration calorimetry, mutagenesis, in vitro DUB activity assays\",\n      \"journal\": \"Journal of structural biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with mutagenesis, biophysical binding measurements, and activity assays; allosteric mechanism defined\",\n      \"pmids\": [\"27650958\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"UAF1 mediates interaction between USP1 and RAD51AP1; depletion of USP1 or UAF1 decreases RAD51AP1 stability; cells expressing a UAF1-interaction-deficient RAD51AP1 mutant show increased chromosomal aberrations and persistent RAD51 foci after DNA damage, indicating the USP1-UAF1 complex promotes a later step of HR repair through RAD51AP1.\",\n      \"method\": \"Co-immunoprecipitation, protein interaction mapping, siRNA knockdown, chromosomal aberration assay, RAD51 focus analysis\",\n      \"journal\": \"Cell cycle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP, mutagenesis of interaction interface, multiple cellular readouts, single lab\",\n      \"pmids\": [\"27463890\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"WDR48 (UAF1) functions as a shared allosteric activator subunit for a subfamily of deubiquitinating enzymes—USP1, USP12, and USP46—binding via their Fingers domains and stimulating catalytic turnover without affecting substrate affinity; the USP1/UAF1 complex is recruited to the nucleus via USP1 NLSs and, upon CDK1-mediated phosphorylation of USP1-Ser313, deubiquitinates key DNA repair substrates (FANCD2-Ub, PCNA-Ub) to regulate the Fanconi anemia pathway and promote homologous recombination repair, while also stabilizing TBK1 and NLRP3 through K48-deubiquitination and interacting with RAD51AP1 to support HR in a USP1-independent manner; WDR48 also forms a USP12-containing complex that stabilizes the tumor suppressor PHLPP1 to suppress Akt signaling, and it is recruited by HPV E1 helicase to the nucleus to maintain viral episomes.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"WDR48 (UAF1) is a WD40-repeat protein that functions as a shared allosteric activator subunit for a subfamily of deubiquitinating enzymes—USP1, USP12, and USP46—stimulating their catalytic turnover (kcat) without altering substrate affinity (KM) [#0, #1]. Structural studies define the mechanism: UAF1 docks onto the distal end of the substrate USP Fingers domain via a high-affinity site, triggering a cascade of conformational changes that reach a ubiquitin-contacting loop near the catalytic cleft [#6, #16]. In the USP12/USP46 complexes a second WD40 protein, WDR20, joins to form a ternary assembly that further stimulates activity, whereas USP1/UAF1 lacks WDR20 [#2]. The USP1/UAF1 complex is the central effector in DNA repair: it is imported to the nucleus via USP1 nuclear localization signals, its activity is gated by CDK1 phosphorylation of USP1-Ser313, and it deubiquitinates the Fanconi anemia and replication substrates FANCD2-Ub and PCNA-Ub to support homologous recombination repair [#10, #11, #15]. Efficient FANCD2 deubiquitination depends on UAF1 DNA binding and an extensive UAF1–FANCI interface that remodels the FANCI-FANCD2 substrate [#8, #9]. UAF1 also acts through SUMO-like domains to recruit RAD51AP1, enhancing RAD51-mediated DNA pairing and promoting a later step of HR—a function that can proceed independently of USP1 [#7, #17]. Beyond genome maintenance, the USP12/UAF1 complex deubiquitinates and stabilizes the tumor suppressor PHLPP1 to suppress PI3K/Akt signaling, and UAF1-containing complexes remove K48-linked ubiquitin from immune regulators TBK1 and NLRP3 to control interferon and inflammasome responses [#4, #12, #13]. WDR48 is also targeted by HPV E1 helicase, which relocalizes it to the nucleus to maintain viral episomes [#14].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Established that WDR48/UAF1 is not a passive scaffold but a catalytic activator, answering how USP1 achieves physiological deubiquitinase activity.\",\n      \"evidence\": \"Affinity purification from HeLa cells with in vitro reconstitution and kinetic analysis using Ub-AMC and monoubiquitinated FANCD2\",\n      \"pmids\": [\"18082604\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of activation unresolved at this stage\", \"Did not address whether other USPs share this regulation\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identified WDR48 as a host factor hijacked by HPV E1 helicase, linking it to viral genome persistence.\",\n      \"evidence\": \"TAP-MS, co-IP, colocalization, and HPV episome maintenance assay in keratinocytes\",\n      \"pmids\": [\"18032488\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which WDR48 supports episome maintenance not defined\", \"Single lab; whether DUB activity is required is unaddressed\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Generalized UAF1's role by showing it is a shared activating subunit of three distinct DUB complexes (USP1, USP12, USP46), defining a regulated DUB subfamily.\",\n      \"evidence\": \"Reciprocal co-IP, complex purification, and in vitro DUB activity assays across three complexes\",\n      \"pmids\": [\"19075014\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Substrates of USP12/UAF1 and USP46/UAF1 not yet identified\", \"Did not explain selectivity of partner usage\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Resolved complex-specific composition by showing WDR20 selectively joins USP12/USP46—but not USP1—complexes and provides additional activation.\",\n      \"evidence\": \"Affinity purification, co-IP, siRNA, and in vitro DUB assays with and without WDR20\",\n      \"pmids\": [\"20147737\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of WDR20 contribution not determined here\", \"Functional consequence of WDR20 absence in USP1 complex unclear\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Placed the USP1/UAF1 complex functionally within DNA double-strand break repair by showing it promotes HR partly by suppressing NHEJ.\",\n      \"evidence\": \"Gene knockout in chicken DT40 cells, chemical sensitivity assays, and epistasis with NHEJ-deficient mutants\",\n      \"pmids\": [\"21482670\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism linking DUB activity to NHEJ suppression not defined\", \"Relevant substrate driving the HR phenotype not pinpointed\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined how the complex is spatially and temporally controlled: USP1 NLSs import UAF1 into the nucleus, and CDK1 phosphorylation of USP1-Ser313 gates complex formation and activity.\",\n      \"evidence\": \"Cellular relocation assays, deletion mutagenesis, immunofluorescence, kinase/phosphatase and DUB activity assays\",\n      \"pmids\": [\"22701671\", \"23116119\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell-cycle dynamics of activation in vivo not fully mapped\", \"Phosphatase responsible for inactivation in cells not identified\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrated UAF1 is essential in vivo and confirmed FANCD2-Ub and PCNA-Ub as physiological substrates underlying genome stability.\",\n      \"evidence\": \"Uaf1 knockout mice, MEF characterization, comet and HR reporter assays, flow cytometry for ubiquitinated DNA repair markers\",\n      \"pmids\": [\"24001775\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cause of E7.5 embryonic lethality not mechanistically dissected\", \"Did not separate USP1-dependent from USP1-independent contributions\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Extended UAF1 function beyond DNA repair by showing the USP12/UAF1 complex stabilizes PHLPP1 to suppress Akt signaling, with a cancer mutation defective in this role.\",\n      \"evidence\": \"TAP-MS, co-IP, ubiquitination, viability/apoptosis assays, and L580F mutagenesis\",\n      \"pmids\": [\"24145035\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"WDR20 contribution to PHLPP1 regulation not addressed\", \"Tumor relevance of L580F beyond cell models untested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Confirmed evolutionary conservation and a neuronal role by showing C. elegans WDR-48 activates USP-46 to control GLR-1 glutamate receptor abundance and behavior.\",\n      \"evidence\": \"In vitro DUB assays plus in vivo genetic loss-of-function and receptor abundance microscopy in worms\",\n      \"pmids\": [\"24356955\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mammalian neuronal relevance not established here\", \"Direct deubiquitination of the receptor not shown biochemically\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Solved the structural basis of allosteric activation, showing UAF1 binds the Fingers domain and transmits conformational changes to the catalytic cleft via a high-affinity site.\",\n      \"evidence\": \"X-ray crystallography of USP12–UAF1, ITC, mutagenesis, and DUB activity assays\",\n      \"pmids\": [\"27373336\", \"27650958\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Function of the second low-affinity UAF1 site undefined\", \"Structures of full-length substrate-engaged complexes still lacking at this point\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Uncovered a USP1-independent UAF1 function in HR through DNA binding and SUMO-like-domain-mediated recruitment of RAD51AP1 to enhance RAD51 strand pairing.\",\n      \"evidence\": \"Biochemical reconstitution, co-IP, DNA binding assays, RAD51 strand-exchange assays, and cellular RAD51 focus/chromosomal aberration analysis\",\n      \"pmids\": [\"27239033\", \"27463890\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Interplay between USP1-dependent and RAD51AP1-dependent HR roles not fully resolved\", \"Regulation of UAF1 DNA binding in cells unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Expanded the substrate repertoire to innate immunity, showing USP1-UAF1 stabilizes TBK1 by removing K48 ubiquitin to promote interferon responses.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, siRNA, IFN-β reporter assays, and ML323 pharmacological inhibition\",\n      \"pmids\": [\"29138248\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vitro reconstitution of TBK1 deubiquitination\", \"Single lab; in vivo immune phenotype not tested here\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Mechanistically explained why UAF1 DNA binding matters, showing it is required for efficient FANCD2 deubiquitination and that RAD51AP1 can substitute for this function in a trimeric complex.\",\n      \"evidence\": \"Fully reconstituted biochemical system with DNA binding and deubiquitination assays plus cellular validation\",\n      \"pmids\": [\"31253762\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How DNA binding positions the substrate not visualized at this stage\", \"Physiological switch between UAF1- and RAD51AP1-dependent modes unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined opposing UAF1 complex roles in inflammasome signaling: USP1/UAF1 stabilizes NLRP3 while USP12/46 complexes stabilize p65 to drive transcription.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, siRNA, Uaf1-deficient mice, and NLRP3 inflammasome activation assays\",\n      \"pmids\": [\"33247121\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vitro reconstitution of NLRP3 or p65 deubiquitination\", \"Single lab; substrate specificity across complexes not biochemically separated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Provided the substrate-engaged structure, revealing that an extensive UAF1–FANCI interface, not direct catalysis by UAF1, drives FANCD2 deubiquitination through substrate remodeling.\",\n      \"evidence\": \"X-ray crystallography of USP1-UAF1 and cryo-EM of the complex bound to monoubiquitinated FANCI-FANCD2, with mutagenesis and biochemical assays\",\n      \"pmids\": [\"33795880\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the RAD51AP1-substituted pathway not resolved\", \"How CDK1 phosphorylation alters this assembly structurally unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How UAF1 complex composition and substrate selection are coordinated across its diverse roles—DNA repair, Akt suppression, innate immunity, and viral episome maintenance—within a single cell remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying model for context-specific substrate routing among USP1/12/46 complexes\", \"Immune substrate deubiquitination lacks in vitro reconstitution\", \"Regulation balancing USP1-dependent vs USP1-independent HR functions undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 2, 6, 16]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [7, 8, 9, 17]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [7, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [14, 15]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [14, 15]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [3, 9, 11]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [12, 13]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [\n      \"USP1/UAF1 complex\",\n      \"USP12/UAF1 complex\",\n      \"USP46/UAF1 complex\",\n      \"USP12-UAF1-WDR20 ternary complex\"\n    ],\n    \"partners\": [\n      \"USP1\",\n      \"USP12\",\n      \"USP46\",\n      \"WDR20\",\n      \"RAD51AP1\",\n      \"FANCI\",\n      \"PHLPP1\",\n      \"HPV E1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}