{"gene":"UBR2","run_date":"2026-04-28T21:43:00","timeline":{"discoveries":[{"year":2003,"finding":"UBR2 is an E3 ubiquitin ligase of the N-end rule pathway with substrate-binding properties highly similar to UBR1, recognizing proteins with destabilizing N-terminal residues (N-degrons). UBR2 knockout mice show spermatocyte apoptosis with arrest between leptotene/zygotene and pachytene, absence of intact synaptonemal complexes, and female embryonic lethality, establishing UBR2 as required for male meiosis and spermatogenesis.","method":"UBR2 knockout mouse construction, substrate-binding assays, histological analysis, genetic background manipulation","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1-2 — KO mouse with defined cellular phenotype, substrate-binding assays, replicated across genetic backgrounds; foundational paper with 130 citations","pmids":["14585983"],"is_preprint":false},{"year":2004,"finding":"UBR2 forms a stable complex with RECQL4 (mutated in Rothmund-Thomson and RAPADILINO syndromes) as isolated from HeLa cells. The RECQL4-UBR1/UBR2 complex has DNA-stimulated ATPase activity. Despite its association with ubiquitin ligases, RECQL4 is not ubiquitylated in vivo and is a long-lived protein.","method":"Co-immunoprecipitation with anti-RECQL4 antibodies, ATPase and helicase assays, in vivo ubiquitylation assays, pulse-chase","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-IP, biochemical activity assays, and in vivo ubiquitylation assays in the same study","pmids":["15317757"],"is_preprint":false},{"year":2004,"finding":"Yeast Ubr2 ubiquitin ligase, partnering with the E2 enzyme Rad6, directly ubiquitinates the transcriptional activator Rpn4 (on internal lysines) to mediate its proteasomal degradation. Rad6 directly interacts with Ubr2 and is required for this ubiquitin-dependent degradation pathway.","method":"In vivo and in vitro ubiquitination assays, genetic deletion analysis, synthetic growth defect assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro ubiquitination assay plus in vivo genetics; first physiological substrate of Ubr2 identified","pmids":["15504724"],"is_preprint":false},{"year":2006,"finding":"UBR2 is required for chromosome stability and homologous recombination repair. UBR2-deficient mouse fibroblasts show elevated chromosomal bridges, micronuclei, spontaneous chromosomal gaps (fragile sites replicated late in S phase), hypersensitivity to mitomycin C, and significantly impaired homologous recombination repair of double-strand breaks, while non-homologous end joining was normal.","method":"UBR2 knockout mouse embryonic fibroblasts, metaphase spreads, DSB repair reporter assay, mitomycin C sensitivity assay, NHEJ assay","journal":"Mutation research","confidence":"High","confidence_rationale":"Tier 2 — KO cells with multiple orthogonal readouts including specific repair pathway assays","pmids":["16488448"],"is_preprint":false},{"year":2006,"finding":"UBR1 and UBR2 double knockout embryos die at midgestation with defects in neurogenesis and cardiovascular development, including reduced proliferation and precocious migration/differentiation of neural progenitor cells, with altered expression of D-type cyclins and Notch1. UBR1 and UBR2 have divergent functions despite similar N-degron recognition.","method":"Double knockout mouse construction, histological and immunohistochemical analysis, gene expression analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — double KO mouse with defined midgestation lethal phenotype and molecular marker changes; 78 citations","pmids":["16606826"],"is_preprint":false},{"year":2010,"finding":"UBR2 localizes to meiotic chromatin (including unsynapsed axial elements) and mediates transcriptional silencing via ubiquitination of histone H2A. UBR2 interacts with the E2 enzyme HR6B and substrate H2A, promotes HR6B-H2A interaction and ubiquitin transfer, and UBR2-deficient spermatocytes fail to ubiquitinate H2A and fail to silence X- and Y-chromosome-linked genes.","method":"Chromatin immunolocalization, co-immunoprecipitation, ubiquitination assays, analysis of gene silencing in UBR2-/- spermatocytes","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 — direct binding, ubiquitin transfer assay, KO phenotype with specific molecular readout; 74 citations","pmids":["20080676"],"is_preprint":false},{"year":2010,"finding":"Yeast Ubr1 and Ubr2 E3 ligases promote degradation of unfolded/misfolded cytosolic proteins as a quality control pathway. Ubr1 catalyzes ubiquitinylation of denatured (but not native) luciferase in a purified system by direct interaction; Hsp70 stimulates polyubiquitinylation. Loss of Ubr1 and Ubr2 suppresses growth arrest from chaperone mutations.","method":"In vitro ubiquitination reconstitution with purified components, genetic suppressor analysis, protein folding assays","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1 — reconstituted in vitro activity plus genetic epistasis; 121 citations","pmids":["20462952"],"is_preprint":false},{"year":2010,"finding":"UBR2 (and UBR1) bind leucine directly via their substrate-recognition domain. UBR1/UBR2 overexpression reduces mTOR-dependent S6K1 phosphorylation, while their knockdown increases S6K1 phosphorylation in amino acid-starved cells. Leucine binding inhibits degradation of N-end rule substrates in vitro, identifying UBR1/UBR2 as negative regulators of the leucine-mTOR signaling pathway.","method":"Leucine-immobilized affinity bead pulldown, overexpression/knockdown S6K1 phosphorylation assay, in vitro N-end rule substrate degradation assay","journal":"Genes to cells","confidence":"Medium","confidence_rationale":"Tier 2 — affinity pulldown plus functional gain/loss-of-function assays, single lab","pmids":["20298436"],"is_preprint":false},{"year":2010,"finding":"UBR2 (Ubr2) forms a stable protein complex with Tex19.1 in mouse testes. Binding of Ubr2 to Tex19.1 metabolically stabilizes Tex19.1 protein during spermatogenesis (Tex19.1 mRNA is transcribed but protein is absent in Ubr2-deficient germ cells), revealing a non-canonical, non-degradative function of Ubr2 outside the N-end rule pathway.","method":"Co-immunoprecipitation, Western blotting in Ubr2-/- testes, genetic phenotype comparison","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP plus KO protein absence, single lab but clear mechanistic conclusion","pmids":["21103378"],"is_preprint":false},{"year":2012,"finding":"UBR2 functions as a scaffold E3 that promotes HR6B/UbcH2-dependent monoubiquitylation and polyubiquitylation of histone H2A and H2B (but not H3 or H4), via a mechanism distinct from typical polyubiquitylation. UBR2's E3 activity in histone ubiquitylation is allosterically activated by dipeptides bearing destabilizing N-terminal residues. UBR2-deficient spermatocytes show impaired DSB repair and pachytene arrest; UBR2-deficient somatic cells show chromosomal instability and hypersensitivity to DNA damage.","method":"Chromatin fractionation, histone ubiquitylation assays, allosteric activation by dipeptide assay, DSB repair assays in KO cells, chromosome stability assays","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1-2 — biochemical ubiquitylation assays plus allosteric mechanism plus multiple KO cellular phenotypes","pmids":["22616001"],"is_preprint":false},{"year":2013,"finding":"Tumor-induced up-regulation of UBR2 in skeletal muscle is mediated by the p38β MAPK isoform, which phosphorylates C/EBPβ at Thr-188, enabling C/EBPβ binding to a functional cis-element in the UBR2 promoter. Genetic gain and loss of function of p38β, and genetic ablation of C/EBPβ, confirmed this signaling pathway is necessary and sufficient for UBR2 up-regulation in cachectic muscle.","method":"Pharmacological inhibition of p38α/β, p38β gain/loss-of-function in C2C12 myotubes, luciferase reporter assay, C/EBPβ KO mice with tumor model","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (pharmacological, genetic, reporter assay, in vivo KO) in one study","pmids":["23568773"],"is_preprint":false},{"year":2013,"finding":"The yeast Mub1/Ubr2 ubiquitin ligase complex associates with kinetochore particles via the CENP-C (Mif2) protein and regulates levels of the outer kinetochore protein Dsn1 via ubiquitylation, functioning as part of a quality control system monitoring kinetochore integrity.","method":"Kinetochore particle purification, co-immunoprecipitation, ubiquitylation assays, genetic deletion rescue of Dsn1 mutant","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 — biochemical purification, ubiquitylation assay, and genetic rescue in one study","pmids":["23408894"],"is_preprint":false},{"year":2019,"finding":"UBR2 is required for NLRP1B inflammasome activation by anthrax lethal toxin (LT). LT cleaves NLRP1B after Lys44, exposing an N-terminal leucine; UBR2 recognizes this neo-N-terminus and mediates ubiquitination and degradation of cleaved NLRP1B in partnership with E2 enzyme UBE2O. This degradation triggers release of the noncovalently bound CARD domain, enabling downstream caspase-1 activation. UBR2 also mediates ubiquitination of constitutively autocleavage-generated NLRP1B fragments.","method":"Genome-wide siRNA screen, CRISPR-Cas9 knockout screen, dual-fluorescence reporter for ASC speck formation and pyroptosis, ubiquitination assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1-2 — two independent genome-wide screens plus mechanistic ubiquitination assays; 84 citations","pmids":["31268597"],"is_preprint":false},{"year":2020,"finding":"UBR2 protects cells from caspase-independent cell death (CICD) via the MAPK/Erk pathway. Genome-wide siRNA screening identified UBR2 as a regulator of CICD; UBR2 downregulation sensitized cells to CICD while overexpression was protective, and this protection required MAPK/Erk signaling.","method":"Genome-wide siRNA lethality screen, UBR2 knockdown/overexpression, MAPK/Erk pathway inhibition","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2-3 — genome-wide screen plus gain/loss-of-function with pathway inhibition, single lab","pmids":["33288741"],"is_preprint":false},{"year":2023,"finding":"UBR1 and UBR2 function as ER stress sensors in mammalian cells. Under normal conditions, UBR1 and UBR2 are polyubiquitinated via Lys48-linked chains and degraded by the 26S proteasome. Under ER stress, UBR1 and UBR2 are stabilized and cells lacking both are hypersensitive to ER stress-induced apoptosis, indicating these cytoplasmic E3 ligases have anti-ER stress activities.","method":"ER stress induction, polyubiquitination assays (K48-linkage), double KO cells, apoptosis assays under ER stress","journal":"Molecules and cells","confidence":"Medium","confidence_rationale":"Tier 2 — linkage-specific ubiquitination assay plus KO cellular phenotype, single lab","pmids":["38376480"],"is_preprint":false},{"year":2024,"finding":"DUSP22 dephosphorylates UBR2 at specific serine residues, leading to ubiquitin-mediated UBR2 degradation (via SCF E3 ligase complex through K48-linked ubiquitination at multiple lysines). UBR2 in turn induces K63-linked ubiquitination of Lck at Lys99 and Lys276, promoting Lck Tyr394 phosphorylation and activation downstream of TCR signaling. UBR2-mediated Lck activation promotes proinflammatory cytokine expression, and UBR2 genomic deletion attenuates inflammatory phenotypes caused by DUSP22 knockout.","method":"Dephosphorylation assays, ubiquitination assays (K48/K63-specific), site-directed mutagenesis of Lck ubiquitination sites, CRISPR KO, single-cell RNA sequencing, T cell activation assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 — multiple biochemical assays (phosphorylation, K63-ubiquitination at defined residues, mutagenesis) plus genetic epistasis and human patient relevance; 18 citations","pmids":["38225265"],"is_preprint":false}],"current_model":"UBR2 is a RING-type E3 ubiquitin ligase and N-recognin of the N-degron/N-end rule pathway that recognizes proteins with destabilizing N-terminal residues for polyubiquitination and proteasomal degradation; beyond canonical proteolysis, UBR2 functions as a scaffold E3 that promotes HR6B-dependent histone H2A/H2B monoubiquitylation to mediate transcriptional silencing during meiosis, ubiquitinates Lck at K63-linked sites to activate TCR signaling, mediates NLRP1B inflammasome activation following anthrax LT cleavage via UBE2O, stabilizes Tex19.1 protein non-degradatively, acts as a leucine sensor that negatively regulates mTOR/S6K1 signaling, participates in ER stress response and cytosolic protein quality control, and is transcriptionally upregulated in cachectic muscle through the p38β–C/EBPβ signaling axis."},"narrative":{"teleology":[{"year":2003,"claim":"Establishing UBR2 as an N-end rule E3 ligase essential for male meiosis answered whether a second mammalian N-recognin existed and had non-redundant physiological roles.","evidence":"UBR2 knockout mice showing spermatocyte arrest and female embryonic lethality, combined with N-degron substrate-binding assays","pmids":["14585983"],"confidence":"High","gaps":["Molecular substrates of UBR2 in meiosis unknown","Basis of female-specific embryonic lethality unresolved","Mechanism of meiotic arrest not defined"]},{"year":2004,"claim":"Identification of UBR2's first physiological substrate (yeast Rpn4) and its partnership with Rad6 established that Ubr2 mediates proteasomal degradation of a transcription factor through internal-lysine ubiquitination.","evidence":"In vitro and in vivo ubiquitination assays in yeast with Ubr2/Rad6 targeting Rpn4","pmids":["15504724"],"confidence":"High","gaps":["Whether mammalian UBR2 degrades transcription factors analogously was unknown","Structural basis of Ubr2-Rad6 interaction not defined"]},{"year":2004,"claim":"Discovery that UBR2 forms a stable complex with the RECQL4 helicase without targeting it for degradation revealed a non-degradative physical interaction, raising the question of whether UBR2 has scaffold functions.","evidence":"Reciprocal co-immunoprecipitation from HeLa cells, pulse-chase showing RECQL4 stability, ATPase assays","pmids":["15317757"],"confidence":"High","gaps":["Functional consequence of UBR2-RECQL4 interaction for DNA repair undefined","Whether UBR2 ubiquitinates other complex members unknown"]},{"year":2006,"claim":"Demonstration that UBR2-deficient somatic cells exhibit chromosomal instability and impaired homologous recombination repair established UBR2 as a genome stability factor beyond its meiotic role.","evidence":"UBR2 KO MEFs with elevated chromosomal aberrations, mitomycin C hypersensitivity, impaired HR reporter assay, normal NHEJ","pmids":["16488448"],"confidence":"High","gaps":["Direct HR substrate of UBR2 ubiquitination unknown","Whether HR defect is secondary to chromatin modification unresolved"]},{"year":2006,"claim":"UBR1/UBR2 double knockout revealed functional divergence and synergistic requirements in neurogenesis and cardiovascular development, showing that these two N-recognins are not fully redundant.","evidence":"Double KO mouse midgestation lethality with altered D-type cyclin and Notch1 expression in neural progenitors","pmids":["16606826"],"confidence":"High","gaps":["Whether developmental phenotypes reflect direct ubiquitination of Notch/cyclin substrates unknown","Individual contributions of UBR1 vs UBR2 to each tissue phenotype not delineated"]},{"year":2010,"claim":"Three contemporaneous discoveries expanded UBR2's mechanism: it ubiquitinates histone H2A via HR6B to silence sex chromosomes during meiosis, it participates in cytosolic misfolded protein quality control, and it binds leucine to negatively regulate mTOR signaling.","evidence":"Chromatin localization and ubiquitination assays in UBR2 KO spermatocytes [PMID:20080676]; reconstituted ubiquitination of denatured luciferase plus genetic suppression of chaperone mutants in yeast [PMID:20462952]; leucine affinity pulldown and S6K1 phosphorylation assays [PMID:20298436]","pmids":["20080676","20462952","20298436"],"confidence":"High","gaps":["Whether leucine-mTOR regulation is direct or via substrate competition unresolved","Identity of misfolded protein substrates in mammalian cells unknown","How allosteric dipeptide activation of histone ubiquitylation is structurally achieved unclear"]},{"year":2010,"claim":"Finding that UBR2 stabilizes Tex19.1 protein without degrading it established a non-canonical, non-degradative function of this E3 ligase in spermatogenesis.","evidence":"Co-IP of UBR2-Tex19.1 complex in testes; Tex19.1 protein absent in Ubr2 KO despite normal mRNA","pmids":["21103378"],"confidence":"Medium","gaps":["Mechanism by which UBR2 binding prevents Tex19.1 degradation unknown","Whether UBR2 shields Tex19.1 from another E3 ligase not tested"]},{"year":2012,"claim":"Biochemical characterization of UBR2 as a scaffold E3 promoting HR6B-dependent mono- and polyubiquitylation of H2A/H2B, allosterically activated by N-degron dipeptides, unified its chromatin and N-end rule functions.","evidence":"In vitro histone ubiquitylation assays with allosteric dipeptide activation, UBR2 KO spermatocyte DSB repair analysis","pmids":["22616001"],"confidence":"High","gaps":["Structural basis for allosteric activation not determined","Whether scaffold mechanism applies to non-histone chromatin substrates unknown"]},{"year":2013,"claim":"Two parallel advances linked UBR2 to kinetochore quality control in yeast (via Dsn1 ubiquitylation with Mub1) and to transcriptional upregulation in cancer cachexia through the p38β–C/EBPβ axis.","evidence":"Kinetochore particle purification and Dsn1 ubiquitylation/genetic rescue in yeast [PMID:23408894]; p38β/C/EBPβ KO mice with tumor cachexia model and UBR2 promoter reporter [PMID:23568773]","pmids":["23408894","23568773"],"confidence":"High","gaps":["Whether mammalian UBR2 regulates kinetochore proteins unknown","Downstream UBR2 substrates mediating muscle wasting not identified"]},{"year":2019,"claim":"Genome-wide screens identified UBR2 as essential for NLRP1B inflammasome activation by anthrax lethal toxin, revealing that N-degron recognition of cleaved NLRP1B triggers its degradation and liberates the CARD domain to activate caspase-1.","evidence":"Two independent genome-wide screens (siRNA and CRISPR), ubiquitination assays identifying UBE2O as E2 partner","pmids":["31268597"],"confidence":"High","gaps":["Whether UBR2 activates other inflammasome sensors via N-degron recognition unknown","Structural basis of NLRP1B neo-N-terminus recognition not resolved"]},{"year":2023,"claim":"Discovery that UBR2 is itself regulated by K48-linked polyubiquitination and proteasomal turnover under basal conditions, with stabilization under ER stress conferring cytoprotection, established UBR2 as an ER stress-responsive factor.","evidence":"K48-linkage-specific ubiquitination assays, UBR1/UBR2 double KO cells hypersensitive to ER stress-induced apoptosis","pmids":["38376480"],"confidence":"Medium","gaps":["The E3 ligase responsible for UBR2 degradation under basal conditions was not identified in this study","Cytoprotective substrates of UBR2 during ER stress unknown","Single-lab finding awaiting independent confirmation"]},{"year":2024,"claim":"Identification of UBR2 as a K63-linked ubiquitin ligase for Lck at defined residues, regulated by DUSP22-mediated dephosphorylation and SCF-dependent degradation, placed UBR2 in TCR signaling and inflammatory cytokine production.","evidence":"K63-specific ubiquitination assays, Lck mutagenesis, DUSP22/UBR2 double KO epistasis, scRNA-seq in T cells","pmids":["38225265"],"confidence":"High","gaps":["Whether UBR2 K63-ubiquitination of Lck involves N-degron recognition unknown","Upstream signals activating UBR2 phosphorylation in T cells not identified"]},{"year":null,"claim":"No structural model of mammalian UBR2 exists, the full repertoire of physiological substrates across tissues remains undefined, and how its N-degron recognition, scaffold E3, and K63-ligase activities are coordinately regulated is unknown.","evidence":"","pmids":[],"confidence":"High","gaps":["No crystal or cryo-EM structure of mammalian UBR2","Systematic substrate identification across cell types not performed","Regulatory post-translational modifications beyond DUSP22-mediated dephosphorylation not mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,2,5,6,9,11,12,15]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[0,2,5,9,12,15]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[5,9]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[7,13]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[7,14]}],"localization":[{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[5,9]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[6,14]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[5,9]}],"pathway":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[5]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,2,6,9,12,15]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[12,15]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[3,9]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[12,13]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[7,15]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[5,9]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[14]},{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[0,5,8]}],"complexes":["UBR2-HR6B (E3-E2 complex)","Mub1-Ubr2 (yeast kinetochore QC complex)","RECQL4-UBR2"],"partners":["HR6B","RECQL4","TEX19","NLRP1","UBE2O","LCK","DUSP22","CEBPB"],"other_free_text":[]},"mechanistic_narrative":"UBR2 is a RING-type E3 ubiquitin ligase of the N-degron (N-end rule) pathway that functions in protein quality control, chromatin regulation, innate immune signaling, and meiotic chromosome dynamics. As an N-recognin, UBR2 recognizes destabilizing N-terminal residues on substrates for polyubiquitination and proteasomal degradation, mediating cytosolic quality control of misfolded proteins and degradation of cleaved NLRP1B to activate the inflammasome following anthrax lethal toxin exposure [PMID:20462952, PMID:31268597]. UBR2 also acts as a scaffold E3 ligase that promotes HR6B-dependent monoubiquitylation of histones H2A and H2B, a function allosterically activated by N-degron dipeptides and essential for meiotic sex chromosome silencing, DNA double-strand break repair, and chromosome stability [PMID:20080676, PMID:22616001, PMID:16488448]. UBR2 additionally catalyzes K63-linked ubiquitination of the kinase Lck to promote TCR signaling [PMID:38225265], stabilizes Tex19.1 protein non-degradatively during spermatogenesis [PMID:21103378], and is transcriptionally upregulated in cachectic muscle via the p38β–C/EBPβ axis [PMID:23568773]."},"prefetch_data":{"uniprot":{"accession":"Q8IWV8","full_name":"E3 ubiquitin-protein ligase UBR2","aliases":["N-recognin-2","Ubiquitin-protein ligase E3-alpha-2","Ubiquitin-protein ligase E3-alpha-II"],"length_aa":1755,"mass_kda":200.5,"function":"E3 ubiquitin-protein ligase which is a component of the N-end rule pathway (PubMed:15548684, PubMed:20835242, PubMed:28392261). Recognizes and binds to proteins bearing specific N-terminal residues (N-degrons) that are destabilizing according to the N-end rule, leading to their ubiquitination and subsequent degradation (PubMed:20835242, PubMed:28392261). Recognizes both type-1 and type-2 N-degrons, containing positively charged amino acids (Arg, Lys and His) and bulky and hydrophobic amino acids, respectively (PubMed:20835242, PubMed:28392261). Does not ubiquitinate proteins that are acetylated at the N-terminus (PubMed:20835242). In contrast, it strongly binds methylated N-degrons (PubMed:28392261). Plays a critical role in chromatin inactivation and chromosome-wide transcriptional silencing during meiosis via ubiquitination of histone H2A (By similarity). Binds leucine and is a negative regulator of the leucine-mTOR signaling pathway, thereby controlling cell growth (PubMed:20298436). Required for spermatogenesis, promotes, with Tex19.1, SPO11-dependent recombination foci to accumulate and drive robust homologous chromosome synapsis (By similarity). Polyubiquitinates LINE-1 retrotransposon encoded, LIRE1, which induces degradation, inhibiting LINE-1 retrotransposon mobilization (By similarity). Catalyzes ubiquitination and degradation of the N-terminal part of NLRP1 following NLRP1 activation by pathogens and other damage-associated signals: ubiquitination promotes degradation of the N-terminal part and subsequent release of the cleaved C-terminal part of NLRP1, which polymerizes and forms the NLRP1 inflammasome followed by host cell pyroptosis (By similarity). Plays a role in T-cell receptor signaling by inducing 'Lys-63'-linked ubiquitination of lymphocyte cell-specific kinase LCK (PubMed:38225265). This activity is regulated by DUSP22, which induces 'Lys-48'-linked ubiquitination of UBR2, leading to its proteasomal degradation by SCF E3 ubiquitin-protein ligase complex (PubMed:38225265)","subcellular_location":"Nucleus; Chromosome","url":"https://www.uniprot.org/uniprotkb/Q8IWV8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/UBR2","classification":"Not Classified","n_dependent_lines":37,"n_total_lines":1208,"dependency_fraction":0.030629139072847682},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/UBR2","total_profiled":1310},"omim":[{"mim_id":"620846","title":"N-TERMINAL GLUTAMINE AMIDASE 1; NTAQ1","url":"https://www.omim.org/entry/620846"},{"mim_id":"620743","title":"SDE2 TELOMERE MAINTENANCE HOMOLOG; SDE2","url":"https://www.omim.org/entry/620743"},{"mim_id":"615367","title":"N-TERMINAL ASPARAGINE AMIDASE; NTAN1","url":"https://www.omim.org/entry/615367"},{"mim_id":"613831","title":"UBIQUITIN PROTEIN LIGASE E3 COMPONENT N-RECOGNIN 3; UBR3","url":"https://www.omim.org/entry/613831"},{"mim_id":"609134","title":"UBIQUITIN-PROTEIN LIGASE E3 COMPONENT N-RECOGNIN 2; UBR2","url":"https://www.omim.org/entry/609134"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Plasma membrane","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/UBR2"},"hgnc":{"alias_symbol":["bA49A4.1","dJ392M17.3","KIAA0349"],"prev_symbol":["C6orf133"]},"alphafold":{"accession":"Q8IWV8","domains":[{"cath_id":"2.10.110.30","chopping":"99-168","consensus_level":"high","plddt":86.0704,"start":99,"end":168},{"cath_id":"-","chopping":"1608-1755","consensus_level":"medium","plddt":84.0517,"start":1608,"end":1755},{"cath_id":"1.10.10","chopping":"776-851","consensus_level":"medium","plddt":90.6878,"start":776,"end":851}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IWV8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IWV8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IWV8-F1-predicted_aligned_error_v6.png","plddt_mean":84.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=UBR2","jax_strain_url":"https://www.jax.org/strain/search?query=UBR2"},"sequence":{"accession":"Q8IWV8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8IWV8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8IWV8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IWV8"}},"corpus_meta":[{"pmid":"14585983","id":"PMC_14585983","title":"Female lethality and apoptosis of spermatocytes in mice lacking the UBR2 ubiquitin ligase of the N-end rule pathway.","date":"2003","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/14585983","citation_count":130,"is_preprint":false},{"pmid":"20462952","id":"PMC_20462952","title":"Ubr1 and Ubr2 function in a quality control pathway for degradation of unfolded cytosolic proteins.","date":"2010","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/20462952","citation_count":121,"is_preprint":false},{"pmid":"15317757","id":"PMC_15317757","title":"RECQL4, mutated in the Rothmund-Thomson and RAPADILINO syndromes, interacts with ubiquitin ligases UBR1 and UBR2 of the N-end rule pathway.","date":"2004","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/15317757","citation_count":89,"is_preprint":false},{"pmid":"31268597","id":"PMC_31268597","title":"The N-end rule ubiquitin ligase UBR2 mediates NLRP1B inflammasome 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spermatogenesis.","date":"2010","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/21103378","citation_count":32,"is_preprint":false},{"pmid":"22616001","id":"PMC_22616001","title":"UBR2 of the N-end rule pathway is required for chromosome stability via histone ubiquitylation in spermatocytes and somatic cells.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22616001","citation_count":32,"is_preprint":false},{"pmid":"20298436","id":"PMC_20298436","title":"Role of N-end rule ubiquitin ligases UBR1 and UBR2 in regulating the leucine-mTOR signaling pathway.","date":"2010","source":"Genes to cells : devoted to molecular & cellular mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/20298436","citation_count":31,"is_preprint":false},{"pmid":"23408894","id":"PMC_23408894","title":"The Mub1/Ubr2 ubiquitin ligase complex regulates the conserved Dsn1 kinetochore protein.","date":"2013","source":"PLoS 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cerevisiae Mub1, a substrate adaptor of E3 ubiquitin ligase Ubr2, modulates sensitivity to cell wall stressors through multiple transcription factors.","date":"2025","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/40165610","citation_count":1,"is_preprint":false},{"pmid":"40511880","id":"PMC_40511880","title":"Upregulation of E3 ligase UBR2 in acetaldehyde-treated C2C12 myotubes and its potential involvement in fast-twitch muscle atrophy in alcohol-fed rats.","date":"2025","source":"Alcohol, clinical & experimental research","url":"https://pubmed.ncbi.nlm.nih.gov/40511880","citation_count":1,"is_preprint":false},{"pmid":"40676335","id":"PMC_40676335","title":"The role of UBR2 in triple-negative breast cancer and its implications for immune checkpoint blockade therapy.","date":"2025","source":"Discover oncology","url":"https://pubmed.ncbi.nlm.nih.gov/40676335","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.07.23.666188","title":"Response 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UBR2 knockout mice show spermatocyte apoptosis with arrest between leptotene/zygotene and pachytene, absence of intact synaptonemal complexes, and female embryonic lethality, establishing UBR2 as required for male meiosis and spermatogenesis.\",\n      \"method\": \"UBR2 knockout mouse construction, substrate-binding assays, histological analysis, genetic background manipulation\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — KO mouse with defined cellular phenotype, substrate-binding assays, replicated across genetic backgrounds; foundational paper with 130 citations\",\n      \"pmids\": [\"14585983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"UBR2 forms a stable complex with RECQL4 (mutated in Rothmund-Thomson and RAPADILINO syndromes) as isolated from HeLa cells. The RECQL4-UBR1/UBR2 complex has DNA-stimulated ATPase activity. Despite its association with ubiquitin ligases, RECQL4 is not ubiquitylated in vivo and is a long-lived protein.\",\n      \"method\": \"Co-immunoprecipitation with anti-RECQL4 antibodies, ATPase and helicase assays, in vivo ubiquitylation assays, pulse-chase\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP, biochemical activity assays, and in vivo ubiquitylation assays in the same study\",\n      \"pmids\": [\"15317757\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Yeast Ubr2 ubiquitin ligase, partnering with the E2 enzyme Rad6, directly ubiquitinates the transcriptional activator Rpn4 (on internal lysines) to mediate its proteasomal degradation. Rad6 directly interacts with Ubr2 and is required for this ubiquitin-dependent degradation pathway.\",\n      \"method\": \"In vivo and in vitro ubiquitination assays, genetic deletion analysis, synthetic growth defect assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro ubiquitination assay plus in vivo genetics; first physiological substrate of Ubr2 identified\",\n      \"pmids\": [\"15504724\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"UBR2 is required for chromosome stability and homologous recombination repair. UBR2-deficient mouse fibroblasts show elevated chromosomal bridges, micronuclei, spontaneous chromosomal gaps (fragile sites replicated late in S phase), hypersensitivity to mitomycin C, and significantly impaired homologous recombination repair of double-strand breaks, while non-homologous end joining was normal.\",\n      \"method\": \"UBR2 knockout mouse embryonic fibroblasts, metaphase spreads, DSB repair reporter assay, mitomycin C sensitivity assay, NHEJ assay\",\n      \"journal\": \"Mutation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO cells with multiple orthogonal readouts including specific repair pathway assays\",\n      \"pmids\": [\"16488448\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"UBR1 and UBR2 double knockout embryos die at midgestation with defects in neurogenesis and cardiovascular development, including reduced proliferation and precocious migration/differentiation of neural progenitor cells, with altered expression of D-type cyclins and Notch1. UBR1 and UBR2 have divergent functions despite similar N-degron recognition.\",\n      \"method\": \"Double knockout mouse construction, histological and immunohistochemical analysis, gene expression analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — double KO mouse with defined midgestation lethal phenotype and molecular marker changes; 78 citations\",\n      \"pmids\": [\"16606826\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"UBR2 localizes to meiotic chromatin (including unsynapsed axial elements) and mediates transcriptional silencing via ubiquitination of histone H2A. UBR2 interacts with the E2 enzyme HR6B and substrate H2A, promotes HR6B-H2A interaction and ubiquitin transfer, and UBR2-deficient spermatocytes fail to ubiquitinate H2A and fail to silence X- and Y-chromosome-linked genes.\",\n      \"method\": \"Chromatin immunolocalization, co-immunoprecipitation, ubiquitination assays, analysis of gene silencing in UBR2-/- spermatocytes\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct binding, ubiquitin transfer assay, KO phenotype with specific molecular readout; 74 citations\",\n      \"pmids\": [\"20080676\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Yeast Ubr1 and Ubr2 E3 ligases promote degradation of unfolded/misfolded cytosolic proteins as a quality control pathway. Ubr1 catalyzes ubiquitinylation of denatured (but not native) luciferase in a purified system by direct interaction; Hsp70 stimulates polyubiquitinylation. Loss of Ubr1 and Ubr2 suppresses growth arrest from chaperone mutations.\",\n      \"method\": \"In vitro ubiquitination reconstitution with purified components, genetic suppressor analysis, protein folding assays\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted in vitro activity plus genetic epistasis; 121 citations\",\n      \"pmids\": [\"20462952\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"UBR2 (and UBR1) bind leucine directly via their substrate-recognition domain. UBR1/UBR2 overexpression reduces mTOR-dependent S6K1 phosphorylation, while their knockdown increases S6K1 phosphorylation in amino acid-starved cells. Leucine binding inhibits degradation of N-end rule substrates in vitro, identifying UBR1/UBR2 as negative regulators of the leucine-mTOR signaling pathway.\",\n      \"method\": \"Leucine-immobilized affinity bead pulldown, overexpression/knockdown S6K1 phosphorylation assay, in vitro N-end rule substrate degradation assay\",\n      \"journal\": \"Genes to cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — affinity pulldown plus functional gain/loss-of-function assays, single lab\",\n      \"pmids\": [\"20298436\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"UBR2 (Ubr2) forms a stable protein complex with Tex19.1 in mouse testes. Binding of Ubr2 to Tex19.1 metabolically stabilizes Tex19.1 protein during spermatogenesis (Tex19.1 mRNA is transcribed but protein is absent in Ubr2-deficient germ cells), revealing a non-canonical, non-degradative function of Ubr2 outside the N-end rule pathway.\",\n      \"method\": \"Co-immunoprecipitation, Western blotting in Ubr2-/- testes, genetic phenotype comparison\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP plus KO protein absence, single lab but clear mechanistic conclusion\",\n      \"pmids\": [\"21103378\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"UBR2 functions as a scaffold E3 that promotes HR6B/UbcH2-dependent monoubiquitylation and polyubiquitylation of histone H2A and H2B (but not H3 or H4), via a mechanism distinct from typical polyubiquitylation. UBR2's E3 activity in histone ubiquitylation is allosterically activated by dipeptides bearing destabilizing N-terminal residues. UBR2-deficient spermatocytes show impaired DSB repair and pachytene arrest; UBR2-deficient somatic cells show chromosomal instability and hypersensitivity to DNA damage.\",\n      \"method\": \"Chromatin fractionation, histone ubiquitylation assays, allosteric activation by dipeptide assay, DSB repair assays in KO cells, chromosome stability assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — biochemical ubiquitylation assays plus allosteric mechanism plus multiple KO cellular phenotypes\",\n      \"pmids\": [\"22616001\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Tumor-induced up-regulation of UBR2 in skeletal muscle is mediated by the p38β MAPK isoform, which phosphorylates C/EBPβ at Thr-188, enabling C/EBPβ binding to a functional cis-element in the UBR2 promoter. Genetic gain and loss of function of p38β, and genetic ablation of C/EBPβ, confirmed this signaling pathway is necessary and sufficient for UBR2 up-regulation in cachectic muscle.\",\n      \"method\": \"Pharmacological inhibition of p38α/β, p38β gain/loss-of-function in C2C12 myotubes, luciferase reporter assay, C/EBPβ KO mice with tumor model\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (pharmacological, genetic, reporter assay, in vivo KO) in one study\",\n      \"pmids\": [\"23568773\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The yeast Mub1/Ubr2 ubiquitin ligase complex associates with kinetochore particles via the CENP-C (Mif2) protein and regulates levels of the outer kinetochore protein Dsn1 via ubiquitylation, functioning as part of a quality control system monitoring kinetochore integrity.\",\n      \"method\": \"Kinetochore particle purification, co-immunoprecipitation, ubiquitylation assays, genetic deletion rescue of Dsn1 mutant\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — biochemical purification, ubiquitylation assay, and genetic rescue in one study\",\n      \"pmids\": [\"23408894\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"UBR2 is required for NLRP1B inflammasome activation by anthrax lethal toxin (LT). LT cleaves NLRP1B after Lys44, exposing an N-terminal leucine; UBR2 recognizes this neo-N-terminus and mediates ubiquitination and degradation of cleaved NLRP1B in partnership with E2 enzyme UBE2O. This degradation triggers release of the noncovalently bound CARD domain, enabling downstream caspase-1 activation. UBR2 also mediates ubiquitination of constitutively autocleavage-generated NLRP1B fragments.\",\n      \"method\": \"Genome-wide siRNA screen, CRISPR-Cas9 knockout screen, dual-fluorescence reporter for ASC speck formation and pyroptosis, ubiquitination assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — two independent genome-wide screens plus mechanistic ubiquitination assays; 84 citations\",\n      \"pmids\": [\"31268597\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"UBR2 protects cells from caspase-independent cell death (CICD) via the MAPK/Erk pathway. Genome-wide siRNA screening identified UBR2 as a regulator of CICD; UBR2 downregulation sensitized cells to CICD while overexpression was protective, and this protection required MAPK/Erk signaling.\",\n      \"method\": \"Genome-wide siRNA lethality screen, UBR2 knockdown/overexpression, MAPK/Erk pathway inhibition\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — genome-wide screen plus gain/loss-of-function with pathway inhibition, single lab\",\n      \"pmids\": [\"33288741\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"UBR1 and UBR2 function as ER stress sensors in mammalian cells. Under normal conditions, UBR1 and UBR2 are polyubiquitinated via Lys48-linked chains and degraded by the 26S proteasome. Under ER stress, UBR1 and UBR2 are stabilized and cells lacking both are hypersensitive to ER stress-induced apoptosis, indicating these cytoplasmic E3 ligases have anti-ER stress activities.\",\n      \"method\": \"ER stress induction, polyubiquitination assays (K48-linkage), double KO cells, apoptosis assays under ER stress\",\n      \"journal\": \"Molecules and cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — linkage-specific ubiquitination assay plus KO cellular phenotype, single lab\",\n      \"pmids\": [\"38376480\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"DUSP22 dephosphorylates UBR2 at specific serine residues, leading to ubiquitin-mediated UBR2 degradation (via SCF E3 ligase complex through K48-linked ubiquitination at multiple lysines). UBR2 in turn induces K63-linked ubiquitination of Lck at Lys99 and Lys276, promoting Lck Tyr394 phosphorylation and activation downstream of TCR signaling. UBR2-mediated Lck activation promotes proinflammatory cytokine expression, and UBR2 genomic deletion attenuates inflammatory phenotypes caused by DUSP22 knockout.\",\n      \"method\": \"Dephosphorylation assays, ubiquitination assays (K48/K63-specific), site-directed mutagenesis of Lck ubiquitination sites, CRISPR KO, single-cell RNA sequencing, T cell activation assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple biochemical assays (phosphorylation, K63-ubiquitination at defined residues, mutagenesis) plus genetic epistasis and human patient relevance; 18 citations\",\n      \"pmids\": [\"38225265\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"UBR2 is a RING-type E3 ubiquitin ligase and N-recognin of the N-degron/N-end rule pathway that recognizes proteins with destabilizing N-terminal residues for polyubiquitination and proteasomal degradation; beyond canonical proteolysis, UBR2 functions as a scaffold E3 that promotes HR6B-dependent histone H2A/H2B monoubiquitylation to mediate transcriptional silencing during meiosis, ubiquitinates Lck at K63-linked sites to activate TCR signaling, mediates NLRP1B inflammasome activation following anthrax LT cleavage via UBE2O, stabilizes Tex19.1 protein non-degradatively, acts as a leucine sensor that negatively regulates mTOR/S6K1 signaling, participates in ER stress response and cytosolic protein quality control, and is transcriptionally upregulated in cachectic muscle through the p38β–C/EBPβ signaling axis.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"UBR2 is a RING-type E3 ubiquitin ligase of the N-degron (N-end rule) pathway that functions in protein quality control, chromatin regulation, innate immune signaling, and meiotic chromosome dynamics. As an N-recognin, UBR2 recognizes destabilizing N-terminal residues on substrates for polyubiquitination and proteasomal degradation, mediating cytosolic quality control of misfolded proteins and degradation of cleaved NLRP1B to activate the inflammasome following anthrax lethal toxin exposure [PMID:20462952, PMID:31268597]. UBR2 also acts as a scaffold E3 ligase that promotes HR6B-dependent monoubiquitylation of histones H2A and H2B, a function allosterically activated by N-degron dipeptides and essential for meiotic sex chromosome silencing, DNA double-strand break repair, and chromosome stability [PMID:20080676, PMID:22616001, PMID:16488448]. UBR2 additionally catalyzes K63-linked ubiquitination of the kinase Lck to promote TCR signaling [PMID:38225265], stabilizes Tex19.1 protein non-degradatively during spermatogenesis [PMID:21103378], and is transcriptionally upregulated in cachectic muscle via the p38β–C/EBPβ axis [PMID:23568773].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Establishing UBR2 as an N-end rule E3 ligase essential for male meiosis answered whether a second mammalian N-recognin existed and had non-redundant physiological roles.\",\n      \"evidence\": \"UBR2 knockout mice showing spermatocyte arrest and female embryonic lethality, combined with N-degron substrate-binding assays\",\n      \"pmids\": [\"14585983\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular substrates of UBR2 in meiosis unknown\", \"Basis of female-specific embryonic lethality unresolved\", \"Mechanism of meiotic arrest not defined\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identification of UBR2's first physiological substrate (yeast Rpn4) and its partnership with Rad6 established that Ubr2 mediates proteasomal degradation of a transcription factor through internal-lysine ubiquitination.\",\n      \"evidence\": \"In vitro and in vivo ubiquitination assays in yeast with Ubr2/Rad6 targeting Rpn4\",\n      \"pmids\": [\"15504724\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether mammalian UBR2 degrades transcription factors analogously was unknown\", \"Structural basis of Ubr2-Rad6 interaction not defined\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Discovery that UBR2 forms a stable complex with the RECQL4 helicase without targeting it for degradation revealed a non-degradative physical interaction, raising the question of whether UBR2 has scaffold functions.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation from HeLa cells, pulse-chase showing RECQL4 stability, ATPase assays\",\n      \"pmids\": [\"15317757\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of UBR2-RECQL4 interaction for DNA repair undefined\", \"Whether UBR2 ubiquitinates other complex members unknown\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Demonstration that UBR2-deficient somatic cells exhibit chromosomal instability and impaired homologous recombination repair established UBR2 as a genome stability factor beyond its meiotic role.\",\n      \"evidence\": \"UBR2 KO MEFs with elevated chromosomal aberrations, mitomycin C hypersensitivity, impaired HR reporter assay, normal NHEJ\",\n      \"pmids\": [\"16488448\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct HR substrate of UBR2 ubiquitination unknown\", \"Whether HR defect is secondary to chromatin modification unresolved\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"UBR1/UBR2 double knockout revealed functional divergence and synergistic requirements in neurogenesis and cardiovascular development, showing that these two N-recognins are not fully redundant.\",\n      \"evidence\": \"Double KO mouse midgestation lethality with altered D-type cyclin and Notch1 expression in neural progenitors\",\n      \"pmids\": [\"16606826\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether developmental phenotypes reflect direct ubiquitination of Notch/cyclin substrates unknown\", \"Individual contributions of UBR1 vs UBR2 to each tissue phenotype not delineated\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Three contemporaneous discoveries expanded UBR2's mechanism: it ubiquitinates histone H2A via HR6B to silence sex chromosomes during meiosis, it participates in cytosolic misfolded protein quality control, and it binds leucine to negatively regulate mTOR signaling.\",\n      \"evidence\": \"Chromatin localization and ubiquitination assays in UBR2 KO spermatocytes [PMID:20080676]; reconstituted ubiquitination of denatured luciferase plus genetic suppression of chaperone mutants in yeast [PMID:20462952]; leucine affinity pulldown and S6K1 phosphorylation assays [PMID:20298436]\",\n      \"pmids\": [\"20080676\", \"20462952\", \"20298436\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether leucine-mTOR regulation is direct or via substrate competition unresolved\", \"Identity of misfolded protein substrates in mammalian cells unknown\", \"How allosteric dipeptide activation of histone ubiquitylation is structurally achieved unclear\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Finding that UBR2 stabilizes Tex19.1 protein without degrading it established a non-canonical, non-degradative function of this E3 ligase in spermatogenesis.\",\n      \"evidence\": \"Co-IP of UBR2-Tex19.1 complex in testes; Tex19.1 protein absent in Ubr2 KO despite normal mRNA\",\n      \"pmids\": [\"21103378\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which UBR2 binding prevents Tex19.1 degradation unknown\", \"Whether UBR2 shields Tex19.1 from another E3 ligase not tested\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Biochemical characterization of UBR2 as a scaffold E3 promoting HR6B-dependent mono- and polyubiquitylation of H2A/H2B, allosterically activated by N-degron dipeptides, unified its chromatin and N-end rule functions.\",\n      \"evidence\": \"In vitro histone ubiquitylation assays with allosteric dipeptide activation, UBR2 KO spermatocyte DSB repair analysis\",\n      \"pmids\": [\"22616001\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for allosteric activation not determined\", \"Whether scaffold mechanism applies to non-histone chromatin substrates unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Two parallel advances linked UBR2 to kinetochore quality control in yeast (via Dsn1 ubiquitylation with Mub1) and to transcriptional upregulation in cancer cachexia through the p38β–C/EBPβ axis.\",\n      \"evidence\": \"Kinetochore particle purification and Dsn1 ubiquitylation/genetic rescue in yeast [PMID:23408894]; p38β/C/EBPβ KO mice with tumor cachexia model and UBR2 promoter reporter [PMID:23568773]\",\n      \"pmids\": [\"23408894\", \"23568773\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether mammalian UBR2 regulates kinetochore proteins unknown\", \"Downstream UBR2 substrates mediating muscle wasting not identified\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Genome-wide screens identified UBR2 as essential for NLRP1B inflammasome activation by anthrax lethal toxin, revealing that N-degron recognition of cleaved NLRP1B triggers its degradation and liberates the CARD domain to activate caspase-1.\",\n      \"evidence\": \"Two independent genome-wide screens (siRNA and CRISPR), ubiquitination assays identifying UBE2O as E2 partner\",\n      \"pmids\": [\"31268597\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether UBR2 activates other inflammasome sensors via N-degron recognition unknown\", \"Structural basis of NLRP1B neo-N-terminus recognition not resolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Discovery that UBR2 is itself regulated by K48-linked polyubiquitination and proteasomal turnover under basal conditions, with stabilization under ER stress conferring cytoprotection, established UBR2 as an ER stress-responsive factor.\",\n      \"evidence\": \"K48-linkage-specific ubiquitination assays, UBR1/UBR2 double KO cells hypersensitive to ER stress-induced apoptosis\",\n      \"pmids\": [\"38376480\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The E3 ligase responsible for UBR2 degradation under basal conditions was not identified in this study\", \"Cytoprotective substrates of UBR2 during ER stress unknown\", \"Single-lab finding awaiting independent confirmation\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identification of UBR2 as a K63-linked ubiquitin ligase for Lck at defined residues, regulated by DUSP22-mediated dephosphorylation and SCF-dependent degradation, placed UBR2 in TCR signaling and inflammatory cytokine production.\",\n      \"evidence\": \"K63-specific ubiquitination assays, Lck mutagenesis, DUSP22/UBR2 double KO epistasis, scRNA-seq in T cells\",\n      \"pmids\": [\"38225265\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether UBR2 K63-ubiquitination of Lck involves N-degron recognition unknown\", \"Upstream signals activating UBR2 phosphorylation in T cells not identified\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"No structural model of mammalian UBR2 exists, the full repertoire of physiological substrates across tissues remains undefined, and how its N-degron recognition, scaffold E3, and K63-ligase activities are coordinately regulated is unknown.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No crystal or cryo-EM structure of mammalian UBR2\", \"Systematic substrate identification across cell types not performed\", \"Regulatory post-translational modifications beyond DUSP22-mediated dephosphorylation not mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 2, 5, 6, 9, 11, 12, 15]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [0, 2, 5, 9, 12, 15]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [5, 9]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [7, 13]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [7, 14]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [5, 9]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [6, 14]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [5, 9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 2, 6, 9, 12, 15]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [12, 15]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [3, 9]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [12, 13]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [7, 15]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [5, 9]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [14]},\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [0, 5, 8]}\n    ],\n    \"complexes\": [\n      \"UBR2-HR6B (E3-E2 complex)\",\n      \"Mub1-Ubr2 (yeast kinetochore QC complex)\",\n      \"RECQL4-UBR2\"\n    ],\n    \"partners\": [\n      \"HR6B\",\n      \"RECQL4\",\n      \"TEX19\",\n      \"NLRP1\",\n      \"UBE2O\",\n      \"LCK\",\n      \"DUSP22\",\n      \"CEBPB\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}