{"gene":"URI1","run_date":"2026-06-10T10:51:56","timeline":{"discoveries":[{"year":2003,"finding":"URI (RMP/NNX3) forms complexes with small-molecular-weight prefoldins and with RPB5, a shared subunit of all three RNA polymerases. Both yeast and human orthologs are targets of TOR kinase-dependent nutrient signaling and participate in TOR-controlled gene expression programs, establishing URI as a component linking nutrient availability to transcription.","method":"Immunoprecipitation/co-IP, yeast and human functional genetics, rapamycin treatment","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP identifying complex components, functional epistasis with TOR pathway validated in both yeast and human orthologs by two independent labs","pmids":["14615539"],"is_preprint":false},{"year":1998,"finding":"RMP (URI1) was identified as an RPB5-binding protein that negatively modulates RNA polymerase II function. RMP binds RPB5 (but not HBx or TBP) in vitro; the central domain of RMP mediates RPB5 binding overlapping the TFIIB- and HBx-binding sites of RPB5. Overexpression of RMP (but not an RPB5-binding-deficient mutant) inhibits HBx transactivation and VP16-dependent transcriptional activation.","method":"Far-Western blot screening, in vitro binding assay, co-immunoprecipitation, luciferase reporter assay, domain-deletion mutagenesis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro binding reconstitution with mutagenesis, reporter functional assay, replicated in multiple reporter contexts","pmids":["9819440"],"is_preprint":false},{"year":2000,"finding":"RMP (URI1) competes with HBx for binding to the d10 domain of TFIIB (TF2B); RMP and HBx mutually disrupt each other's interaction with TFIIB in vitro, and overexpression of TFIIB rescues RMP-mediated repression of HBx transactivation, indicating that competitive TFIIB binding underlies RMP's transcriptional co-repressor function.","method":"In vitro pull-down (protein-protein binding competition assay), CAT reporter assay, co-expression in COS-1 cells","journal":"Zhonghua gan zang bing za zhi","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — in vitro competition binding plus reporter assay; single lab, overlaps mechanistically with PMID 9819440","pmids":["10712776"],"is_preprint":false},{"year":2003,"finding":"RMP (URI1) also suppresses activated transcription through direct interaction with both subunits of general transcription factor IIF (RAP30 and RAP74). The C-terminal D5 domain of RMP (118 aa) is sufficient for TFIIF binding and is required for transcriptional repression; deletion of D5 abolishes both TFIIF binding and suppression of Gal-VP16-activated transcription.","method":"In vitro pull-down, Far-Western analysis, co-immunoprecipitation in COS1 cells, domain-deletion mutagenesis, luciferase reporter assay","journal":"Cell research","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro binding confirmed by multiple methods plus mutagenesis with functional reporter validation","pmids":["12737519"],"is_preprint":false},{"year":2007,"finding":"URI is a mitochondrial substrate of S6K1. In growth-factor-deprived or rapamycin-treated cells, URI forms stable complexes with PP1γ at mitochondria, inhibiting PP1γ activity. Growth factor stimulation induces S6K1-mediated phosphorylation of URI at serine 371, disassembling URI/PP1γ complexes, activating PP1γ-dependent dephosphorylation of S6K1 and BAD, thereby reducing S6K1 survival signaling and lowering the apoptotic threshold.","method":"Co-immunoprecipitation, subcellular fractionation, in vitro kinase assay, phospho-specific antibodies, S371A/D mutants, rapamycin treatment, PP1γ activity assay","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro kinase assay identifying phosphorylation site, reciprocal co-IP, mitochondrial fractionation, phospho-dead/mimic mutants with functional apoptosis readout; single lab but multiple orthogonal methods","pmids":["17936702"],"is_preprint":false},{"year":2006,"finding":"C. elegans uri-1 is essential for germ cell proliferation and genome integrity. URI-1-deficient cells exhibit cell cycle arrest, DNA breaks (TUNEL-positive and HUS-1::GFP foci), and p53-dependent germline apoptosis, placing URI-1 in a pathway required to suppress endogenous genotoxic DNA damage in mitotic and meiotic cells.","method":"RNAi loss-of-function, uri-1(lf) allele, TUNEL staining, HUS-1::GFP foci imaging, genetic epistasis with p53 pathway","journal":"Development","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic loss-of-function with multiple cellular phenotype readouts (cell cycle, DNA breaks, apoptosis) and p53 epistasis; replicated by both RNAi and mutant allele","pmids":["16436622"],"is_preprint":false},{"year":2008,"finding":"Drosophila Uri binds PP1α with much higher affinity than PP1β, and this PP1α selectivity is conserved in humans. Most Uri is cytoplasmic, but some associates with active RNAPII on chromatin. Loss of uri in Drosophila causes lethality, transcriptional defects, reduced germline cell viability and differentiation, and nuclear DNA damage accumulation.","method":"PP1 binding/affinity assay (discriminating PP1α vs PP1β), chromatin immunoprecipitation (active RNAPII), uri loss-of-function allele generation, TUNEL/γH2AX for DNA damage","journal":"BMC molecular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — binding specificity demonstrated biochemically, confirmed in human cells, genetic KO with multiple phenotypic readouts across two organisms","pmids":["18412953"],"is_preprint":false},{"year":2011,"finding":"URI is amplified/overexpressed in ovarian cancer and functions as an oncogene required for tumor cell survival by constitutively sequestering PP1γ in inactive complexes, thereby sustaining S6K1-BAD survival signaling under growth-factor-limiting conditions and conferring resistance to cisplatin.","method":"FISH/copy-number analysis, siRNA knockdown, cell viability assays, cisplatin sensitivity, co-immunoprecipitation of URI/PP1γ complexes","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic amplification confirmed by FISH, mechanism tied to PP1γ inhibition via co-IP, loss-of-function with specific survival and drug-resistance phenotype","pmids":["21397856"],"is_preprint":false},{"year":2011,"finding":"URI is a transcriptional repressor of androgen receptor (AR)-mediated transcription in prostate cancer cells. URI is phosphorylated upon androgen treatment; URI binds and regulates the AR corepressor Art-27; URI occupies chromatin at AR target gene promoters prior to hormone-dependent AR recruitment; depletion of URI increases AR occupancy and NKX-3.1 expression while decreasing Art-27 recruitment.","method":"Co-immunoprecipitation, chromatin immunoprecipitation (ChIP), genome-wide expression profiling (microarray), siRNA knockdown, phosphorylation detection by western blot","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, ChIP, genome-wide expression with overlapping KD signatures for URI and Art-27; multiple orthogonal methods in single lab","pmids":["21730289"],"is_preprint":false},{"year":2013,"finding":"URI interacts with all components of the R2TP/prefoldin-like complex in the nucleus, binds and regulates RPB5 protein stability and transcription. URI nuclear/cytoplasmic shuttling is sensitive to RNA pol II stalling (α-amanitin, actinomycin-D) and is mediated by the CRM1 nuclear export pathway (blocked by leptomycin B). URI also interacts with PDRG1 and stabilizes it. Novel URI phosphorylation and acetylation sites were identified.","method":"Mass spectrometry-based nuclear proteomics, co-immunoprecipitation, leptomycin B/α-amanitin/actinomycin-D treatment, western blot for protein stability","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-based interactome with validation by co-IP and drug treatments; single lab, nuclear localization mechanistically tied to CRM1 export","pmids":["23667685"],"is_preprint":false},{"year":2014,"finding":"URI inhibits aryl hydrocarbon receptor (AhR)- and estrogen receptor (ER)-mediated transcription of enzymes in the L-tryptophan/kynurenine/NAD+ biosynthesis pathway, thereby reducing intracellular NAD+ levels, causing DNA damage at early stages of hepatocarcinogenesis. Restoring NAD+ with nicotinamide riboside prevents URI-driven DNA damage and tumor formation in mouse models.","method":"Hepatocyte-specific URI transgenic and conditional knockout mice (genetically engineered mouse models), RNA-seq/transcriptome analysis, NAD+ metabolite quantification, nicotinamide riboside rescue experiment, DEN-induced HCC model","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo gain- and loss-of-function genetic models, metabolic rescue experiment, mechanistic pathway confirmed by transcriptomics and metabolomics; multiple orthogonal methods","pmids":["25453901"],"is_preprint":false},{"year":2014,"finding":"RMP (URI1) promotes HCC venous metastasis and tumor-initiating cell self-renewal by interacting with NF-κB p65 and RPB5 to activate IL-6 transcription, thereby expanding cancer stem cell populations and inducing epithelial-mesenchymal transition.","method":"Co-immunoprecipitation (RMP with p65/RPB5), reporter assays for IL-6 transcription, IL-6 neutralization assay, in vitro and in vivo metastasis models, shRNA knockdown","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus reporter plus neutralization rescue assay; single lab, multiple methods supporting IL-6 mechanism","pmids":["24704835"],"is_preprint":false},{"year":2014,"finding":"URI modulates STAT3 activity in multiple myeloma cells through regulation of IL-6 transcription via interaction with NFκB p65.","method":"shRNA knockdown, co-immunoprecipitation, STAT3 phosphorylation assay, IL-6 reporter/quantification","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus functional pathway assays; single lab","pmids":["24625985"],"is_preprint":false},{"year":2016,"finding":"URI, PP1γ, and OGT form a functional complex that is maintained by glucose. Glucose deprivation activates PKA, which phosphorylates URI at Ser-371, releasing PP1γ and causing URI-mediated OGT inhibition. Reduced OGT activity lowers O-GlcNAcylation and promotes c-MYC degradation. In the presence of glucose, PP1γ-bound URI maintains high OGT activity and c-MYC levels. Mice expressing non-phosphorylatable URI (S371A) show constitutively high OGT and c-MYC, accelerating liver tumorigenesis.","method":"Co-immunoprecipitation (URI/PP1γ/OGT complex), phospho-specific URI-S371 antibody, S371A knock-in mouse, OGT activity assay, O-GlcNAcylation western blot, c-MYC protein stability assay, glucose deprivation/PKA inhibitor experiments","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — reciprocal co-IP identifying trimeric complex, phospho-specific site validation, S371A knock-in mouse, enzymatic OGT activity assay, in vivo tumor phenotype; multiple orthogonal methods","pmids":["27505673"],"is_preprint":false},{"year":2016,"finding":"URI interacts with KAP1 and recruits PP2A phosphatase, reducing KAP1 phosphorylation. The URI-KAP1-PP2A complex mediates retrotransposon (LINE-1/L1PA2) repression in prostate cancer cells; URI knockdown selectively increases LINE-1 and L1PA2 transcription.","method":"Co-immunoprecipitation (URI with KAP1 and PP2A), PP2A phosphatase activity assay, KAP1 phosphorylation western blot, microarray analysis of transposable elements, siRNA knockdown","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — co-IP plus phosphatase activity assay plus genome-wide expression analysis; single lab, multiple orthogonal methods","pmids":["27780869"],"is_preprint":false},{"year":2016,"finding":"In URI1-dependent colorectal cancer cells, URI1 deficiency (but not in URI1-independent cells) causes non-genotoxic p53 activation and p53-dependent apoptosis, implicating the URI1 prefoldin chaperone complex (URI1C, comprising URI1 and partner STAP1) in suppression of p53 surveillance.","method":"siRNA/conditional knockdown, p53 reporter assay, apoptosis assay, p53 target gene expression, xenograft tumor model with conditional URI1 depletion","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined molecular phenotype (p53 activation), in vivo xenograft confirmation; single lab","pmids":["27105489"],"is_preprint":false},{"year":2019,"finding":"URI overexpression in intestinal crypt protects mice from radiation-induced gastrointestinal syndrome (GIS) by inhibiting β-catenin in stem cell-like label-retaining (LR) cells. URI reduction activates β-catenin-induced c-MYC expression, causing DNA damage and radiosensitization of LR cells. URI thus maintains the radiotolerant state of intestinal LR stem cells required for organ regeneration.","method":"Intestine-specific URI transgenic and URI heterozygous knockout mice, irradiation model, β-catenin reporter assay, c-MYC expression analysis, BrdU/label-retaining cell imaging, DNA damage markers (γH2AX)","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo gain- and loss-of-function genetic models with mechanistic pathway (URI→β-catenin→c-MYC) and specific stem-cell phenotype; multiple orthogonal methods","pmids":["31147493"],"is_preprint":false},{"year":2020,"finding":"CVB4 viral infection and genetic URI ablation in mouse pancreas both cause loss of PDX1 in β cells. Mechanistically, URI loss triggers estrogen receptor nuclear translocation, leading to DNMT1 expression, which induces Pdx1 promoter hypermethylation and silencing. Demethylating agent procainamide (DNMT1 inhibitor) restores PDX1 expression and protects against diabetes in pancreatic URI-depleted mice.","method":"Pancreas-specific URI knockout mice, CVB4 infection model in human islet-engrafted mice, estrogen receptor nuclear translocation imaging, DNMT1 expression western blot, Pdx1 promoter methylation bisulfite sequencing, procainamide rescue experiment, PDX1-overexpression rescue in URI-OE diabetic mice","journal":"Cell reports. Medicine","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — genetic mouse model, epigenetic mechanism (promoter methylation), pharmacological rescue, and viral infection model converge; multiple orthogonal methods","pmids":["33205075"],"is_preprint":false},{"year":2014,"finding":"The yeast URI orthologue Bud27 associates with RNA pol II phosphorylated forms (CTD-Ser5P and CTD-Ser2P) and with the Sth1 subunit of the chromatin remodeling complex RSC, mediating RSC association with RNA pol II; its absence affects RNA pol II occupancy of transcribed genes. In addition to contributing to Rpb5 folding, Bud27 modulates RNA pol II transcription elongation.","method":"Co-immunoprecipitation (Bud27 with RNA pol II CTD forms and RSC/Sth1), ChIP analysis of RNA pol II occupancy, bud27 deletion strain","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and ChIP in yeast; single lab, confirmed in ortholog (yeast model of mammalian URI)","pmids":["25081216"],"is_preprint":false},{"year":2017,"finding":"RMP (URI1) promotes EMT in HCC by activating NF-κB, which directly induces expression of COP9 signalosome subunit CSN2, which in turn represses Snail degradation, causing Snail accumulation and EMT/metastasis.","method":"Co-immunoprecipitation (RMP/p65), NF-κB reporter, CSN2 promoter luciferase assay, Snail stability assay (cycloheximide chase), shRNA knockdown, in vivo pulmonary metastasis mouse model, IHC of human HCC tissues","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus reporter plus protein stability assay plus in vivo model; single lab with multiple methods","pmids":["28423737"],"is_preprint":false},{"year":2023,"finding":"URI directly interacts with TRIM28 and promotes p53 ubiquitination and degradation in a TRIM28-MDM2-dependent manner. High URI suppresses p53, which normally represses SCD1 transcription; consequently, URI overexpression elevates SCD1 and reprograms lipid metabolism to confer resistance to TKI-induced ferroptosis in p53-wild-type HCC.","method":"Co-immunoprecipitation (URI/TRIM28/MDM2), ubiquitination assay, p53 ChIP at SCD1 promoter, SCD1 promoter luciferase reporter, lipid metabolism profiling, patient-derived organoids, xenograft models","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — co-IP identifying complex, ubiquitination assay, ChIP at target gene promoter, organoid/xenograft validation; multiple orthogonal methods in single study","pmids":["37805657"],"is_preprint":false},{"year":2022,"finding":"Macrophage RMP regulates M1/M2 polarization after myocardial infarction through the HSP90-p38 signaling pathway; macrophage-specific RMP knockout promotes M1 polarization and inhibits angiogenesis, while RMP overexpression promotes M2 polarization and angiogenesis.","method":"Macrophage-specific RMP knockout (LysM-Cre), bone marrow-derived macrophage transfer, MI mouse model, immunoblotting and immunofluorescence for polarization markers and HSP90/p38 pathway","journal":"Oxidative medicine and cellular longevity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-type-specific KO plus BMDM adoptive transfer with pathway markers; single lab","pmids":["36092156"],"is_preprint":false},{"year":2019,"finding":"RMP/URI inhibits both intrinsic (cisplatin-induced) and extrinsic (TRAIL-induced) apoptosis via distinct mechanisms: in intrinsic apoptosis, RMP promotes Bcl-xl expression and activates NF-κB/p65 through ATM phosphorylation; in extrinsic apoptosis, RMP suppresses p53 transcription and expression, and forced p53 expression offsets this inhibitory effect.","method":"Flow cytometry (apoptosis rate), western blot (Bcl-xl, p65, pATM, p53), overexpression and knockdown, p53 rescue experiment","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — distinct pathway dissection by functional rescue; single lab with western blot and genetic rescue","pmids":["31754340"],"is_preprint":false}],"current_model":"URI1 (RMP/NNX3/PPP1R19) is a prefoldin-family co-chaperone and transcriptional co-repressor that functions as a nutrient/growth-factor-sensitive scaffold: it binds RPB5 (shared RNA polymerase subunit), TFIIB, and TFIIF to repress transcription; sequesters PP1γ in inactive mitochondrial/cytoplasmic complexes to sustain S6K1-BAD survival signaling; is phosphorylated at Ser-371 by S6K1 (or PKA under glucose deprivation) to release PP1γ and modulate OGT/c-MYC or apoptotic thresholds; recruits PP2A to KAP1 to suppress retrotransposon transcription; promotes p53 degradation via TRIM28-MDM2 to derepress SCD1/lipid metabolism; regulates β-catenin and c-MYC in intestinal stem cells; and controls PDX1 expression in pancreatic β cells by modulating estrogen-receptor-driven DNMT1 expression and Pdx1 promoter methylation."},"narrative":{"mechanistic_narrative":"URI1 (RMP/RPB5-mediating protein) is a prefoldin-family co-chaperone and nutrient/growth-factor-responsive scaffold that links signaling to transcription, phosphatase control, and cell survival [PMID:14615539, PMID:17936702]. As a transcriptional co-repressor it binds RPB5, the subunit shared by all three RNA polymerases, through a central domain that overlaps the TFIIB- and HBx-binding surfaces, and additionally engages TFIIB and both subunits of TFIIF (RAP30/RAP74) via its C-terminal D5 domain to suppress activated transcription [PMID:9819440, PMID:10712776, PMID:12737519]. URI1 assembles with the R2TP/prefoldin-like complex in the nucleus, regulates RPB5 stability, and shuttles between nucleus and cytoplasm through CRM1-dependent export sensitive to RNA polymerase II stalling [PMID:23667685]. A central regulatory module is its control of protein phosphatase 1: URI1 sequesters PP1γ in inactive complexes, and S6K1-mediated phosphorylation at Ser-371 (or PKA phosphorylation under glucose deprivation) disassembles these complexes to govern S6K1–BAD survival signaling and an OGT–c-MYC axis [PMID:17936702, PMID:27505673]. Through these activities URI1 acts as an oncogene that sustains tumor-cell survival, suppresses p53 surveillance via a TRIM28–MDM2 axis to reprogram SCD1-driven lipid metabolism, and represses retrotransposons by recruiting PP2A to KAP1 [PMID:21397856, PMID:37805657, PMID:27780869]. URI1 also maintains genome integrity and tissue homeostasis: its loss provokes DNA damage and p53-dependent apoptosis in germline and tumor cells, and it protects intestinal stem cells by restraining β-catenin–c-MYC signaling [PMID:16436622, PMID:18412953, PMID:31147493]. In pancreatic β cells URI1 loss drives estrogen-receptor–dependent DNMT1 expression and Pdx1 promoter hypermethylation, silencing PDX1 [PMID:33205075].","teleology":[{"year":1998,"claim":"Established URI1's founding biochemical identity as an RPB5-binding protein that negatively modulates RNA polymerase II, defining it as a transcriptional co-repressor.","evidence":"Far-Western screening, in vitro binding with domain-deletion mutants, and luciferase reporter assays in human cells","pmids":["9819440"],"confidence":"High","gaps":["Did not place URI1 in a broader cellular signaling pathway","Did not resolve whether repression occurs on chromatin in vivo"]},{"year":2000,"claim":"Defined the molecular basis of repression by showing URI1 competes with HBx for the TFIIB d10 domain, with TFIIB overexpression rescuing repression.","evidence":"In vitro competition pull-down and CAT reporter assays in COS-1 cells","pmids":["10712776"],"confidence":"Medium","gaps":["Overlaps mechanistically with the RPB5-binding work and is from a single lab","Did not test endogenous gene targets"]},{"year":2003,"claim":"Extended the co-repressor mechanism to TFIIF and embedded URI1 in nutrient signaling by linking it to prefoldins and TOR-controlled transcription.","evidence":"TFIIF pull-down/Far-Western with D5 domain mapping (Cell Research); co-IP of prefoldin/RPB5 complexes and rapamycin epistasis in yeast and human (Science)","pmids":["12737519","14615539"],"confidence":"High","gaps":["Did not identify the kinase coupling nutrient status to URI1","Did not resolve the structure of the URI1–prefoldin complex"]},{"year":2006,"claim":"Demonstrated an in vivo requirement for URI1 in genome integrity by showing germline loss causes DNA breaks and p53-dependent apoptosis.","evidence":"RNAi and mutant allele of C. elegans uri-1 with TUNEL, HUS-1::GFP foci, and p53 genetic epistasis","pmids":["16436622"],"confidence":"High","gaps":["Did not define the molecular source of endogenous DNA damage","Did not connect the phenotype to a specific URI1 biochemical activity"]},{"year":2007,"claim":"Identified URI1 as an S6K1 substrate whose Ser-371 phosphorylation toggles PP1γ sequestration, mechanistically coupling growth-factor signaling to the apoptotic threshold.","evidence":"In vitro kinase assay, mitochondrial fractionation, phospho-specific antibodies, S371A/D mutants, and PP1γ activity assays","pmids":["17936702"],"confidence":"High","gaps":["Did not establish whether the PP1γ module operates in non-mitochondrial compartments","Did not address transcriptional consequences of the switch"]},{"year":2008,"claim":"Refined the phosphatase interaction by showing conserved PP1α selectivity and dual cytoplasmic/chromatin localization, linking URI1 to active RNAPII while confirming its genome-stability role across organisms.","evidence":"PP1α/β discriminating binding assays, ChIP of active RNAPII, and Drosophila uri loss-of-function with DNA damage readouts","pmids":["18412953"],"confidence":"High","gaps":["Did not reconcile PP1α selectivity in flies with mammalian PP1γ-focused models","Did not define how chromatin and cytoplasmic pools are partitioned"]},{"year":2011,"claim":"Established URI1 as an amplified oncogene and a context-dependent transcriptional regulator, sustaining survival via PP1γ sequestration in ovarian cancer and repressing AR target genes in prostate cancer.","evidence":"FISH copy-number, siRNA with viability/cisplatin assays and URI/PP1γ co-IP (Cancer Cell); ChIP, microarray, and Art-27 co-IP in prostate cells (MCB)","pmids":["21397856","21730289"],"confidence":"High","gaps":["Did not unify the survival-signaling and transcriptional-repression roles","Did not define how androgen-induced URI1 phosphorylation alters chromatin occupancy"]},{"year":2013,"claim":"Mapped URI1's nuclear interactome to the R2TP/prefoldin-like complex and PDRG1 and defined CRM1-dependent, transcription-state-sensitive shuttling controlling RPB5 stability.","evidence":"MS-based nuclear proteomics, co-IP, and leptomycin B/α-amanitin/actinomycin-D treatments","pmids":["23667685"],"confidence":"Medium","gaps":["Functional consequences of identified phospho/acetyl sites untested","Single-lab interactome without reciprocal validation for all partners"]},{"year":2014,"claim":"Connected URI1 to metabolic genome protection and tumor-promoting transcription, showing it suppresses NAD+ biosynthesis to cause DNA damage and activates NF-κB/RPB5–driven IL-6 to expand cancer stem cells.","evidence":"Hepatocyte URI transgenic/knockout mice with RNA-seq, NAD+ metabolomics and nicotinamide riboside rescue (Cancer Cell); p65/RPB5 co-IP, IL-6 reporter and metastasis models (Oncogene); p65 co-IP and STAT3/IL-6 assays in myeloma (Cell Death Dis); yeast Bud27–RSC/RNAPII CTD co-IP and ChIP (NAR)","pmids":["25453901","24704835","24625985","25081216"],"confidence":"High","gaps":["Did not reconcile URI1 acting as both a repressor and an NF-κB co-activator","Relationship between metabolic NAD+ control and the PP1γ module unresolved"]},{"year":2016,"claim":"Defined nutrient- and phosphatase-coupled mechanisms downstream of URI1: a glucose-sensing URI1/PP1γ/OGT–c-MYC switch, PP2A recruitment to KAP1 for retrotransposon silencing, and URI1-complex suppression of p53 surveillance.","evidence":"URI/PP1γ/OGT co-IP with S371A knock-in mouse and OGT/O-GlcNAc assays (Cancer Cell); URI/KAP1/PP2A co-IP, phosphatase assay and transposon microarray (JBC); conditional knockdown with p53 reporter and xenograft (Oncotarget)","pmids":["27505673","27780869","27105489"],"confidence":"High","gaps":["Did not establish how the same Ser-371 switch is interpreted by S6K1 versus PKA in different tissues","STAP1-containing URI1C composition not fully defined biochemically"]},{"year":2019,"claim":"Showed URI1 governs stem-cell radiotolerance in vivo by restraining β-catenin–induced c-MYC to limit DNA damage in intestinal label-retaining cells.","evidence":"Intestine-specific URI transgenic and heterozygous knockout mice, irradiation, β-catenin reporter, and γH2AX/label-retaining-cell imaging","pmids":["31147493"],"confidence":"High","gaps":["Did not define the direct biochemical link between URI1 and β-catenin","Did not test whether the PP1γ/OGT module participates in stem-cell protection"]},{"year":2020,"claim":"Revealed a tissue-specific epigenetic mechanism in which URI1 loss drives ER-dependent DNMT1 expression and Pdx1 promoter hypermethylation, silencing PDX1 and predisposing to diabetes.","evidence":"Pancreas-specific URI knockout and CVB4 infection mouse models, bisulfite sequencing, and procainamide/PDX1-overexpression rescue","pmids":["33205075"],"confidence":"High","gaps":["Did not define how URI1 normally restrains ER nuclear translocation","Did not connect β-cell PDX1 control to URI1's transcription/PP1γ roles"]},{"year":2023,"claim":"Established a TRIM28–MDM2–p53–SCD1 axis by which URI1 promotes p53 degradation to reprogram lipid metabolism and confer ferroptosis resistance.","evidence":"URI/TRIM28/MDM2 co-IP, ubiquitination assay, p53 ChIP at SCD1, lipid profiling, and organoid/xenograft models","pmids":["37805657"],"confidence":"High","gaps":["Did not determine whether prefoldin/co-chaperone activity is required for TRIM28 binding","Relationship to NAD+-mediated p53/DNA-damage effects not integrated"]},{"year":2022,"claim":"Extended URI1 function to immune-cell biology by linking macrophage RMP to M1/M2 polarization and angiogenesis after myocardial infarction.","evidence":"Macrophage-specific RMP knockout, BMDM adoptive transfer, MI model, and HSP90/p38 pathway markers","pmids":["36092156"],"confidence":"Medium","gaps":["Single-lab study without biochemical demonstration of URI1–HSP90 interaction","Connection to URI1's transcriptional/phosphatase roles unclear"]},{"year":null,"claim":"How URI1's distinct activities — prefoldin co-chaperone, RPB5/TFII transcriptional repressor, PP1γ/PP2A scaffold, and p53/β-catenin/ER modulator — are coordinated within a single protein, and what determines which axis dominates in a given cell type, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model integrating the co-chaperone, RPB5-binding, and phosphatase-scaffolding surfaces","Switching logic between repressor and NF-κB co-activator roles undefined","No unified model linking the Ser-371 phospho-switch to tissue-specific outcomes"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0044183","term_label":"protein folding chaperone","supporting_discovery_ids":[0,9]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1,3,8]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4,13,14]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[4,13,20]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[9,6]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[6,9]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[4]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[6,18]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,1,3]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,13]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[4,22,15]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[7,10,20]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[10,13,20]}],"complexes":["R2TP/prefoldin-like complex","URI1/PP1γ/OGT complex","URI1-KAP1-PP2A complex","URI1C (URI1-STAP1 prefoldin chaperone complex)"],"partners":["RPB5","PP1Γ","OGT","TRIM28","KAP1","RELA (P65)","PDRG1","TFIIB"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O94763","full_name":"Unconventional prefoldin RPB5 interactor 1","aliases":["Protein NNX3","Protein phosphatase 1 regulatory subunit 19","RNA polymerase II subunit 5-mediating protein","RPB5-mediating protein"],"length_aa":535,"mass_kda":59.8,"function":"Involved in gene transcription regulation. Acts as a transcriptional repressor in concert with the corepressor UXT to regulate androgen receptor (AR) transcription. May act as a tumor suppressor to repress AR-mediated gene transcription and to inhibit anchorage-independent growth in prostate cancer cells. Required for cell survival in ovarian cancer cells. Together with UXT, associates with chromatin to the NKX3-1 promoter region. Antagonizes transcriptional modulation via hepatitis B virus X protein Plays a central role in maintaining S6K1 signaling and BAD phosphorylation under normal growth conditions thereby protecting cells from potential deleterious effects of sustained S6K1 signaling. The URI1-PPP1CC complex acts as a central component of a negative feedback mechanism that counteracts excessive S6K1 survival signaling to BAD in response to growth factors. Mediates inhibition of PPP1CC phosphatase activity in mitochondria. Coordinates the regulation of nutrient-sensitive gene expression availability in a mTOR-dependent manner. Seems to be a scaffolding protein able to assemble a prefoldin-like complex that contains PFDs and proteins with roles in transcription and ubiquitination","subcellular_location":"Nucleus; Cytoplasm; Mitochondrion; Cell projection, dendrite","url":"https://www.uniprot.org/uniprotkb/O94763/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/URI1","classification":"Common 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hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/10712776","citation_count":6,"is_preprint":false},{"pmid":"36788118","id":"PMC_36788118","title":"An isotope dilution-liquid chromatography-tandem mass spectrometry (ID-LC-MS/MS)-based candidate reference measurement procedure (RMP) for the quantification of methotrexate in human serum and plasma.","date":"2023","source":"Clinical chemistry and laboratory medicine","url":"https://pubmed.ncbi.nlm.nih.gov/36788118","citation_count":6,"is_preprint":false},{"pmid":"31435513","id":"PMC_31435513","title":"Rpb5, a subunit shared by eukaryotic RNA polymerases, cooperates with prefoldin-like Bud27/URI.","date":"2018","source":"AIMS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/31435513","citation_count":5,"is_preprint":false},{"pmid":"36092156","id":"PMC_36092156","title":"Macrophage Rmp Ameliorates Myocardial Infarction by Modulating Macrophage Polarization in Mice.","date":"2022","source":"Oxidative medicine and cellular longevity","url":"https://pubmed.ncbi.nlm.nih.gov/36092156","citation_count":5,"is_preprint":false},{"pmid":"38407268","id":"PMC_38407268","title":"An isotope dilution-liquid chromatography-tandem mass spectrometry (ID-LC-MS/MS)-based candidate reference measurement procedure (RMP) for the quantification of phenobarbital in human serum and plasma.","date":"2024","source":"Clinical chemistry and laboratory medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38407268","citation_count":5,"is_preprint":false},{"pmid":"9034225","id":"PMC_9034225","title":"Intravenous infusion of RMP-7 increases ocular uptake of ganciclovir.","date":"1997","source":"Pharmaceutical research","url":"https://pubmed.ncbi.nlm.nih.gov/9034225","citation_count":5,"is_preprint":false},{"pmid":"27520751","id":"PMC_27520751","title":"RMP-7 : Potential as an Adjuvant to the Drug Treatment of Brain Tumours.","date":"1997","source":"CNS drugs","url":"https://pubmed.ncbi.nlm.nih.gov/27520751","citation_count":5,"is_preprint":false},{"pmid":"30416863","id":"PMC_30416863","title":"URI knockdown induces autophagic flux in gastric cancer cells.","date":"2018","source":"American journal of cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/30416863","citation_count":4,"is_preprint":false},{"pmid":"8887712","id":"PMC_8887712","title":"A competitive chemiluminescent enzyme-linked immunosorbent assay for the determination of RMP-7 in human blood.","date":"1996","source":"Journal of pharmaceutical and biomedical analysis","url":"https://pubmed.ncbi.nlm.nih.gov/8887712","citation_count":3,"is_preprint":false},{"pmid":"27411585","id":"PMC_27411585","title":"P(URI)fying Novel Drivers of NASH and HCC: A Feedforward Loop of IL17A via White Adipose Tissue.","date":"2016","source":"Cancer cell","url":"https://pubmed.ncbi.nlm.nih.gov/27411585","citation_count":2,"is_preprint":false},{"pmid":"39794779","id":"PMC_39794779","title":"Evaluation of the role of unconventional prefoldin RPB5 interactor (URI1) in hepatitis B virus infection.","date":"2025","source":"Virology journal","url":"https://pubmed.ncbi.nlm.nih.gov/39794779","citation_count":1,"is_preprint":false},{"pmid":"25620477","id":"PMC_25620477","title":"[Biological function and molecular mechanism of URI in HepG2 cells].","date":"2014","source":"Zhonghua zhong liu za zhi [Chinese journal of oncology]","url":"https://pubmed.ncbi.nlm.nih.gov/25620477","citation_count":1,"is_preprint":false},{"pmid":"14992004","id":"PMC_14992004","title":"[Effect of RMP-7 and its derivatives on the transportation of liposome into the brain].","date":"2003","source":"Yao xue xue bao = Acta pharmaceutica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/14992004","citation_count":1,"is_preprint":false},{"pmid":"31333787","id":"PMC_31333787","title":"RMP promotes the proliferation and radioresistance of esophageal carcinoma.","date":"2019","source":"Journal of Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/31333787","citation_count":0,"is_preprint":false},{"pmid":"41727467","id":"PMC_41727467","title":"Hot-yet-suppressed under PD-1 blockade: an RMP-NRF2-PD-L1 axis associated with a reduced proportional response in hepatocellular carcinoma.","date":"2026","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/41727467","citation_count":0,"is_preprint":false},{"pmid":"40487485","id":"PMC_40487485","title":"Retraction Notice to: The Expression of MicroRNA-598 Inhibits Ovarian Cancer Cell Proliferation and Metastasis by Targeting URI.","date":"2025","source":"Molecular therapy. Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/40487485","citation_count":0,"is_preprint":false},{"pmid":"18611707","id":"PMC_18611707","title":"Open-label titration study of the safety of RMP-7 in patients with the acquired immune deficiency syndrome.","date":"1996","source":"International journal of antimicrobial agents","url":"https://pubmed.ncbi.nlm.nih.gov/18611707","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.09.20.677538","title":"The acquisition of  <i>rmpADC</i>  can increase virulence of classical  <i>Klebsiella pneumoniae</i>  in the absence of other hypervirulence-associated genes","date":"2025-09-21","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.20.677538","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.09.12.675794","title":"Simple Sequence Repeats Mediate Phase Variation of the Mucoid Phenotype in Hypervirulent  <i>Klebsiella pneumoniae</i>","date":"2025-09-12","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.12.675794","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.07.23.666473","title":"FGF13 regulates cardiomyocyte impulse propagation via Cx43 trafficking independent of voltage-gated sodium channels","date":"2025-07-27","source":"bioRxiv","url":"https://doi.org/10.1101/2025.07.23.666473","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.11.10.687661","title":"Distinct and Shared Impacts of Virulence Plasmids on the Phenotype and Transcriptome in Convergent Carbapenem-Resistant and Hypervirulent  <i>Klebsiella pneumoniae</i>","date":"2025-11-10","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.10.687661","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.05.28.656494","title":"Establishing a Digital PCR-Based Reference Measurement Procedure for Monkeypox Virus: An Inter-laboratory Assessment and Standardization Study","date":"2025-05-29","source":"bioRxiv","url":"https://doi.org/10.1101/2025.05.28.656494","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":52850,"output_tokens":6342,"usd":0.12684,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":15368,"output_tokens":5462,"usd":0.106695,"stage2_stop_reason":"end_turn"},"total_usd":0.233535,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2003,\n      \"finding\": \"URI (RMP/NNX3) forms complexes with small-molecular-weight prefoldins and with RPB5, a shared subunit of all three RNA polymerases. Both yeast and human orthologs are targets of TOR kinase-dependent nutrient signaling and participate in TOR-controlled gene expression programs, establishing URI as a component linking nutrient availability to transcription.\",\n      \"method\": \"Immunoprecipitation/co-IP, yeast and human functional genetics, rapamycin treatment\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP identifying complex components, functional epistasis with TOR pathway validated in both yeast and human orthologs by two independent labs\",\n      \"pmids\": [\"14615539\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"RMP (URI1) was identified as an RPB5-binding protein that negatively modulates RNA polymerase II function. RMP binds RPB5 (but not HBx or TBP) in vitro; the central domain of RMP mediates RPB5 binding overlapping the TFIIB- and HBx-binding sites of RPB5. Overexpression of RMP (but not an RPB5-binding-deficient mutant) inhibits HBx transactivation and VP16-dependent transcriptional activation.\",\n      \"method\": \"Far-Western blot screening, in vitro binding assay, co-immunoprecipitation, luciferase reporter assay, domain-deletion mutagenesis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro binding reconstitution with mutagenesis, reporter functional assay, replicated in multiple reporter contexts\",\n      \"pmids\": [\"9819440\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"RMP (URI1) competes with HBx for binding to the d10 domain of TFIIB (TF2B); RMP and HBx mutually disrupt each other's interaction with TFIIB in vitro, and overexpression of TFIIB rescues RMP-mediated repression of HBx transactivation, indicating that competitive TFIIB binding underlies RMP's transcriptional co-repressor function.\",\n      \"method\": \"In vitro pull-down (protein-protein binding competition assay), CAT reporter assay, co-expression in COS-1 cells\",\n      \"journal\": \"Zhonghua gan zang bing za zhi\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro competition binding plus reporter assay; single lab, overlaps mechanistically with PMID 9819440\",\n      \"pmids\": [\"10712776\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"RMP (URI1) also suppresses activated transcription through direct interaction with both subunits of general transcription factor IIF (RAP30 and RAP74). The C-terminal D5 domain of RMP (118 aa) is sufficient for TFIIF binding and is required for transcriptional repression; deletion of D5 abolishes both TFIIF binding and suppression of Gal-VP16-activated transcription.\",\n      \"method\": \"In vitro pull-down, Far-Western analysis, co-immunoprecipitation in COS1 cells, domain-deletion mutagenesis, luciferase reporter assay\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro binding confirmed by multiple methods plus mutagenesis with functional reporter validation\",\n      \"pmids\": [\"12737519\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"URI is a mitochondrial substrate of S6K1. In growth-factor-deprived or rapamycin-treated cells, URI forms stable complexes with PP1γ at mitochondria, inhibiting PP1γ activity. Growth factor stimulation induces S6K1-mediated phosphorylation of URI at serine 371, disassembling URI/PP1γ complexes, activating PP1γ-dependent dephosphorylation of S6K1 and BAD, thereby reducing S6K1 survival signaling and lowering the apoptotic threshold.\",\n      \"method\": \"Co-immunoprecipitation, subcellular fractionation, in vitro kinase assay, phospho-specific antibodies, S371A/D mutants, rapamycin treatment, PP1γ activity assay\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro kinase assay identifying phosphorylation site, reciprocal co-IP, mitochondrial fractionation, phospho-dead/mimic mutants with functional apoptosis readout; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"17936702\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"C. elegans uri-1 is essential for germ cell proliferation and genome integrity. URI-1-deficient cells exhibit cell cycle arrest, DNA breaks (TUNEL-positive and HUS-1::GFP foci), and p53-dependent germline apoptosis, placing URI-1 in a pathway required to suppress endogenous genotoxic DNA damage in mitotic and meiotic cells.\",\n      \"method\": \"RNAi loss-of-function, uri-1(lf) allele, TUNEL staining, HUS-1::GFP foci imaging, genetic epistasis with p53 pathway\",\n      \"journal\": \"Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic loss-of-function with multiple cellular phenotype readouts (cell cycle, DNA breaks, apoptosis) and p53 epistasis; replicated by both RNAi and mutant allele\",\n      \"pmids\": [\"16436622\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Drosophila Uri binds PP1α with much higher affinity than PP1β, and this PP1α selectivity is conserved in humans. Most Uri is cytoplasmic, but some associates with active RNAPII on chromatin. Loss of uri in Drosophila causes lethality, transcriptional defects, reduced germline cell viability and differentiation, and nuclear DNA damage accumulation.\",\n      \"method\": \"PP1 binding/affinity assay (discriminating PP1α vs PP1β), chromatin immunoprecipitation (active RNAPII), uri loss-of-function allele generation, TUNEL/γH2AX for DNA damage\",\n      \"journal\": \"BMC molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — binding specificity demonstrated biochemically, confirmed in human cells, genetic KO with multiple phenotypic readouts across two organisms\",\n      \"pmids\": [\"18412953\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"URI is amplified/overexpressed in ovarian cancer and functions as an oncogene required for tumor cell survival by constitutively sequestering PP1γ in inactive complexes, thereby sustaining S6K1-BAD survival signaling under growth-factor-limiting conditions and conferring resistance to cisplatin.\",\n      \"method\": \"FISH/copy-number analysis, siRNA knockdown, cell viability assays, cisplatin sensitivity, co-immunoprecipitation of URI/PP1γ complexes\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic amplification confirmed by FISH, mechanism tied to PP1γ inhibition via co-IP, loss-of-function with specific survival and drug-resistance phenotype\",\n      \"pmids\": [\"21397856\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"URI is a transcriptional repressor of androgen receptor (AR)-mediated transcription in prostate cancer cells. URI is phosphorylated upon androgen treatment; URI binds and regulates the AR corepressor Art-27; URI occupies chromatin at AR target gene promoters prior to hormone-dependent AR recruitment; depletion of URI increases AR occupancy and NKX-3.1 expression while decreasing Art-27 recruitment.\",\n      \"method\": \"Co-immunoprecipitation, chromatin immunoprecipitation (ChIP), genome-wide expression profiling (microarray), siRNA knockdown, phosphorylation detection by western blot\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, ChIP, genome-wide expression with overlapping KD signatures for URI and Art-27; multiple orthogonal methods in single lab\",\n      \"pmids\": [\"21730289\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"URI interacts with all components of the R2TP/prefoldin-like complex in the nucleus, binds and regulates RPB5 protein stability and transcription. URI nuclear/cytoplasmic shuttling is sensitive to RNA pol II stalling (α-amanitin, actinomycin-D) and is mediated by the CRM1 nuclear export pathway (blocked by leptomycin B). URI also interacts with PDRG1 and stabilizes it. Novel URI phosphorylation and acetylation sites were identified.\",\n      \"method\": \"Mass spectrometry-based nuclear proteomics, co-immunoprecipitation, leptomycin B/α-amanitin/actinomycin-D treatment, western blot for protein stability\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-based interactome with validation by co-IP and drug treatments; single lab, nuclear localization mechanistically tied to CRM1 export\",\n      \"pmids\": [\"23667685\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"URI inhibits aryl hydrocarbon receptor (AhR)- and estrogen receptor (ER)-mediated transcription of enzymes in the L-tryptophan/kynurenine/NAD+ biosynthesis pathway, thereby reducing intracellular NAD+ levels, causing DNA damage at early stages of hepatocarcinogenesis. Restoring NAD+ with nicotinamide riboside prevents URI-driven DNA damage and tumor formation in mouse models.\",\n      \"method\": \"Hepatocyte-specific URI transgenic and conditional knockout mice (genetically engineered mouse models), RNA-seq/transcriptome analysis, NAD+ metabolite quantification, nicotinamide riboside rescue experiment, DEN-induced HCC model\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo gain- and loss-of-function genetic models, metabolic rescue experiment, mechanistic pathway confirmed by transcriptomics and metabolomics; multiple orthogonal methods\",\n      \"pmids\": [\"25453901\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"RMP (URI1) promotes HCC venous metastasis and tumor-initiating cell self-renewal by interacting with NF-κB p65 and RPB5 to activate IL-6 transcription, thereby expanding cancer stem cell populations and inducing epithelial-mesenchymal transition.\",\n      \"method\": \"Co-immunoprecipitation (RMP with p65/RPB5), reporter assays for IL-6 transcription, IL-6 neutralization assay, in vitro and in vivo metastasis models, shRNA knockdown\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus reporter plus neutralization rescue assay; single lab, multiple methods supporting IL-6 mechanism\",\n      \"pmids\": [\"24704835\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"URI modulates STAT3 activity in multiple myeloma cells through regulation of IL-6 transcription via interaction with NFκB p65.\",\n      \"method\": \"shRNA knockdown, co-immunoprecipitation, STAT3 phosphorylation assay, IL-6 reporter/quantification\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus functional pathway assays; single lab\",\n      \"pmids\": [\"24625985\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"URI, PP1γ, and OGT form a functional complex that is maintained by glucose. Glucose deprivation activates PKA, which phosphorylates URI at Ser-371, releasing PP1γ and causing URI-mediated OGT inhibition. Reduced OGT activity lowers O-GlcNAcylation and promotes c-MYC degradation. In the presence of glucose, PP1γ-bound URI maintains high OGT activity and c-MYC levels. Mice expressing non-phosphorylatable URI (S371A) show constitutively high OGT and c-MYC, accelerating liver tumorigenesis.\",\n      \"method\": \"Co-immunoprecipitation (URI/PP1γ/OGT complex), phospho-specific URI-S371 antibody, S371A knock-in mouse, OGT activity assay, O-GlcNAcylation western blot, c-MYC protein stability assay, glucose deprivation/PKA inhibitor experiments\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — reciprocal co-IP identifying trimeric complex, phospho-specific site validation, S371A knock-in mouse, enzymatic OGT activity assay, in vivo tumor phenotype; multiple orthogonal methods\",\n      \"pmids\": [\"27505673\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"URI interacts with KAP1 and recruits PP2A phosphatase, reducing KAP1 phosphorylation. The URI-KAP1-PP2A complex mediates retrotransposon (LINE-1/L1PA2) repression in prostate cancer cells; URI knockdown selectively increases LINE-1 and L1PA2 transcription.\",\n      \"method\": \"Co-immunoprecipitation (URI with KAP1 and PP2A), PP2A phosphatase activity assay, KAP1 phosphorylation western blot, microarray analysis of transposable elements, siRNA knockdown\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — co-IP plus phosphatase activity assay plus genome-wide expression analysis; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"27780869\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In URI1-dependent colorectal cancer cells, URI1 deficiency (but not in URI1-independent cells) causes non-genotoxic p53 activation and p53-dependent apoptosis, implicating the URI1 prefoldin chaperone complex (URI1C, comprising URI1 and partner STAP1) in suppression of p53 surveillance.\",\n      \"method\": \"siRNA/conditional knockdown, p53 reporter assay, apoptosis assay, p53 target gene expression, xenograft tumor model with conditional URI1 depletion\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined molecular phenotype (p53 activation), in vivo xenograft confirmation; single lab\",\n      \"pmids\": [\"27105489\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"URI overexpression in intestinal crypt protects mice from radiation-induced gastrointestinal syndrome (GIS) by inhibiting β-catenin in stem cell-like label-retaining (LR) cells. URI reduction activates β-catenin-induced c-MYC expression, causing DNA damage and radiosensitization of LR cells. URI thus maintains the radiotolerant state of intestinal LR stem cells required for organ regeneration.\",\n      \"method\": \"Intestine-specific URI transgenic and URI heterozygous knockout mice, irradiation model, β-catenin reporter assay, c-MYC expression analysis, BrdU/label-retaining cell imaging, DNA damage markers (γH2AX)\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo gain- and loss-of-function genetic models with mechanistic pathway (URI→β-catenin→c-MYC) and specific stem-cell phenotype; multiple orthogonal methods\",\n      \"pmids\": [\"31147493\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CVB4 viral infection and genetic URI ablation in mouse pancreas both cause loss of PDX1 in β cells. Mechanistically, URI loss triggers estrogen receptor nuclear translocation, leading to DNMT1 expression, which induces Pdx1 promoter hypermethylation and silencing. Demethylating agent procainamide (DNMT1 inhibitor) restores PDX1 expression and protects against diabetes in pancreatic URI-depleted mice.\",\n      \"method\": \"Pancreas-specific URI knockout mice, CVB4 infection model in human islet-engrafted mice, estrogen receptor nuclear translocation imaging, DNMT1 expression western blot, Pdx1 promoter methylation bisulfite sequencing, procainamide rescue experiment, PDX1-overexpression rescue in URI-OE diabetic mice\",\n      \"journal\": \"Cell reports. Medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — genetic mouse model, epigenetic mechanism (promoter methylation), pharmacological rescue, and viral infection model converge; multiple orthogonal methods\",\n      \"pmids\": [\"33205075\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The yeast URI orthologue Bud27 associates with RNA pol II phosphorylated forms (CTD-Ser5P and CTD-Ser2P) and with the Sth1 subunit of the chromatin remodeling complex RSC, mediating RSC association with RNA pol II; its absence affects RNA pol II occupancy of transcribed genes. In addition to contributing to Rpb5 folding, Bud27 modulates RNA pol II transcription elongation.\",\n      \"method\": \"Co-immunoprecipitation (Bud27 with RNA pol II CTD forms and RSC/Sth1), ChIP analysis of RNA pol II occupancy, bud27 deletion strain\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and ChIP in yeast; single lab, confirmed in ortholog (yeast model of mammalian URI)\",\n      \"pmids\": [\"25081216\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"RMP (URI1) promotes EMT in HCC by activating NF-κB, which directly induces expression of COP9 signalosome subunit CSN2, which in turn represses Snail degradation, causing Snail accumulation and EMT/metastasis.\",\n      \"method\": \"Co-immunoprecipitation (RMP/p65), NF-κB reporter, CSN2 promoter luciferase assay, Snail stability assay (cycloheximide chase), shRNA knockdown, in vivo pulmonary metastasis mouse model, IHC of human HCC tissues\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus reporter plus protein stability assay plus in vivo model; single lab with multiple methods\",\n      \"pmids\": [\"28423737\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"URI directly interacts with TRIM28 and promotes p53 ubiquitination and degradation in a TRIM28-MDM2-dependent manner. High URI suppresses p53, which normally represses SCD1 transcription; consequently, URI overexpression elevates SCD1 and reprograms lipid metabolism to confer resistance to TKI-induced ferroptosis in p53-wild-type HCC.\",\n      \"method\": \"Co-immunoprecipitation (URI/TRIM28/MDM2), ubiquitination assay, p53 ChIP at SCD1 promoter, SCD1 promoter luciferase reporter, lipid metabolism profiling, patient-derived organoids, xenograft models\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — co-IP identifying complex, ubiquitination assay, ChIP at target gene promoter, organoid/xenograft validation; multiple orthogonal methods in single study\",\n      \"pmids\": [\"37805657\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Macrophage RMP regulates M1/M2 polarization after myocardial infarction through the HSP90-p38 signaling pathway; macrophage-specific RMP knockout promotes M1 polarization and inhibits angiogenesis, while RMP overexpression promotes M2 polarization and angiogenesis.\",\n      \"method\": \"Macrophage-specific RMP knockout (LysM-Cre), bone marrow-derived macrophage transfer, MI mouse model, immunoblotting and immunofluorescence for polarization markers and HSP90/p38 pathway\",\n      \"journal\": \"Oxidative medicine and cellular longevity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-type-specific KO plus BMDM adoptive transfer with pathway markers; single lab\",\n      \"pmids\": [\"36092156\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"RMP/URI inhibits both intrinsic (cisplatin-induced) and extrinsic (TRAIL-induced) apoptosis via distinct mechanisms: in intrinsic apoptosis, RMP promotes Bcl-xl expression and activates NF-κB/p65 through ATM phosphorylation; in extrinsic apoptosis, RMP suppresses p53 transcription and expression, and forced p53 expression offsets this inhibitory effect.\",\n      \"method\": \"Flow cytometry (apoptosis rate), western blot (Bcl-xl, p65, pATM, p53), overexpression and knockdown, p53 rescue experiment\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — distinct pathway dissection by functional rescue; single lab with western blot and genetic rescue\",\n      \"pmids\": [\"31754340\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"URI1 (RMP/NNX3/PPP1R19) is a prefoldin-family co-chaperone and transcriptional co-repressor that functions as a nutrient/growth-factor-sensitive scaffold: it binds RPB5 (shared RNA polymerase subunit), TFIIB, and TFIIF to repress transcription; sequesters PP1γ in inactive mitochondrial/cytoplasmic complexes to sustain S6K1-BAD survival signaling; is phosphorylated at Ser-371 by S6K1 (or PKA under glucose deprivation) to release PP1γ and modulate OGT/c-MYC or apoptotic thresholds; recruits PP2A to KAP1 to suppress retrotransposon transcription; promotes p53 degradation via TRIM28-MDM2 to derepress SCD1/lipid metabolism; regulates β-catenin and c-MYC in intestinal stem cells; and controls PDX1 expression in pancreatic β cells by modulating estrogen-receptor-driven DNMT1 expression and Pdx1 promoter methylation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"URI1 (RMP/RPB5-mediating protein) is a prefoldin-family co-chaperone and nutrient/growth-factor-responsive scaffold that links signaling to transcription, phosphatase control, and cell survival [#0, #4]. As a transcriptional co-repressor it binds RPB5, the subunit shared by all three RNA polymerases, through a central domain that overlaps the TFIIB- and HBx-binding surfaces, and additionally engages TFIIB and both subunits of TFIIF (RAP30/RAP74) via its C-terminal D5 domain to suppress activated transcription [#1, #2, #3]. URI1 assembles with the R2TP/prefoldin-like complex in the nucleus, regulates RPB5 stability, and shuttles between nucleus and cytoplasm through CRM1-dependent export sensitive to RNA polymerase II stalling [#9]. A central regulatory module is its control of protein phosphatase 1: URI1 sequesters PP1\\u03b3 in inactive complexes, and S6K1-mediated phosphorylation at Ser-371 (or PKA phosphorylation under glucose deprivation) disassembles these complexes to govern S6K1\\u2013BAD survival signaling and an OGT\\u2013c-MYC axis [#4, #13]. Through these activities URI1 acts as an oncogene that sustains tumor-cell survival, suppresses p53 surveillance via a TRIM28\\u2013MDM2 axis to reprogram SCD1-driven lipid metabolism, and represses retrotransposons by recruiting PP2A to KAP1 [#7, #20, #14]. URI1 also maintains genome integrity and tissue homeostasis: its loss provokes DNA damage and p53-dependent apoptosis in germline and tumor cells, and it protects intestinal stem cells by restraining \\u03b2-catenin\\u2013c-MYC signaling [#5, #6, #16]. In pancreatic \\u03b2 cells URI1 loss drives estrogen-receptor\\u2013dependent DNMT1 expression and Pdx1 promoter hypermethylation, silencing PDX1 [#17].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established URI1's founding biochemical identity as an RPB5-binding protein that negatively modulates RNA polymerase II, defining it as a transcriptional co-repressor.\",\n      \"evidence\": \"Far-Western screening, in vitro binding with domain-deletion mutants, and luciferase reporter assays in human cells\",\n      \"pmids\": [\"9819440\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not place URI1 in a broader cellular signaling pathway\", \"Did not resolve whether repression occurs on chromatin in vivo\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Defined the molecular basis of repression by showing URI1 competes with HBx for the TFIIB d10 domain, with TFIIB overexpression rescuing repression.\",\n      \"evidence\": \"In vitro competition pull-down and CAT reporter assays in COS-1 cells\",\n      \"pmids\": [\"10712776\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Overlaps mechanistically with the RPB5-binding work and is from a single lab\", \"Did not test endogenous gene targets\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Extended the co-repressor mechanism to TFIIF and embedded URI1 in nutrient signaling by linking it to prefoldins and TOR-controlled transcription.\",\n      \"evidence\": \"TFIIF pull-down/Far-Western with D5 domain mapping (Cell Research); co-IP of prefoldin/RPB5 complexes and rapamycin epistasis in yeast and human (Science)\",\n      \"pmids\": [\"12737519\", \"14615539\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the kinase coupling nutrient status to URI1\", \"Did not resolve the structure of the URI1\\u2013prefoldin complex\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Demonstrated an in vivo requirement for URI1 in genome integrity by showing germline loss causes DNA breaks and p53-dependent apoptosis.\",\n      \"evidence\": \"RNAi and mutant allele of C. elegans uri-1 with TUNEL, HUS-1::GFP foci, and p53 genetic epistasis\",\n      \"pmids\": [\"16436622\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the molecular source of endogenous DNA damage\", \"Did not connect the phenotype to a specific URI1 biochemical activity\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identified URI1 as an S6K1 substrate whose Ser-371 phosphorylation toggles PP1\\u03b3 sequestration, mechanistically coupling growth-factor signaling to the apoptotic threshold.\",\n      \"evidence\": \"In vitro kinase assay, mitochondrial fractionation, phospho-specific antibodies, S371A/D mutants, and PP1\\u03b3 activity assays\",\n      \"pmids\": [\"17936702\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish whether the PP1\\u03b3 module operates in non-mitochondrial compartments\", \"Did not address transcriptional consequences of the switch\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Refined the phosphatase interaction by showing conserved PP1\\u03b1 selectivity and dual cytoplasmic/chromatin localization, linking URI1 to active RNAPII while confirming its genome-stability role across organisms.\",\n      \"evidence\": \"PP1\\u03b1/\\u03b2 discriminating binding assays, ChIP of active RNAPII, and Drosophila uri loss-of-function with DNA damage readouts\",\n      \"pmids\": [\"18412953\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not reconcile PP1\\u03b1 selectivity in flies with mammalian PP1\\u03b3-focused models\", \"Did not define how chromatin and cytoplasmic pools are partitioned\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Established URI1 as an amplified oncogene and a context-dependent transcriptional regulator, sustaining survival via PP1\\u03b3 sequestration in ovarian cancer and repressing AR target genes in prostate cancer.\",\n      \"evidence\": \"FISH copy-number, siRNA with viability/cisplatin assays and URI/PP1\\u03b3 co-IP (Cancer Cell); ChIP, microarray, and Art-27 co-IP in prostate cells (MCB)\",\n      \"pmids\": [\"21397856\", \"21730289\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not unify the survival-signaling and transcriptional-repression roles\", \"Did not define how androgen-induced URI1 phosphorylation alters chromatin occupancy\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Mapped URI1's nuclear interactome to the R2TP/prefoldin-like complex and PDRG1 and defined CRM1-dependent, transcription-state-sensitive shuttling controlling RPB5 stability.\",\n      \"evidence\": \"MS-based nuclear proteomics, co-IP, and leptomycin B/\\u03b1-amanitin/actinomycin-D treatments\",\n      \"pmids\": [\"23667685\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequences of identified phospho/acetyl sites untested\", \"Single-lab interactome without reciprocal validation for all partners\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Connected URI1 to metabolic genome protection and tumor-promoting transcription, showing it suppresses NAD+ biosynthesis to cause DNA damage and activates NF-\\u03baB/RPB5\\u2013driven IL-6 to expand cancer stem cells.\",\n      \"evidence\": \"Hepatocyte URI transgenic/knockout mice with RNA-seq, NAD+ metabolomics and nicotinamide riboside rescue (Cancer Cell); p65/RPB5 co-IP, IL-6 reporter and metastasis models (Oncogene); p65 co-IP and STAT3/IL-6 assays in myeloma (Cell Death Dis); yeast Bud27\\u2013RSC/RNAPII CTD co-IP and ChIP (NAR)\",\n      \"pmids\": [\"25453901\", \"24704835\", \"24625985\", \"25081216\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not reconcile URI1 acting as both a repressor and an NF-\\u03baB co-activator\", \"Relationship between metabolic NAD+ control and the PP1\\u03b3 module unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined nutrient- and phosphatase-coupled mechanisms downstream of URI1: a glucose-sensing URI1/PP1\\u03b3/OGT\\u2013c-MYC switch, PP2A recruitment to KAP1 for retrotransposon silencing, and URI1-complex suppression of p53 surveillance.\",\n      \"evidence\": \"URI/PP1\\u03b3/OGT co-IP with S371A knock-in mouse and OGT/O-GlcNAc assays (Cancer Cell); URI/KAP1/PP2A co-IP, phosphatase assay and transposon microarray (JBC); conditional knockdown with p53 reporter and xenograft (Oncotarget)\",\n      \"pmids\": [\"27505673\", \"27780869\", \"27105489\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish how the same Ser-371 switch is interpreted by S6K1 versus PKA in different tissues\", \"STAP1-containing URI1C composition not fully defined biochemically\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed URI1 governs stem-cell radiotolerance in vivo by restraining \\u03b2-catenin\\u2013induced c-MYC to limit DNA damage in intestinal label-retaining cells.\",\n      \"evidence\": \"Intestine-specific URI transgenic and heterozygous knockout mice, irradiation, \\u03b2-catenin reporter, and \\u03b3H2AX/label-retaining-cell imaging\",\n      \"pmids\": [\"31147493\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the direct biochemical link between URI1 and \\u03b2-catenin\", \"Did not test whether the PP1\\u03b3/OGT module participates in stem-cell protection\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Revealed a tissue-specific epigenetic mechanism in which URI1 loss drives ER-dependent DNMT1 expression and Pdx1 promoter hypermethylation, silencing PDX1 and predisposing to diabetes.\",\n      \"evidence\": \"Pancreas-specific URI knockout and CVB4 infection mouse models, bisulfite sequencing, and procainamide/PDX1-overexpression rescue\",\n      \"pmids\": [\"33205075\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define how URI1 normally restrains ER nuclear translocation\", \"Did not connect \\u03b2-cell PDX1 control to URI1's transcription/PP1\\u03b3 roles\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established a TRIM28\\u2013MDM2\\u2013p53\\u2013SCD1 axis by which URI1 promotes p53 degradation to reprogram lipid metabolism and confer ferroptosis resistance.\",\n      \"evidence\": \"URI/TRIM28/MDM2 co-IP, ubiquitination assay, p53 ChIP at SCD1, lipid profiling, and organoid/xenograft models\",\n      \"pmids\": [\"37805657\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not determine whether prefoldin/co-chaperone activity is required for TRIM28 binding\", \"Relationship to NAD+-mediated p53/DNA-damage effects not integrated\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extended URI1 function to immune-cell biology by linking macrophage RMP to M1/M2 polarization and angiogenesis after myocardial infarction.\",\n      \"evidence\": \"Macrophage-specific RMP knockout, BMDM adoptive transfer, MI model, and HSP90/p38 pathway markers\",\n      \"pmids\": [\"36092156\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab study without biochemical demonstration of URI1\\u2013HSP90 interaction\", \"Connection to URI1's transcriptional/phosphatase roles unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How URI1's distinct activities \\u2014 prefoldin co-chaperone, RPB5/TFII transcriptional repressor, PP1\\u03b3/PP2A scaffold, and p53/\\u03b2-catenin/ER modulator \\u2014 are coordinated within a single protein, and what determines which axis dominates in a given cell type, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model integrating the co-chaperone, RPB5-binding, and phosphatase-scaffolding surfaces\", \"Switching logic between repressor and NF-\\u03baB co-activator roles undefined\", \"No unified model linking the Ser-371 phospho-switch to tissue-specific outcomes\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0044183\", \"supporting_discovery_ids\": [0, 9]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1, 3, 8]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4, 13, 14]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [4, 13, 20]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [9, 6]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [6, 9]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [6, 18]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 13]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [4, 22, 15]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [7, 10, 20]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [10, 13, 20]}\n    ],\n    \"complexes\": [\n      \"R2TP/prefoldin-like complex\",\n      \"URI1/PP1\\u03b3/OGT complex\",\n      \"URI1-KAP1-PP2A complex\",\n      \"URI1C (URI1-STAP1 prefoldin chaperone complex)\"\n    ],\n    \"partners\": [\n      \"RPB5\",\n      \"PP1\\u03b3\",\n      \"OGT\",\n      \"TRIM28\",\n      \"KAP1\",\n      \"RELA (p65)\",\n      \"PDRG1\",\n      \"TFIIB\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":7,"faith_pct":85.71428571428571}}