{"gene":"TRAIP","run_date":"2026-04-28T21:42:59","timeline":{"discoveries":[{"year":1997,"finding":"TRAIP (TRIP) was identified as a novel component of TNFR2 and CD30 signaling complexes that associates with TRAF proteins and inhibits TRAF2-mediated NF-κB activation, containing a RING finger motif and an extended coiled-coil domain.","method":"Protein interaction studies (yeast two-hybrid, co-immunoprecipitation), NF-κB reporter assays","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 — original discovery paper with multiple orthogonal methods, replicated by subsequent studies","pmids":["9104814"],"is_preprint":false},{"year":2007,"finding":"TRAIP (TRIP) is a RING-dependent E3 ubiquitin ligase that undergoes auto-ubiquitination; intact RING domain is required for ligase activity. TRIP interacts with TRAF1, 2, 3, 5, and 6 but not CYLD or NIK.","method":"In vitro ubiquitination assay, RING domain mutagenesis, co-immunoprecipitation","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1 — in vitro E3 ligase assay with mutagenesis confirming RING domain requirement","pmids":["17544371"],"is_preprint":false},{"year":2003,"finding":"TRAIP (TRIP) interacts with the tumor suppressor CYLD through its C-terminal domain; CYLD's central domain binds TRIP's C-terminal end, and this interaction contributes to down-regulation of NF-κB activation by TNF-α.","method":"Yeast two-hybrid screen, far-Western analysis, co-immunoprecipitation in mammalian cells, NF-κB reporter assays","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods including yeast two-hybrid, far-Western, and Co-IP in mammalian cells","pmids":["14676304"],"is_preprint":false},{"year":2007,"finding":"TRAIP (TRIP) is essential for early embryonic development; homozygous TRIP-deficient mouse embryos die shortly after implantation due to proliferation defects and excessive cell death.","method":"Gene knockout in mice, embryo phenotyping","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 2 — clean KO with defined developmental phenotype","pmids":["17927961"],"is_preprint":false},{"year":2012,"finding":"TRAIP (TRIP) promotes proteasomal degradation of TBK1 by directly binding TBK1 and promoting K48-linked polyubiquitination, thereby negatively regulating TLR3/4- and RIG-I-induced IFN-β production and antiviral responses.","method":"Co-immunoprecipitation, ubiquitination assays, siRNA knockdown/overexpression, IRF3 activation assays, viral replication assays","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 1–2 — direct binding, K48-linked ubiquitination of TBK1 shown, multiple orthogonal methods","pmids":["22945920"],"is_preprint":false},{"year":2014,"finding":"TRAIP is a nucleolar E3 ubiquitin ligase that localizes close to mitotic chromosomes; its depletion decreases early mitosis progression time, increases chromosome alignment defects and lagging chromosomes, and reduces MAD2 levels at kinetochores — effects requiring intact ubiquitin ligase activity.","method":"RNAi knockdown in HeLa cells, live cell imaging, immunofluorescence, rescue with WT vs. ligase-dead TRAIP","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 — clean KD with defined mitotic phenotypes, ligase-activity rescue experiments, replicated findings","pmids":["25335891"],"is_preprint":false},{"year":2015,"finding":"TRAIP is a PCNA-binding E3 ubiquitin ligase that interacts directly with PCNA via a conserved PIP box motif and promotes ATR-dependent checkpoint signaling by facilitating RPA-bound single-stranded DNA generation upon replication stress; loss of TRAIP causes chromosomal instability.","method":"Co-immunoprecipitation, PIP box mutagenesis, ATR/RPA2 phosphorylation assays, chromosomal instability assays, siRNA knockdown","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1–2 — direct PCNA interaction mapped, E3 ligase activity required, multiple orthogonal methods","pmids":["26711499"],"is_preprint":false},{"year":2015,"finding":"Mutations in TRAIP (an E3 RING ubiquitin ligase) cause microcephalic primordial dwarfism; TRAIP relocalizes to sites of DNA damage where it is required for optimal phosphorylation of H2AX and RPA2 during S-phase in response to UV irradiation, and is necessary for fork progression through UV-induced lesions.","method":"Human genetics, patient-derived cells, immunofluorescence/live imaging of damage recruitment, H2AX/RPA2 phosphorylation assays, DNA fiber assays","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (genetic, cell biology, biochemical), strong mechanistic follow-up","pmids":["26595769"],"is_preprint":false},{"year":2016,"finding":"TRAIP (RNF206) is required for recruitment of RAP80 to DNA damage sites; TRAIP acts upstream of RAP80, and the N-terminus of TRAIP mediates RAP80 interaction while the C-terminus mediates TRAIP localization to damage sites through direct interaction with RNF20-RNF40. TRAIP promotes homologous recombination and BRCA1 accumulation at damage sites.","method":"Co-immunoprecipitation, domain mapping, siRNA knockdown, immunofluorescence at DNA damage foci","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, domain mapping, genetic epistasis for RAP80/BRCA1 recruitment","pmids":["26781088"],"is_preprint":false},{"year":2016,"finding":"TRAIP (RNF206) interacts with PCNA via a conserved PIP box on its C-terminus, localizes to stalled replication forks as a nucleolar protein, and is required for replication fork recovery and progression; inactivation of TRAIP or its PCNA interaction leads to chromosome instability.","method":"Co-immunoprecipitation, PIP box mutagenesis, DNA fiber assay, chromosomal instability assays","journal":"Cell discovery","confidence":"Medium","confidence_rationale":"Tier 2 — direct interaction mapped with mutagenesis, functional consequences shown; single lab","pmids":["27462463"],"is_preprint":false},{"year":2019,"finding":"TRAIP is the master E3 ubiquitin ligase controlling replication-coupled interstrand crosslink (ICL) repair pathway choice: when two replisomes converge at an ICL, TRAIP ubiquitylates the CMG helicase; short ubiquitin chains recruit NEIL3 glycosylase (simpler pathway) while longer chains trigger CMG unloading by p97 ATPase enabling the Fanconi anemia pathway.","method":"Xenopus egg extract reconstitution, ubiquitin chain analysis, CMG unloading assays, NEIL3 binding assays, p97 inhibition, TRAIP depletion/add-back","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 — reconstituted biochemical system in Xenopus egg extracts with multiple orthogonal methods and precise mechanistic dissection of ubiquitin chain length controlling pathway choice","pmids":["30842657"],"is_preprint":false},{"year":2019,"finding":"TRAIP ubiquitin ligase drives replisome disassembly in response to incomplete DNA replication during mitosis (MiDAS); TRAIP is essential for mitotic DNA repair synthesis in human cells and prevents mitotic segregation errors.","method":"C. elegans genetics, human cell siRNA knockdown, DNA fiber assay, chromosome segregation analysis","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 — cross-species validation (C. elegans and human cells), defined cellular phenotype, replicated with multiple approaches","pmids":["31545170"],"is_preprint":false},{"year":2019,"finding":"Mitotic replisome disassembly depends on TRAIP ubiquitin ligase activity: in Xenopus egg extracts, TRAIP forms K6- and K63-linked ubiquitin chains on Mcm7, and p97/VCP protein segregase is required for subsequent chromatin extraction of replisomes retained until mitosis.","method":"Xenopus egg extract reconstitution, ubiquitin chain linkage analysis (K6/K63), p97 inhibition, chromatin fractionation","journal":"Life science alliance","confidence":"High","confidence_rationale":"Tier 1 — biochemical reconstitution in Xenopus extracts with specific ubiquitin chain type identification","pmids":["30979826"],"is_preprint":false},{"year":2021,"finding":"TRAIP ubiquitin ligase mediates a second CMG disassembly pathway during mitosis in mammalian cells; CUL2LRR1 ubiquitylates CMG-MCM7 during S-phase for p97-dependent disassembly, while TRAIP activates a distinct mitotic CMG disassembly pathway in mouse embryonic stem cells.","method":"Mouse embryonic stem cell model, auxin-inducible degron system, chromatin fractionation, ubiquitylation assays","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 — clean inducible depletion system in mammalian cells, epistasis between two ubiquitin ligases established","pmids":["33590678"],"is_preprint":false},{"year":2021,"finding":"TRAIP promotes KANK1 polyubiquitination and subsequent degradation, which downregulates IGFBP3 and activates the AKT pathway in osteosarcoma cells, enhancing invasion and proliferation.","method":"Co-immunoprecipitation, ubiquitination assays, siRNA knockdown/overexpression, AKT pathway analysis, invasion/proliferation assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2–3 — direct ubiquitination of KANK1 shown, pathway placement established; single lab","pmids":["34349117"],"is_preprint":false},{"year":2015,"finding":"TRAIP dimerizes through its coiled-coil (CC) domain; cells expressing a CC domain-deleted mutant unable to form homodimers show increased mitotic index and altered mitotic progression.","method":"Co-immunoprecipitation with deletion mutants, mitotic index analysis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 — single Co-IP mapping of dimerization domain with functional consequence shown","pmids":["26093298"],"is_preprint":false},{"year":2014,"finding":"TRAIP/NOPO E3 ubiquitin ligase promotes ubiquitylation of DNA polymerase η (Polη) to positively regulate its activity in translesion synthesis; TRIP and NOPO co-immunoprecipitate with human and Drosophila Polη, and genetic interaction was confirmed by overexpression of dPolη suppressing nopo phenotypes.","method":"Yeast two-hybrid, co-immunoprecipitation, ubiquitination assays, Drosophila genetics (null mutation, overexpression epistasis), UV sensitivity assays","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 1–2 — biochemical ubiquitination assay, genetic epistasis in Drosophila ortholog, Co-IP in human cells, multiple orthogonal methods","pmids":["24553286"],"is_preprint":false},{"year":2010,"finding":"TRAIP (TRIP) is required for keratinocyte proliferation; TRIP knockdown causes G1/S growth arrest, increased expression of differentiation markers (keratin 1, filaggrin), and reduced proliferation; these effects are independent of NF-κB activity in keratinocytes.","method":"Lentiviral shRNA knockdown, cell cycle analysis (FACS), differentiation marker immunofluorescence, NF-κB reporter assay","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 2 — clean KD with multiple cellular readouts, NF-κB independence established; single lab","pmids":["21068752"],"is_preprint":false},{"year":2009,"finding":"TRAIP (TRIP) interacts with the protein-tyrosine kinase Syk via its C-terminal region; this interaction is enhanced by TNF and Syk tyrosine phosphorylation. Syk and TRIP have opposing functions in NF-κB activation by TNF: Syk enhances NF-κB activation while TRIP inhibits it.","method":"Yeast two-hybrid screen, co-immunoprecipitation, NF-κB reporter assays, TNF-induced apoptosis assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2–3 — yeast two-hybrid confirmed by Co-IP, functional antagonism demonstrated; single lab","pmids":["19151749"],"is_preprint":false},{"year":2023,"finding":"TRAIP works specifically in S-phase to prevent DNA damage at transcription start sites caused by replication-transcription conflicts; rapid TRAIP degradation in S-phase causes cells to arrest in G2 and undergo senescence, while TRAIP depletion in other cell cycle phases does not have the same effect.","method":"Auxin-inducible degron (AID) system for cell-cycle-specific TRAIP depletion, DNA damage markers (γH2AX), transcription start site analysis, cell cycle analysis, senescence assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — precise temporal depletion system, cell-cycle-stage specificity established, mechanistic pathway identified","pmids":["37604812"],"is_preprint":false}],"current_model":"TRAIP is a replisome-associated RING-domain E3 ubiquitin ligase that, during S-phase, binds PCNA via a PIP box, resolves replication-transcription conflicts, promotes ATR checkpoint signaling and translesion synthesis (by ubiquitylating DNA polymerase η), and controls DNA interstrand crosslink repair pathway choice by ubiquitylating the CMG helicase (short chains recruit NEIL3; long chains trigger p97-dependent CMG unloading enabling Fanconi anemia repair); during mitosis, TRAIP ubiquitylates CMG-MCM7 with K6/K63-linked chains to drive disassembly of all remaining replisomes via p97, thereby preventing mis-segregation, while also regulating the spindle assembly checkpoint through MAD2 kinetochore levels; additionally, TRAIP inhibits TRAF2-mediated NF-κB activation and promotes proteasomal degradation of TBK1 to negatively regulate antiviral IFN-β responses."},"narrative":{"teleology":[{"year":1997,"claim":"Establishing TRAIP as a TRAF-interacting RING-finger protein that inhibits NF-κB signaling resolved how TNFR2/CD30 pathways are negatively regulated at the level of TRAF2.","evidence":"Yeast two-hybrid, co-immunoprecipitation, and NF-κB reporter assays in mammalian cells","pmids":["9104814"],"confidence":"High","gaps":["Ubiquitin ligase activity not yet tested","In vivo relevance of NF-κB inhibition unknown","Substrates of the RING domain unidentified"]},{"year":2003,"claim":"Identification of the TRAIP–CYLD interaction revealed a cooperative axis for NF-κB suppression and placed TRAIP within the deubiquitinase regulatory network.","evidence":"Yeast two-hybrid, far-Western, co-immunoprecipitation, NF-κB reporter assays","pmids":["14676304"],"confidence":"High","gaps":["Whether CYLD deubiquitinates TRAIP substrates not tested","Physiological tissue contexts not explored"]},{"year":2007,"claim":"Demonstration that TRAIP is a bona fide RING-dependent E3 ubiquitin ligase with auto-ubiquitination activity established its enzymatic identity, while knockout mice revealed essential roles in embryonic proliferation.","evidence":"In vitro ubiquitination assay with RING mutants; homozygous knockout mouse embryo phenotyping","pmids":["17544371","17927961"],"confidence":"High","gaps":["Physiological substrates remain unidentified","Mechanism of embryonic lethality (proliferation versus apoptosis) not dissected at molecular level"]},{"year":2012,"claim":"Showing that TRAIP promotes K48-linked polyubiquitination and proteasomal degradation of TBK1 established TRAIP as a negative regulator of innate antiviral IFN-β signaling, broadening its functional scope beyond NF-κB.","evidence":"Co-immunoprecipitation, ubiquitination assays, siRNA knockdown, viral replication assays in mammalian cells","pmids":["22945920"],"confidence":"High","gaps":["Whether TBK1 is a direct TRAIP substrate reconstituted in vitro not shown","In vivo antiviral phenotype not tested in animal model"]},{"year":2014,"claim":"Discovery that TRAIP ubiquitylates DNA polymerase η to promote translesion synthesis, and that TRAIP localizes near mitotic chromosomes where it regulates spindle assembly checkpoint through MAD2 kinetochore levels, pivoted the field toward replication and mitotic functions.","evidence":"Ubiquitination assays and Drosophila genetic epistasis for Polη; RNAi in HeLa with live imaging and ligase-dead rescue for mitotic phenotypes","pmids":["24553286","25335891"],"confidence":"High","gaps":["Identity of mitotic substrates at kinetochores unknown","How Polη ubiquitylation activates translesion synthesis mechanistically unclear"]},{"year":2015,"claim":"Mapping TRAIP's PCNA interaction via a PIP box and linking it to ATR checkpoint signaling and replication fork integrity established TRAIP as a replisome-associated E3 ligase, while patient mutations causing microcephalic primordial dwarfism validated its essentiality for replication through DNA lesions in humans.","evidence":"PIP box mutagenesis, ATR/RPA2 phosphorylation assays, DNA fiber assays, human genetics with patient-derived cells","pmids":["26711499","26595769"],"confidence":"High","gaps":["Direct TRAIP substrate at stalled forks generating ssDNA not identified","Whether disease mutations selectively affect replication versus mitotic functions unknown"]},{"year":2016,"claim":"Placing TRAIP upstream of RAP80 and BRCA1 recruitment at DNA damage sites through interaction with RNF20-RNF40 connected TRAIP to homologous recombination repair.","evidence":"Reciprocal co-immunoprecipitation, domain mapping, siRNA epistasis, immunofluorescence at DNA damage foci","pmids":["26781088"],"confidence":"High","gaps":["Whether TRAIP directly ubiquitylates a substrate to recruit RAP80 or acts as a scaffold not resolved","Relationship between PCNA-binding and damage-site recruitment functions unclear"]},{"year":2019,"claim":"Reconstitution of TRAIP-dependent ICL repair pathway choice—where ubiquitin chain length on CMG helicase determines NEIL3 versus Fanconi anemia pathway engagement—and parallel demonstration that TRAIP drives mitotic replisome disassembly via K6/K63-linked chains on MCM7 with p97 extraction, established the unified mechanism by which TRAIP controls replisome fate.","evidence":"Xenopus egg extract reconstitution with ubiquitin chain analysis, CMG unloading assays, p97 inhibition; cross-species validation in C. elegans and human cells with DNA fiber and segregation assays","pmids":["30842657","30979826","31545170"],"confidence":"High","gaps":["How TRAIP is activated specifically at converged forks versus mitotic replisomes not known","Structural basis of chain-length-dependent pathway switching unresolved"]},{"year":2021,"claim":"Epistasis experiments distinguishing CUL2-LRR1 (S-phase) from TRAIP (mitotic) CMG disassembly pathways in mammalian cells confirmed two-pathway replisome removal, while identification of KANK1 as a TRAIP substrate linked TRAIP to AKT signaling in osteosarcoma.","evidence":"Auxin-inducible degron in mouse ES cells with chromatin fractionation; co-immunoprecipitation and ubiquitination assays with KANK1 in osteosarcoma cells","pmids":["33590678","34349117"],"confidence":"High","gaps":["Whether KANK1 ubiquitylation occurs at replication forks or independently unknown","TRAIP activation mechanism during mitosis versus S-phase not dissected"]},{"year":2023,"claim":"Precise temporal depletion revealed that TRAIP's essential S-phase function is preventing DNA damage at transcription start sites from replication-transcription conflicts, with loss causing G2 arrest and senescence rather than mitotic failure.","evidence":"Auxin-inducible degron for cell-cycle-specific TRAIP depletion, γH2AX mapping to transcription start sites, senescence assays","pmids":["37604812"],"confidence":"High","gaps":["Direct substrate at replication-transcription conflict sites not identified","Whether conflict resolution involves CMG ubiquitylation or a distinct mechanism unclear"]},{"year":null,"claim":"The structural basis for TRAIP's regulation, its activation at converged versus stalled forks, the mechanism by which ubiquitin chain length is controlled to determine repair pathway choice, and the identity of TRAIP substrates at replication-transcription conflict sites remain unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No structural model of TRAIP or TRAIP-CMG complex","Mechanism controlling ubiquitin chain length on CMG unknown","Substrate at replication-transcription conflicts not identified","Relationship between NF-κB/innate immunity functions and replication functions in vivo not integrated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,4,10,12,14,16]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[1,10,12]}],"localization":[{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[5,9]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[5,7,8]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[5,12]}],"pathway":[{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[7,8,10,16]},{"term_id":"R-HSA-69306","term_label":"DNA Replication","supporting_discovery_ids":[6,9,10,19]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[5,11,12,13]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,2,4]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[4]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[1,10,12,14]}],"complexes":[],"partners":["PCNA","TRAF2","CYLD","TBK1","MCM7","POLH","RAP80","KANK1"],"other_free_text":[]},"mechanistic_narrative":"TRAIP is a RING-domain E3 ubiquitin ligase that functions as a central regulator of DNA replication integrity, replisome dynamics, and replication-coupled DNA repair. During S-phase, TRAIP binds PCNA via a conserved PIP box and operates at replication forks to promote ATR checkpoint signaling, facilitate translesion synthesis through ubiquitylation of DNA polymerase η, resolve replication-transcription conflicts at transcription start sites, and control interstrand crosslink repair pathway choice by ubiquitylating the CMG helicase—where short ubiquitin chains recruit NEIL3 and longer chains trigger p97-dependent CMG unloading enabling Fanconi anemia repair [PMID:26711499, PMID:30842657, PMID:24553286, PMID:37604812]. During mitosis, TRAIP drives disassembly of residual replisomes by generating K6/K63-linked ubiquitin chains on MCM7, enabling p97-mediated extraction to prevent chromosome mis-segregation, and regulates spindle assembly checkpoint function through MAD2 kinetochore levels [PMID:30979826, PMID:31545170, PMID:25335891]. Biallelic TRAIP mutations cause microcephalic primordial dwarfism, consistent with its essential roles in replication fork progression through DNA lesions and embryonic cell proliferation [PMID:26595769, PMID:17927961]."},"prefetch_data":{"uniprot":{"accession":"Q9BWF2","full_name":"E3 ubiquitin-protein ligase TRAIP","aliases":["RING finger protein 206","TRAF-interacting protein"],"length_aa":469,"mass_kda":53.3,"function":"E3 ubiquitin ligase required to protect genome stability in response to replication stress (PubMed:25335891, PubMed:26595769, PubMed:26711499, PubMed:26781088, PubMed:27462463, PubMed:31545170). Acts as a key regulator of interstrand cross-link repair, which takes place when both strands of duplex DNA are covalently tethered together, thereby blocking replication and transcription (By similarity). Controls the choice between the two pathways of replication-coupled interstrand-cross-link repair by mediating ubiquitination of MCM7 subunit of the CMG helicase complex (By similarity). Short ubiquitin chains on MCM7 promote recruitment of DNA glycosylase NEIL3 (By similarity). If the interstrand cross-link cannot be cleaved by NEIL3, the ubiquitin chains continue to grow on MCM7, promoting the unloading of the CMG helicase complex by the VCP/p97 ATPase, enabling the Fanconi anemia DNA repair pathway (By similarity). Only catalyzes ubiquitination of MCM7 when forks converge (By similarity). Also involved in the repair of covalent DNA-protein cross-links (DPCs) during DNA synthesis: promotes ubiquitination of DPCs, leading to their degradation by the proteasome (By similarity). Has also been proposed to play a role in promoting translesion synthesis by mediating the assembly of 'Lys-63'-linked poly-ubiquitin chains on the Y-family polymerase POLN in order to facilitate bypass of DNA lesions and preserve genomic integrity (PubMed:24553286). The function in translesion synthesis is however controversial (PubMed:26595769). Acts as a regulator of the spindle assembly checkpoint (PubMed:25335891). Also acts as a negative regulator of innate immune signaling by inhibiting activation of NF-kappa-B mediated by TNF (PubMed:22945920). Negatively regulates TLR3/4- and RIG-I-mediated IRF3 activation and subsequent IFNB1 production and cellular antiviral response by promoting 'Lys-48'-linked polyubiquitination of TNK1 leading to its proteasomal degradation (PubMed:22945920)","subcellular_location":"Nucleus, nucleoplasm; Nucleus, nucleolus; Chromosome; Cytoplasm; Cytoplasm, perinuclear region","url":"https://www.uniprot.org/uniprotkb/Q9BWF2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/TRAIP","classification":"Common Essential","n_dependent_lines":1016,"n_total_lines":1208,"dependency_fraction":0.8410596026490066},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TRAIP","total_profiled":1310},"omim":[{"mim_id":"616777","title":"SECKEL SYNDROME 9; SCKL9","url":"https://www.omim.org/entry/616777"},{"mim_id":"605958","title":"TRAF-INTERACTING PROTEIN; TRAIP","url":"https://www.omim.org/entry/605958"},{"mim_id":"210600","title":"SECKEL SYNDROME 1; SCKL1","url":"https://www.omim.org/entry/210600"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TRAIP"},"hgnc":{"alias_symbol":["TRIP","RNF206"],"prev_symbol":[]},"alphafold":{"accession":"Q9BWF2","domains":[{"cath_id":"3.30.40.10","chopping":"2-66","consensus_level":"medium","plddt":85.6554,"start":2,"end":66},{"cath_id":"1.20.5","chopping":"76-174","consensus_level":"medium","plddt":96.527,"start":76,"end":174},{"cath_id":"1.20.5","chopping":"188-275","consensus_level":"medium","plddt":95.1033,"start":188,"end":275}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BWF2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BWF2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BWF2-F1-predicted_aligned_error_v6.png","plddt_mean":74.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TRAIP","jax_strain_url":"https://www.jax.org/strain/search?query=TRAIP"},"sequence":{"accession":"Q9BWF2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9BWF2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9BWF2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BWF2"}},"corpus_meta":[{"pmid":"14729177","id":"PMC_14729177","title":"A trip to the ER: coping with stress.","date":"2004","source":"Trends in cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/14729177","citation_count":1186,"is_preprint":false},{"pmid":"19373241","id":"PMC_19373241","title":"The trip of the tip: understanding the growth cone machinery.","date":"2009","source":"Nature reviews. Molecular cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/19373241","citation_count":572,"is_preprint":false},{"pmid":"27145841","id":"PMC_27145841","title":"Enjoy the Trip: Calcium in Mitochondria Back and Forth.","date":"2016","source":"Annual review of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/27145841","citation_count":336,"is_preprint":false},{"pmid":"19933148","id":"PMC_19933148","title":"Evolutionary conservation and adaptation in the mechanism that regulates SREBP action: what a long, strange tRIP it's been.","date":"2009","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/19933148","citation_count":215,"is_preprint":false},{"pmid":"19587457","id":"PMC_19587457","title":"Laminopathies and the long strange trip from basic cell biology to therapy.","date":"2009","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/19587457","citation_count":214,"is_preprint":false},{"pmid":"16012814","id":"PMC_16012814","title":"TRP channels: a TR(I)P through a world of multifunctional cation channels.","date":"2005","source":"Pflugers Archiv : European journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/16012814","citation_count":183,"is_preprint":false},{"pmid":"31546924","id":"PMC_31546924","title":"FOXO3a from the Nucleus to the Mitochondria: A Round Trip in Cellular Stress Response.","date":"2019","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/31546924","citation_count":178,"is_preprint":false},{"pmid":"10467344","id":"PMC_10467344","title":"Galectins: an evolutionarily conserved family of animal lectins with multifunctional properties; a trip from the gene to clinical therapy.","date":"1999","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/10467344","citation_count":173,"is_preprint":false},{"pmid":"9104814","id":"PMC_9104814","title":"TRAF-interacting protein (TRIP): a novel component of the tumor necrosis factor receptor (TNFR)- and CD30-TRAF signaling complexes that inhibits TRAF2-mediated NF-kappaB activation.","date":"1997","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/9104814","citation_count":171,"is_preprint":false},{"pmid":"8561468","id":"PMC_8561468","title":"Environmental virology: from detection of virus in sewage and water by isolation to identification by molecular biology--a trip of over 50 years.","date":"1995","source":"Annual review of microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/8561468","citation_count":164,"is_preprint":false},{"pmid":"34612177","id":"PMC_34612177","title":"Pathogenicity and virulence of Listeria monocytogenes: A trip from environmental to medical microbiology.","date":"2021","source":"Virulence","url":"https://pubmed.ncbi.nlm.nih.gov/34612177","citation_count":151,"is_preprint":false},{"pmid":"30842657","id":"PMC_30842657","title":"TRAIP is a master regulator of DNA interstrand crosslink repair.","date":"2019","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/30842657","citation_count":149,"is_preprint":false},{"pmid":"27167299","id":"PMC_27167299","title":"BDNF isoforms: a round trip ticket between neurogenesis and serotonin?","date":"2016","source":"Journal of neurochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/27167299","citation_count":148,"is_preprint":false},{"pmid":"23808332","id":"PMC_23808332","title":"Tip growth in filamentous fungi: a road trip to the apex.","date":"2013","source":"Annual review of microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/23808332","citation_count":141,"is_preprint":false},{"pmid":"18394317","id":"PMC_18394317","title":"A forest bathing trip increases human natural killer activity and expression of anti-cancer proteins in female subjects.","date":"2008","source":"Journal of biological regulators and homeostatic agents","url":"https://pubmed.ncbi.nlm.nih.gov/18394317","citation_count":125,"is_preprint":false},{"pmid":"35171647","id":"PMC_35171647","title":"Phloem Loading and Unloading of Sucrose: What a Long, Strange Trip from Source to Sink.","date":"2022","source":"Annual review of plant biology","url":"https://pubmed.ncbi.nlm.nih.gov/35171647","citation_count":121,"is_preprint":false},{"pmid":"22945920","id":"PMC_22945920","title":"TRAF-interacting protein (TRIP) negatively regulates IFN-β production and antiviral response by promoting proteasomal degradation of TANK-binding kinase 1.","date":"2012","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/22945920","citation_count":117,"is_preprint":false},{"pmid":"18717601","id":"PMC_18717601","title":"Ligand customization and DNA functionalization of gold nanorods via round-trip phase transfer ligand exchange.","date":"2008","source":"Langmuir : the ACS journal of surfaces and colloids","url":"https://pubmed.ncbi.nlm.nih.gov/18717601","citation_count":116,"is_preprint":false},{"pmid":"20819070","id":"PMC_20819070","title":"Carbonic anhydrase inhibition/activation: trip of a scientist around the world in the search of novel chemotypes and drug targets.","date":"2010","source":"Current pharmaceutical design","url":"https://pubmed.ncbi.nlm.nih.gov/20819070","citation_count":114,"is_preprint":false},{"pmid":"11331592","id":"PMC_11331592","title":"TRIP-Br: a novel family of PHD zinc finger- and bromodomain-interacting proteins that regulate the transcriptional activity of E2F-1/DP-1.","date":"2001","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/11331592","citation_count":102,"is_preprint":false},{"pmid":"9813058","id":"PMC_9813058","title":"The type II transforming growth factor (TGF)-beta receptor-interacting protein TRIP-1 acts as a modulator of the TGF-beta response.","date":"1998","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9813058","citation_count":101,"is_preprint":false},{"pmid":"14676304","id":"PMC_14676304","title":"The tumor suppressor CYLD interacts with TRIP and regulates negatively nuclear factor kappaB activation by tumor necrosis factor.","date":"2003","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/14676304","citation_count":101,"is_preprint":false},{"pmid":"24766768","id":"PMC_24766768","title":"MeCP2: the long trip from a chromatin protein to neurological disorders.","date":"2014","source":"Trends in molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/24766768","citation_count":83,"is_preprint":false},{"pmid":"29211894","id":"PMC_29211894","title":"Acid growth: an ongoing trip.","date":"2018","source":"Journal of experimental botany","url":"https://pubmed.ncbi.nlm.nih.gov/29211894","citation_count":79,"is_preprint":false},{"pmid":"26595769","id":"PMC_26595769","title":"TRAIP promotes DNA damage response during genome replication and is mutated in primordial dwarfism.","date":"2015","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/26595769","citation_count":77,"is_preprint":false},{"pmid":"23291629","id":"PMC_23291629","title":"Ablation of TRIP-Br2, a regulator of fat lipolysis, thermogenesis and oxidative metabolism, prevents diet-induced obesity and insulin resistance.","date":"2013","source":"Nature medicine","url":"https://pubmed.ncbi.nlm.nih.gov/23291629","citation_count":75,"is_preprint":false},{"pmid":"31275168","id":"PMC_31275168","title":"A TR(i)P to Cell Migration: New Roles of TRP Channels in Mechanotransduction and Cancer.","date":"2019","source":"Frontiers in physiology","url":"https://pubmed.ncbi.nlm.nih.gov/31275168","citation_count":73,"is_preprint":false},{"pmid":"31545170","id":"PMC_31545170","title":"TRAIP drives replisome disassembly and mitotic DNA repair synthesis at sites of incomplete DNA replication.","date":"2019","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/31545170","citation_count":66,"is_preprint":false},{"pmid":"34307295","id":"PMC_34307295","title":"α-Synuclein: An All-Inclusive Trip Around its Structure, Influencing Factors and Applied Techniques.","date":"2021","source":"Frontiers in chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/34307295","citation_count":65,"is_preprint":false},{"pmid":"26711499","id":"PMC_26711499","title":"TRAIP is a PCNA-binding ubiquitin ligase that protects genome stability after replication stress.","date":"2015","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/26711499","citation_count":62,"is_preprint":false},{"pmid":"20377327","id":"PMC_20377327","title":"Hypercoagulability, platelet function, inflammation and coronary artery disease acuity: results of the Thrombotic RIsk Progression (TRIP) study.","date":"2010","source":"Platelets","url":"https://pubmed.ncbi.nlm.nih.gov/20377327","citation_count":62,"is_preprint":false},{"pmid":"20487629","id":"PMC_20487629","title":"A day trip to a forest park increases human natural killer activity and the expression of anti-cancer proteins in male subjects.","date":"2010","source":"Journal of biological regulators and homeostatic agents","url":"https://pubmed.ncbi.nlm.nih.gov/20487629","citation_count":58,"is_preprint":false},{"pmid":"24911203","id":"PMC_24911203","title":"A trip in the \"New Microbiology\" with the bacterial pathogen Listeria monocytogenes.","date":"2014","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/24911203","citation_count":57,"is_preprint":false},{"pmid":"33995117","id":"PMC_33995117","title":"Bone-to-Brain: A Round Trip in the Adaptation to Mechanical Stimuli.","date":"2021","source":"Frontiers in physiology","url":"https://pubmed.ncbi.nlm.nih.gov/33995117","citation_count":54,"is_preprint":false},{"pmid":"24345078","id":"PMC_24345078","title":"New insights into pharmacological tools to TR(i)P cancer up.","date":"2014","source":"British journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/24345078","citation_count":53,"is_preprint":false},{"pmid":"30984193","id":"PMC_30984193","title":"The RANKL-RANK Axis: A Bone to Thymus Round Trip.","date":"2019","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/30984193","citation_count":49,"is_preprint":false},{"pmid":"19209153","id":"PMC_19209153","title":"A TR(I)P to pruritus research: role of TRPV3 in inflammation and itch.","date":"2009","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/19209153","citation_count":49,"is_preprint":false},{"pmid":"21671881","id":"PMC_21671881","title":"Therapeutic targeting of TRP channels--the TR(i)P to pain relief.","date":"2011","source":"Current topics in medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21671881","citation_count":47,"is_preprint":false},{"pmid":"9671805","id":"PMC_9671805","title":"TRIP: a novel double stranded RNA binding protein which interacts with the leucine rich repeat of flightless I.","date":"1998","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/9671805","citation_count":46,"is_preprint":false},{"pmid":"30979826","id":"PMC_30979826","title":"Mitotic replisome disassembly depends on TRAIP ubiquitin ligase activity.","date":"2019","source":"Life science alliance","url":"https://pubmed.ncbi.nlm.nih.gov/30979826","citation_count":44,"is_preprint":false},{"pmid":"19151749","id":"PMC_19151749","title":"The protein-tyrosine kinase Syk interacts with TRAF-interacting protein TRIP in breast epithelial cells.","date":"2009","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/19151749","citation_count":43,"is_preprint":false},{"pmid":"21666994","id":"PMC_21666994","title":"From hydra regeneration to human brain structural plasticity: a long trip through narrowing roads.","date":"2011","source":"TheScientificWorldJournal","url":"https://pubmed.ncbi.nlm.nih.gov/21666994","citation_count":42,"is_preprint":false},{"pmid":"34782762","id":"PMC_34782762","title":"Supplying the trip to antibody production-nutrients, signaling, and the programming of cellular metabolism in the mature B lineage.","date":"2021","source":"Cellular & molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/34782762","citation_count":42,"is_preprint":false},{"pmid":"27109496","id":"PMC_27109496","title":"The obesity-induced transcriptional regulator TRIP-Br2 mediates visceral fat endoplasmic reticulum stress-induced inflammation.","date":"2016","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/27109496","citation_count":42,"is_preprint":false},{"pmid":"17927961","id":"PMC_17927961","title":"Early embryonic lethality caused by targeted disruption of the TRAF-interacting protein (TRIP) gene.","date":"2007","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/17927961","citation_count":41,"is_preprint":false},{"pmid":"26781088","id":"PMC_26781088","title":"TRAIP/RNF206 is required for recruitment of RAP80 to sites of DNA damage.","date":"2016","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/26781088","citation_count":40,"is_preprint":false},{"pmid":"32510635","id":"PMC_32510635","title":"Allogeneic cord blood transfusions prevent fetal haemoglobin depletion in preterm neonates. Results of the CB-TrIP study.","date":"2020","source":"British journal of haematology","url":"https://pubmed.ncbi.nlm.nih.gov/32510635","citation_count":40,"is_preprint":false},{"pmid":"30429249","id":"PMC_30429249","title":"PIK3IP1/TrIP restricts activation of T cells through inhibition of PI3K/Akt.","date":"2018","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/30429249","citation_count":40,"is_preprint":false},{"pmid":"15881891","id":"PMC_15881891","title":"How to pack the genome for a safe trip.","date":"2005","source":"Progress in molecular and subcellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/15881891","citation_count":38,"is_preprint":false},{"pmid":"27462463","id":"PMC_27462463","title":"TRAIP regulates replication fork recovery and progression via PCNA.","date":"2016","source":"Cell discovery","url":"https://pubmed.ncbi.nlm.nih.gov/27462463","citation_count":36,"is_preprint":false},{"pmid":"30680888","id":"PMC_30680888","title":"Metabolic reconstruction of the genome of candidate Desulfatiglans TRIP_1 and identification of key candidate enzymes for anaerobic phenanthrene degradation.","date":"2019","source":"Environmental microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/30680888","citation_count":34,"is_preprint":false},{"pmid":"24810036","id":"PMC_24810036","title":"Using TRIP for genome-wide position effect analysis in cultured cells.","date":"2014","source":"Nature protocols","url":"https://pubmed.ncbi.nlm.nih.gov/24810036","citation_count":33,"is_preprint":false},{"pmid":"33590678","id":"PMC_33590678","title":"CUL2LRR1 , TRAIP and p97 control CMG helicase disassembly in the mammalian cell cycle.","date":"2021","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/33590678","citation_count":32,"is_preprint":false},{"pmid":"34349117","id":"PMC_34349117","title":"TRAIP modulates the IGFBP3/AKT pathway to enhance the invasion and proliferation of osteosarcoma by promoting KANK1 degradation.","date":"2021","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/34349117","citation_count":31,"is_preprint":false},{"pmid":"32636648","id":"PMC_32636648","title":"LncRNA SLC7A11-AS1 Contributes to Lung Cancer Progression Through Facilitating TRAIP Expression by Inhibiting miR-4775.","date":"2020","source":"OncoTargets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/32636648","citation_count":31,"is_preprint":false},{"pmid":"17544371","id":"PMC_17544371","title":"TRAF-interacting protein (TRIP) is a RING-dependent ubiquitin ligase.","date":"2007","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/17544371","citation_count":31,"is_preprint":false},{"pmid":"30798946","id":"PMC_30798946","title":"Establishing life is a calcium-dependent TRiP: Transient receptor potential channels in reproduction.","date":"2018","source":"Biochimica et biophysica acta. Molecular cell research","url":"https://pubmed.ncbi.nlm.nih.gov/30798946","citation_count":29,"is_preprint":false},{"pmid":"23200723","id":"PMC_23200723","title":"Taking a cellular road-trip: mRNA transport and anchoring.","date":"2012","source":"Current opinion in cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/23200723","citation_count":29,"is_preprint":false},{"pmid":"29884330","id":"PMC_29884330","title":"Shiga toxin-producing Escherichia coli O103:H2 outbreak in Germany after school trip to Austria due to raw cow milk, 2017 - The important role of international collaboration for outbreak investigations.","date":"2018","source":"International journal of medical microbiology : IJMM","url":"https://pubmed.ncbi.nlm.nih.gov/29884330","citation_count":29,"is_preprint":false},{"pmid":"33317933","id":"PMC_33317933","title":"The Ubiquitin Ligase TRAIP: Double-Edged Sword at the Replisome.","date":"2020","source":"Trends in cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/33317933","citation_count":28,"is_preprint":false},{"pmid":"29797770","id":"PMC_29797770","title":"Transient receptor potential (TRP) channels: a metabolic TR(i)P to obesity prevention and therapy.","date":"2018","source":"Obesity reviews : an official journal of the International Association for the Study of Obesity","url":"https://pubmed.ncbi.nlm.nih.gov/29797770","citation_count":28,"is_preprint":false},{"pmid":"19604485","id":"PMC_19604485","title":"A nonself RNA pattern: tri-p to panhandle.","date":"2009","source":"Immunity","url":"https://pubmed.ncbi.nlm.nih.gov/19604485","citation_count":28,"is_preprint":false},{"pmid":"18947889","id":"PMC_18947889","title":"Brain TRPV1: a depressing TR(i)P down memory lane?","date":"2008","source":"Trends in pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/18947889","citation_count":28,"is_preprint":false},{"pmid":"18399935","id":"PMC_18399935","title":"The long strange trip of Borrelia burgdorferi outer-surface protein C.","date":"2008","source":"Molecular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/18399935","citation_count":27,"is_preprint":false},{"pmid":"21068752","id":"PMC_21068752","title":"The TRAF-interacting protein (TRIP) is a regulator of keratinocyte proliferation.","date":"2010","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/21068752","citation_count":27,"is_preprint":false},{"pmid":"17141982","id":"PMC_17141982","title":"Transcriptional and subcellular regulation of the TRIP-Br family.","date":"2006","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/17141982","citation_count":26,"is_preprint":false},{"pmid":"25335891","id":"PMC_25335891","title":"TRAIP is a regulator of the spindle assembly checkpoint.","date":"2014","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/25335891","citation_count":26,"is_preprint":false},{"pmid":"35475019","id":"PMC_35475019","title":"Benefits of Taking a Virtual Field Trip in Immersive Virtual Reality: Evidence for the Immersion Principle in Multimedia Learning.","date":"2022","source":"Educational psychology review","url":"https://pubmed.ncbi.nlm.nih.gov/35475019","citation_count":26,"is_preprint":false},{"pmid":"32189459","id":"PMC_32189459","title":"tRIP-seq reveals repression of premature polyadenylation by co-transcriptional FUS-U1 snRNP assembly.","date":"2020","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/32189459","citation_count":26,"is_preprint":false},{"pmid":"24553286","id":"PMC_24553286","title":"TRIP/NOPO E3 ubiquitin ligase promotes ubiquitylation of DNA polymerase η.","date":"2014","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/24553286","citation_count":24,"is_preprint":false},{"pmid":"15075352","id":"PMC_15075352","title":"Leukocyte circulation: one-way or round-trip? Lessons from primary immunodeficiency patients.","date":"2004","source":"Journal of leukocyte biology","url":"https://pubmed.ncbi.nlm.nih.gov/15075352","citation_count":24,"is_preprint":false},{"pmid":"28345582","id":"PMC_28345582","title":"Enhancing titres of therapeutic viral vectors using the transgene repression in vector production (TRiP) system.","date":"2017","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/28345582","citation_count":24,"is_preprint":false},{"pmid":"25546511","id":"PMC_25546511","title":"One-way trip: influenza virus' adaptation to gallinaceous poultry may limit its pandemic potential.","date":"2014","source":"BioEssays : news and reviews in molecular, cellular and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/25546511","citation_count":24,"is_preprint":false},{"pmid":"17662722","id":"PMC_17662722","title":"Where do animal alpha-amylases come from? An interkingdom trip.","date":"2007","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/17662722","citation_count":24,"is_preprint":false},{"pmid":"31036678","id":"PMC_31036678","title":"A Genetic Screen Using the Drosophila melanogaster TRiP RNAi Collection To Identify Metabolic Enzymes Required for Eye Development.","date":"2019","source":"G3 (Bethesda, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/31036678","citation_count":23,"is_preprint":false},{"pmid":"23431269","id":"PMC_23431269","title":"A force-activated trip switch triggers rapid dissociation of a colicin from its immunity protein.","date":"2013","source":"PLoS biology","url":"https://pubmed.ncbi.nlm.nih.gov/23431269","citation_count":23,"is_preprint":false},{"pmid":"26334958","id":"PMC_26334958","title":"TRIP-Br1 oncoprotein inhibits autophagy, apoptosis, and necroptosis under nutrient/serum-deprived condition.","date":"2015","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/26334958","citation_count":21,"is_preprint":false},{"pmid":"10511977","id":"PMC_10511977","title":"A comparison of thick smears, QBC malaria, PCR and PATH falciparum malaria test trip in Plasmodium falciparum diagnosis.","date":"1999","source":"Parasite (Paris, France)","url":"https://pubmed.ncbi.nlm.nih.gov/10511977","citation_count":21,"is_preprint":false},{"pmid":"19152710","id":"PMC_19152710","title":"TRIP-Br2 promotes oncogenesis in nude mice and is frequently overexpressed in multiple human tumors.","date":"2009","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/19152710","citation_count":21,"is_preprint":false},{"pmid":"34967048","id":"PMC_34967048","title":"β3-Adrenoceptor, a novel player in the round-trip from neonatal diseases to cancer: Suggestive clues from embryo.","date":"2021","source":"Medicinal research reviews","url":"https://pubmed.ncbi.nlm.nih.gov/34967048","citation_count":21,"is_preprint":false},{"pmid":"15467469","id":"PMC_15467469","title":"TRIP-Br links E2F to novel functions in the regulation of cyclin E expression during cell cycle progression and in the maintenance of genomic stability.","date":"2004","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/15467469","citation_count":21,"is_preprint":false},{"pmid":"20851834","id":"PMC_20851834","title":"TRIP Database: a manually curated database of protein-protein interactions for mammalian TRP channels.","date":"2010","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/20851834","citation_count":20,"is_preprint":false},{"pmid":"21378021","id":"PMC_21378021","title":"TRIP-1 regulates TGF-β1-induced epithelial-mesenchymal transition of human lung epithelial cell line A549.","date":"2011","source":"American journal of physiology. Lung cellular and molecular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/21378021","citation_count":20,"is_preprint":false},{"pmid":"33738577","id":"PMC_33738577","title":"A TRiP Through the Roles of Transient Receptor Potential Cation Channels in Type 2 Upper Airway Inflammation.","date":"2021","source":"Current allergy and asthma reports","url":"https://pubmed.ncbi.nlm.nih.gov/33738577","citation_count":19,"is_preprint":false},{"pmid":"28656888","id":"PMC_28656888","title":"The complex of TRIP-Br1 and XIAP ubiquitinates and degrades multiple adenylyl cyclase isoforms.","date":"2017","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/28656888","citation_count":19,"is_preprint":false},{"pmid":"25691055","id":"PMC_25691055","title":"Nutrient/serum starvation derived TRIP-Br3 down-regulation accelerates apoptosis by destabilizing XIAP.","date":"2015","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/25691055","citation_count":19,"is_preprint":false},{"pmid":"28285800","id":"PMC_28285800","title":"Perspectives on cardiovascular effects of incretin-based drugs: From bedside to bench, return trip.","date":"2017","source":"International journal of cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/28285800","citation_count":18,"is_preprint":false},{"pmid":"34966365","id":"PMC_34966365","title":"A Round Trip to the Desert: In situ Nanopore Sequencing Informs Targeted Bioprospecting.","date":"2021","source":"Frontiers in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/34966365","citation_count":17,"is_preprint":false},{"pmid":"32993478","id":"PMC_32993478","title":"TRIP - T cell receptor/immunoglobulin profiler.","date":"2020","source":"BMC bioinformatics","url":"https://pubmed.ncbi.nlm.nih.gov/32993478","citation_count":16,"is_preprint":false},{"pmid":"31442608","id":"PMC_31442608","title":"Recognition of TRAIP with TRAFs: Current understanding and associated diseases.","date":"2019","source":"The international journal of biochemistry & cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/31442608","citation_count":16,"is_preprint":false},{"pmid":"16721052","id":"PMC_16721052","title":"The TRIP-Br family of transcriptional regulators is essential for the execution of cyclin E-mediated cell cycle progression.","date":"2006","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/16721052","citation_count":16,"is_preprint":false},{"pmid":"22460930","id":"PMC_22460930","title":"TRIP-1: a regulator of osteoblast function.","date":"2012","source":"Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research","url":"https://pubmed.ncbi.nlm.nih.gov/22460930","citation_count":16,"is_preprint":false},{"pmid":"20385357","id":"PMC_20385357","title":"The TRIP from ULF to ARF.","date":"2010","source":"Cancer cell","url":"https://pubmed.ncbi.nlm.nih.gov/20385357","citation_count":16,"is_preprint":false},{"pmid":"37604812","id":"PMC_37604812","title":"TRAIP resolves DNA replication-transcription conflicts during the S-phase of unperturbed cells.","date":"2023","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/37604812","citation_count":15,"is_preprint":false},{"pmid":"27071116","id":"PMC_27071116","title":"Apicomplexa-specific tRip facilitates import of exogenous tRNAs into malaria parasites.","date":"2016","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/27071116","citation_count":15,"is_preprint":false},{"pmid":"24785793","id":"PMC_24785793","title":"You never know when your last day will come and your trip will be over--existential expressions from a melanoma diagnosis.","date":"2014","source":"European journal of oncology nursing : the official journal of European Oncology Nursing Society","url":"https://pubmed.ncbi.nlm.nih.gov/24785793","citation_count":15,"is_preprint":false},{"pmid":"28451521","id":"PMC_28451521","title":"T3SS-Independent Uptake of the Short-Trip Toxin-Related Recombinant NleC Effector of Enteropathogenic Escherichia coli Leads to NF-κB p65 Cleavage.","date":"2017","source":"Frontiers in cellular and infection microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/28451521","citation_count":15,"is_preprint":false},{"pmid":"9169003","id":"PMC_9169003","title":"Expression of co-factors (SMRT and Trip-1) for retinoic acid receptors in human neuroectodermal cell lines.","date":"1997","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/9169003","citation_count":15,"is_preprint":false},{"pmid":"26093298","id":"PMC_26093298","title":"Dimerization of TRAF-interacting protein (TRAIP) regulates the mitotic progression.","date":"2015","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/26093298","citation_count":14,"is_preprint":false},{"pmid":"18940248","id":"PMC_18940248","title":"Identification of PP2A as a novel interactor and regulator of TRIP-Br1.","date":"2008","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/18940248","citation_count":14,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":41145,"output_tokens":4499,"usd":0.09546},"stage2":{"model":"claude-opus-4-6","input_tokens":8073,"output_tokens":2938,"usd":0.170722},"total_usd":0.266182,"stage1_batch_id":"msgbatch_01RPbVc9PDH9zQmYK5Hs6srm","stage2_batch_id":"msgbatch_01JVbVLzeKN2yVrsGp3zC8aM","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1997,\n      \"finding\": \"TRAIP (TRIP) was identified as a novel component of TNFR2 and CD30 signaling complexes that associates with TRAF proteins and inhibits TRAF2-mediated NF-κB activation, containing a RING finger motif and an extended coiled-coil domain.\",\n      \"method\": \"Protein interaction studies (yeast two-hybrid, co-immunoprecipitation), NF-κB reporter assays\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — original discovery paper with multiple orthogonal methods, replicated by subsequent studies\",\n      \"pmids\": [\"9104814\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"TRAIP (TRIP) is a RING-dependent E3 ubiquitin ligase that undergoes auto-ubiquitination; intact RING domain is required for ligase activity. TRIP interacts with TRAF1, 2, 3, 5, and 6 but not CYLD or NIK.\",\n      \"method\": \"In vitro ubiquitination assay, RING domain mutagenesis, co-immunoprecipitation\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro E3 ligase assay with mutagenesis confirming RING domain requirement\",\n      \"pmids\": [\"17544371\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"TRAIP (TRIP) interacts with the tumor suppressor CYLD through its C-terminal domain; CYLD's central domain binds TRIP's C-terminal end, and this interaction contributes to down-regulation of NF-κB activation by TNF-α.\",\n      \"method\": \"Yeast two-hybrid screen, far-Western analysis, co-immunoprecipitation in mammalian cells, NF-κB reporter assays\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods including yeast two-hybrid, far-Western, and Co-IP in mammalian cells\",\n      \"pmids\": [\"14676304\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"TRAIP (TRIP) is essential for early embryonic development; homozygous TRIP-deficient mouse embryos die shortly after implantation due to proliferation defects and excessive cell death.\",\n      \"method\": \"Gene knockout in mice, embryo phenotyping\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined developmental phenotype\",\n      \"pmids\": [\"17927961\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"TRAIP (TRIP) promotes proteasomal degradation of TBK1 by directly binding TBK1 and promoting K48-linked polyubiquitination, thereby negatively regulating TLR3/4- and RIG-I-induced IFN-β production and antiviral responses.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, siRNA knockdown/overexpression, IRF3 activation assays, viral replication assays\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — direct binding, K48-linked ubiquitination of TBK1 shown, multiple orthogonal methods\",\n      \"pmids\": [\"22945920\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TRAIP is a nucleolar E3 ubiquitin ligase that localizes close to mitotic chromosomes; its depletion decreases early mitosis progression time, increases chromosome alignment defects and lagging chromosomes, and reduces MAD2 levels at kinetochores — effects requiring intact ubiquitin ligase activity.\",\n      \"method\": \"RNAi knockdown in HeLa cells, live cell imaging, immunofluorescence, rescue with WT vs. ligase-dead TRAIP\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KD with defined mitotic phenotypes, ligase-activity rescue experiments, replicated findings\",\n      \"pmids\": [\"25335891\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TRAIP is a PCNA-binding E3 ubiquitin ligase that interacts directly with PCNA via a conserved PIP box motif and promotes ATR-dependent checkpoint signaling by facilitating RPA-bound single-stranded DNA generation upon replication stress; loss of TRAIP causes chromosomal instability.\",\n      \"method\": \"Co-immunoprecipitation, PIP box mutagenesis, ATR/RPA2 phosphorylation assays, chromosomal instability assays, siRNA knockdown\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — direct PCNA interaction mapped, E3 ligase activity required, multiple orthogonal methods\",\n      \"pmids\": [\"26711499\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Mutations in TRAIP (an E3 RING ubiquitin ligase) cause microcephalic primordial dwarfism; TRAIP relocalizes to sites of DNA damage where it is required for optimal phosphorylation of H2AX and RPA2 during S-phase in response to UV irradiation, and is necessary for fork progression through UV-induced lesions.\",\n      \"method\": \"Human genetics, patient-derived cells, immunofluorescence/live imaging of damage recruitment, H2AX/RPA2 phosphorylation assays, DNA fiber assays\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (genetic, cell biology, biochemical), strong mechanistic follow-up\",\n      \"pmids\": [\"26595769\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TRAIP (RNF206) is required for recruitment of RAP80 to DNA damage sites; TRAIP acts upstream of RAP80, and the N-terminus of TRAIP mediates RAP80 interaction while the C-terminus mediates TRAIP localization to damage sites through direct interaction with RNF20-RNF40. TRAIP promotes homologous recombination and BRCA1 accumulation at damage sites.\",\n      \"method\": \"Co-immunoprecipitation, domain mapping, siRNA knockdown, immunofluorescence at DNA damage foci\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, domain mapping, genetic epistasis for RAP80/BRCA1 recruitment\",\n      \"pmids\": [\"26781088\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TRAIP (RNF206) interacts with PCNA via a conserved PIP box on its C-terminus, localizes to stalled replication forks as a nucleolar protein, and is required for replication fork recovery and progression; inactivation of TRAIP or its PCNA interaction leads to chromosome instability.\",\n      \"method\": \"Co-immunoprecipitation, PIP box mutagenesis, DNA fiber assay, chromosomal instability assays\",\n      \"journal\": \"Cell discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct interaction mapped with mutagenesis, functional consequences shown; single lab\",\n      \"pmids\": [\"27462463\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TRAIP is the master E3 ubiquitin ligase controlling replication-coupled interstrand crosslink (ICL) repair pathway choice: when two replisomes converge at an ICL, TRAIP ubiquitylates the CMG helicase; short ubiquitin chains recruit NEIL3 glycosylase (simpler pathway) while longer chains trigger CMG unloading by p97 ATPase enabling the Fanconi anemia pathway.\",\n      \"method\": \"Xenopus egg extract reconstitution, ubiquitin chain analysis, CMG unloading assays, NEIL3 binding assays, p97 inhibition, TRAIP depletion/add-back\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted biochemical system in Xenopus egg extracts with multiple orthogonal methods and precise mechanistic dissection of ubiquitin chain length controlling pathway choice\",\n      \"pmids\": [\"30842657\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TRAIP ubiquitin ligase drives replisome disassembly in response to incomplete DNA replication during mitosis (MiDAS); TRAIP is essential for mitotic DNA repair synthesis in human cells and prevents mitotic segregation errors.\",\n      \"method\": \"C. elegans genetics, human cell siRNA knockdown, DNA fiber assay, chromosome segregation analysis\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — cross-species validation (C. elegans and human cells), defined cellular phenotype, replicated with multiple approaches\",\n      \"pmids\": [\"31545170\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Mitotic replisome disassembly depends on TRAIP ubiquitin ligase activity: in Xenopus egg extracts, TRAIP forms K6- and K63-linked ubiquitin chains on Mcm7, and p97/VCP protein segregase is required for subsequent chromatin extraction of replisomes retained until mitosis.\",\n      \"method\": \"Xenopus egg extract reconstitution, ubiquitin chain linkage analysis (K6/K63), p97 inhibition, chromatin fractionation\",\n      \"journal\": \"Life science alliance\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — biochemical reconstitution in Xenopus extracts with specific ubiquitin chain type identification\",\n      \"pmids\": [\"30979826\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TRAIP ubiquitin ligase mediates a second CMG disassembly pathway during mitosis in mammalian cells; CUL2LRR1 ubiquitylates CMG-MCM7 during S-phase for p97-dependent disassembly, while TRAIP activates a distinct mitotic CMG disassembly pathway in mouse embryonic stem cells.\",\n      \"method\": \"Mouse embryonic stem cell model, auxin-inducible degron system, chromatin fractionation, ubiquitylation assays\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean inducible depletion system in mammalian cells, epistasis between two ubiquitin ligases established\",\n      \"pmids\": [\"33590678\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TRAIP promotes KANK1 polyubiquitination and subsequent degradation, which downregulates IGFBP3 and activates the AKT pathway in osteosarcoma cells, enhancing invasion and proliferation.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, siRNA knockdown/overexpression, AKT pathway analysis, invasion/proliferation assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — direct ubiquitination of KANK1 shown, pathway placement established; single lab\",\n      \"pmids\": [\"34349117\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TRAIP dimerizes through its coiled-coil (CC) domain; cells expressing a CC domain-deleted mutant unable to form homodimers show increased mitotic index and altered mitotic progression.\",\n      \"method\": \"Co-immunoprecipitation with deletion mutants, mitotic index analysis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP mapping of dimerization domain with functional consequence shown\",\n      \"pmids\": [\"26093298\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TRAIP/NOPO E3 ubiquitin ligase promotes ubiquitylation of DNA polymerase η (Polη) to positively regulate its activity in translesion synthesis; TRIP and NOPO co-immunoprecipitate with human and Drosophila Polη, and genetic interaction was confirmed by overexpression of dPolη suppressing nopo phenotypes.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, ubiquitination assays, Drosophila genetics (null mutation, overexpression epistasis), UV sensitivity assays\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — biochemical ubiquitination assay, genetic epistasis in Drosophila ortholog, Co-IP in human cells, multiple orthogonal methods\",\n      \"pmids\": [\"24553286\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"TRAIP (TRIP) is required for keratinocyte proliferation; TRIP knockdown causes G1/S growth arrest, increased expression of differentiation markers (keratin 1, filaggrin), and reduced proliferation; these effects are independent of NF-κB activity in keratinocytes.\",\n      \"method\": \"Lentiviral shRNA knockdown, cell cycle analysis (FACS), differentiation marker immunofluorescence, NF-κB reporter assay\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KD with multiple cellular readouts, NF-κB independence established; single lab\",\n      \"pmids\": [\"21068752\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"TRAIP (TRIP) interacts with the protein-tyrosine kinase Syk via its C-terminal region; this interaction is enhanced by TNF and Syk tyrosine phosphorylation. Syk and TRIP have opposing functions in NF-κB activation by TNF: Syk enhances NF-κB activation while TRIP inhibits it.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation, NF-κB reporter assays, TNF-induced apoptosis assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — yeast two-hybrid confirmed by Co-IP, functional antagonism demonstrated; single lab\",\n      \"pmids\": [\"19151749\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TRAIP works specifically in S-phase to prevent DNA damage at transcription start sites caused by replication-transcription conflicts; rapid TRAIP degradation in S-phase causes cells to arrest in G2 and undergo senescence, while TRAIP depletion in other cell cycle phases does not have the same effect.\",\n      \"method\": \"Auxin-inducible degron (AID) system for cell-cycle-specific TRAIP depletion, DNA damage markers (γH2AX), transcription start site analysis, cell cycle analysis, senescence assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — precise temporal depletion system, cell-cycle-stage specificity established, mechanistic pathway identified\",\n      \"pmids\": [\"37604812\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TRAIP is a replisome-associated RING-domain E3 ubiquitin ligase that, during S-phase, binds PCNA via a PIP box, resolves replication-transcription conflicts, promotes ATR checkpoint signaling and translesion synthesis (by ubiquitylating DNA polymerase η), and controls DNA interstrand crosslink repair pathway choice by ubiquitylating the CMG helicase (short chains recruit NEIL3; long chains trigger p97-dependent CMG unloading enabling Fanconi anemia repair); during mitosis, TRAIP ubiquitylates CMG-MCM7 with K6/K63-linked chains to drive disassembly of all remaining replisomes via p97, thereby preventing mis-segregation, while also regulating the spindle assembly checkpoint through MAD2 kinetochore levels; additionally, TRAIP inhibits TRAF2-mediated NF-κB activation and promotes proteasomal degradation of TBK1 to negatively regulate antiviral IFN-β responses.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"TRAIP is a RING-domain E3 ubiquitin ligase that functions as a central regulator of DNA replication integrity, replisome dynamics, and replication-coupled DNA repair. During S-phase, TRAIP binds PCNA via a conserved PIP box and operates at replication forks to promote ATR checkpoint signaling, facilitate translesion synthesis through ubiquitylation of DNA polymerase η, resolve replication-transcription conflicts at transcription start sites, and control interstrand crosslink repair pathway choice by ubiquitylating the CMG helicase—where short ubiquitin chains recruit NEIL3 and longer chains trigger p97-dependent CMG unloading enabling Fanconi anemia repair [PMID:26711499, PMID:30842657, PMID:24553286, PMID:37604812]. During mitosis, TRAIP drives disassembly of residual replisomes by generating K6/K63-linked ubiquitin chains on MCM7, enabling p97-mediated extraction to prevent chromosome mis-segregation, and regulates spindle assembly checkpoint function through MAD2 kinetochore levels [PMID:30979826, PMID:31545170, PMID:25335891]. Biallelic TRAIP mutations cause microcephalic primordial dwarfism, consistent with its essential roles in replication fork progression through DNA lesions and embryonic cell proliferation [PMID:26595769, PMID:17927961].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Establishing TRAIP as a TRAF-interacting RING-finger protein that inhibits NF-κB signaling resolved how TNFR2/CD30 pathways are negatively regulated at the level of TRAF2.\",\n      \"evidence\": \"Yeast two-hybrid, co-immunoprecipitation, and NF-κB reporter assays in mammalian cells\",\n      \"pmids\": [\"9104814\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ubiquitin ligase activity not yet tested\", \"In vivo relevance of NF-κB inhibition unknown\", \"Substrates of the RING domain unidentified\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identification of the TRAIP–CYLD interaction revealed a cooperative axis for NF-κB suppression and placed TRAIP within the deubiquitinase regulatory network.\",\n      \"evidence\": \"Yeast two-hybrid, far-Western, co-immunoprecipitation, NF-κB reporter assays\",\n      \"pmids\": [\"14676304\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CYLD deubiquitinates TRAIP substrates not tested\", \"Physiological tissue contexts not explored\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Demonstration that TRAIP is a bona fide RING-dependent E3 ubiquitin ligase with auto-ubiquitination activity established its enzymatic identity, while knockout mice revealed essential roles in embryonic proliferation.\",\n      \"evidence\": \"In vitro ubiquitination assay with RING mutants; homozygous knockout mouse embryo phenotyping\",\n      \"pmids\": [\"17544371\", \"17927961\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological substrates remain unidentified\", \"Mechanism of embryonic lethality (proliferation versus apoptosis) not dissected at molecular level\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showing that TRAIP promotes K48-linked polyubiquitination and proteasomal degradation of TBK1 established TRAIP as a negative regulator of innate antiviral IFN-β signaling, broadening its functional scope beyond NF-κB.\",\n      \"evidence\": \"Co-immunoprecipitation, ubiquitination assays, siRNA knockdown, viral replication assays in mammalian cells\",\n      \"pmids\": [\"22945920\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether TBK1 is a direct TRAIP substrate reconstituted in vitro not shown\", \"In vivo antiviral phenotype not tested in animal model\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Discovery that TRAIP ubiquitylates DNA polymerase η to promote translesion synthesis, and that TRAIP localizes near mitotic chromosomes where it regulates spindle assembly checkpoint through MAD2 kinetochore levels, pivoted the field toward replication and mitotic functions.\",\n      \"evidence\": \"Ubiquitination assays and Drosophila genetic epistasis for Polη; RNAi in HeLa with live imaging and ligase-dead rescue for mitotic phenotypes\",\n      \"pmids\": [\"24553286\", \"25335891\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of mitotic substrates at kinetochores unknown\", \"How Polη ubiquitylation activates translesion synthesis mechanistically unclear\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Mapping TRAIP's PCNA interaction via a PIP box and linking it to ATR checkpoint signaling and replication fork integrity established TRAIP as a replisome-associated E3 ligase, while patient mutations causing microcephalic primordial dwarfism validated its essentiality for replication through DNA lesions in humans.\",\n      \"evidence\": \"PIP box mutagenesis, ATR/RPA2 phosphorylation assays, DNA fiber assays, human genetics with patient-derived cells\",\n      \"pmids\": [\"26711499\", \"26595769\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct TRAIP substrate at stalled forks generating ssDNA not identified\", \"Whether disease mutations selectively affect replication versus mitotic functions unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Placing TRAIP upstream of RAP80 and BRCA1 recruitment at DNA damage sites through interaction with RNF20-RNF40 connected TRAIP to homologous recombination repair.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation, domain mapping, siRNA epistasis, immunofluorescence at DNA damage foci\",\n      \"pmids\": [\"26781088\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether TRAIP directly ubiquitylates a substrate to recruit RAP80 or acts as a scaffold not resolved\", \"Relationship between PCNA-binding and damage-site recruitment functions unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Reconstitution of TRAIP-dependent ICL repair pathway choice—where ubiquitin chain length on CMG helicase determines NEIL3 versus Fanconi anemia pathway engagement—and parallel demonstration that TRAIP drives mitotic replisome disassembly via K6/K63-linked chains on MCM7 with p97 extraction, established the unified mechanism by which TRAIP controls replisome fate.\",\n      \"evidence\": \"Xenopus egg extract reconstitution with ubiquitin chain analysis, CMG unloading assays, p97 inhibition; cross-species validation in C. elegans and human cells with DNA fiber and segregation assays\",\n      \"pmids\": [\"30842657\", \"30979826\", \"31545170\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How TRAIP is activated specifically at converged forks versus mitotic replisomes not known\", \"Structural basis of chain-length-dependent pathway switching unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Epistasis experiments distinguishing CUL2-LRR1 (S-phase) from TRAIP (mitotic) CMG disassembly pathways in mammalian cells confirmed two-pathway replisome removal, while identification of KANK1 as a TRAIP substrate linked TRAIP to AKT signaling in osteosarcoma.\",\n      \"evidence\": \"Auxin-inducible degron in mouse ES cells with chromatin fractionation; co-immunoprecipitation and ubiquitination assays with KANK1 in osteosarcoma cells\",\n      \"pmids\": [\"33590678\", \"34349117\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether KANK1 ubiquitylation occurs at replication forks or independently unknown\", \"TRAIP activation mechanism during mitosis versus S-phase not dissected\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Precise temporal depletion revealed that TRAIP's essential S-phase function is preventing DNA damage at transcription start sites from replication-transcription conflicts, with loss causing G2 arrest and senescence rather than mitotic failure.\",\n      \"evidence\": \"Auxin-inducible degron for cell-cycle-specific TRAIP depletion, γH2AX mapping to transcription start sites, senescence assays\",\n      \"pmids\": [\"37604812\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct substrate at replication-transcription conflict sites not identified\", \"Whether conflict resolution involves CMG ubiquitylation or a distinct mechanism unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis for TRAIP's regulation, its activation at converged versus stalled forks, the mechanism by which ubiquitin chain length is controlled to determine repair pathway choice, and the identity of TRAIP substrates at replication-transcription conflict sites remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural model of TRAIP or TRAIP-CMG complex\", \"Mechanism controlling ubiquitin chain length on CMG unknown\", \"Substrate at replication-transcription conflicts not identified\", \"Relationship between NF-κB/innate immunity functions and replication functions in vivo not integrated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 4, 10, 12, 14, 16]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [1, 10, 12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [5, 9]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [5, 7, 8]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [5, 12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [7, 8, 10, 16]},\n      {\"term_id\": \"R-HSA-69306\", \"supporting_discovery_ids\": [6, 9, 10, 19]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [5, 11, 12, 13]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 2, 4]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [1, 10, 12, 14]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"PCNA\",\n      \"TRAF2\",\n      \"CYLD\",\n      \"TBK1\",\n      \"MCM7\",\n      \"POLH\",\n      \"RAP80\",\n      \"KANK1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}