{"gene":"UBE2G1","run_date":"2026-06-10T10:51:56","timeline":{"discoveries":[{"year":2018,"finding":"UBE2G1 plays a distinct role from UBE2D3 in substrate ubiquitination by CRL4CRBN: UBE2D3 acts to prime targets via monoubiquitination while UBE2G1 functions to extend polyubiquitin chains with lysine 48 linkages, as established by CRISPR-Cas9 genome-wide screening and functional validation.","method":"Genome-wide CRISPR-Cas9 screen with IKZF3 degron reporter, functional validation of E2 roles in CRL4CRBN-mediated substrate ubiquitination","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR screen plus functional validation with defined molecular readout, replicated in a second CRISPR screen (PMID:31300418)","pmids":["30042095","31300418"],"is_preprint":false},{"year":2011,"finding":"UBE2G1 (and UBE2G2), members of the UBE2G family, cooperate with the CRL4(Cdt2) E3 ubiquitin ligase to polyubiquitylate and degrade the replication licensing factor Cdt1 after UV irradiation, an activity critical for preventing origin re-licensing in DNA-damaged cells. In contrast, UBE2G1 was not required for CRL4(Cdt2)-mediated ubiquitylation of p21 or Set8, nor for PCNA monoubiquitylation.","method":"siRNA knockdown, proteomic analysis of Cdt2-associated proteins, in vivo ubiquitylation assays, cell cycle analysis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal proteomic identification plus siRNA depletion with defined substrate-specific phenotypic readouts and multiple substrates tested","pmids":["21628527"],"is_preprint":false},{"year":2014,"finding":"Ube2g1 synthesizes Lys-48-linked polyubiquitin chains without an E3 ligase; Tyr-102 and Tyr-104 in its acidic loop enhance ubiquitin binding and Lys-48-ubiquitylation activity, distinguishing Ube2g1 from the truncated form of Ube2r1. Intramolecular interaction between the acidic loop and the attached donor ubiquitin regulates this activity.","method":"In vitro ubiquitylation assays, NMR spectroscopy with oxyester and disulfide E2~UB thioester mimics, site-directed mutagenesis of acidic loop residues","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution combined with NMR structural analysis and mutagenesis in a single rigorous study","pmids":["25471371"],"is_preprint":false},{"year":2019,"finding":"A ubiquitin variant (UbV) targeting the backside of Ube2G1 (opposite the active site) impeded the generation of thioester-linked ubiquitin at the active-site cysteine of Ube2G1 by the E1 enzyme, indicating that the E2 backside is required for efficient E1-mediated charging of Ube2G1.","method":"Phage display selection of UbVs, crystal structure of UbV–Ube2G1 complex, in vitro charging assays","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure plus functional in vitro charging assay with defined inhibitory mechanism in one rigorous study","pmids":["31634471"],"is_preprint":false},{"year":2019,"finding":"UBE2G1 has robust in vitro K48-linked chain extension activity with SCF cullin-RING ligases and buffers against the loss of UBE2R1/2 in human cells; UBE2G1 knockdown in cells lacking UBE2R1/2 results in stabilization of SCF substrates p27 and CYCLIN E, and the CUL2-RING ligase substrate HIF1α.","method":"Genome-wide CRISPR screen, in vitro ubiquitylation reconstitution with purified proteins, mass spectrometry-based quantification of E2 levels, siRNA knockdown with substrate stability readouts","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro reconstitution at physiological concentrations plus CRISPR screen plus siRNA knockdown with multiple substrate readouts","pmids":["31868589"],"is_preprint":false},{"year":2021,"finding":"CUL2LRR1 uses UBE2G1 (or UBE2G2) to extend a single K48-linked ubiquitin chain on CMG helicase MCM7 subunit after initial monoubiquitylation by UBE2D-class E2 enzymes, converting CMG into a substrate for p97 during DNA replication termination.","method":"In vitro reconstitution of CMG-MCM7 ubiquitylation with purified human proteins including neddylated CUL2LRR1 and a panel of E2 enzymes","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — biochemical reconstitution with purified components and defined chain-linkage specificity in a single rigorous study","pmids":["34195792"],"is_preprint":false},{"year":2006,"finding":"UBE2G1 cannot substitute for E2-25K (UBE2K) in supporting US11-triggered retro-translocation and polyubiquitination of MHC class I heavy chains in a permeabilized cell system, even though the related enzyme HsUbc7/Ube2G2 participates in ERAD.","method":"Permeabilized cell system with fractionated cytosol substitution, purified recombinant E2 complementation assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean biochemical complementation assay but this is a negative result (UBE2G1 unable to substitute) in a single study","pmids":["16868077"],"is_preprint":false},{"year":2024,"finding":"UBE2G1 forms a complex with the RING-type E3 ligase TRAF7 and mediates K48-linked polyubiquitination and proteasomal degradation of the circadian transcription factor DBP, thereby contributing to circadian period determination.","method":"Dominant-negative E2 screen (19 E2s), proteomic analysis of DBP-interacting proteins, co-immunoprecipitation, ubiquitination assay in cultured cells, TRAF7 overexpression/knockdown/knockout","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — dominant-negative screen identified UBE2G1, co-IP confirmed TRAF7 complex, cell-based ubiquitination assay confirmed K48 linkage; single lab but multiple orthogonal methods","pmids":["39379486"],"is_preprint":false},{"year":1996,"finding":"UBE2G1 (originally named UBE2G) encodes a human ubiquitin-conjugating enzyme of 170 amino acids with 74% identity to C. elegans UBC7, strongly expressed in skeletal muscle, and maps to chromosome 17p13.3.","method":"cDNA cloning from fetal brain library, Northern blot, radiation-hybrid mapping","journal":"Cytogenetics and cell genetics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — original molecular cloning with tissue expression and chromosomal localization; sequence-based identification replicated by subsequent studies","pmids":["8893823"],"is_preprint":false},{"year":2010,"finding":"siRNA-mediated knockdown of Ube2g1 (together with Ube2i) in neonatal rat cardiomyocytes causes downregulation of α- and β-myosin heavy chain expression, disruption of sarcomere structures, and increased PRMT-I expression and ADMA synthesis, implicating Ube2g1 in maintaining cardiomyocyte sarcomere integrity via the ubiquitin-proteasome system.","method":"siRNA knockdown in primary neonatal rat cardiomyocytes, immunofluorescence for sarcomere structure, Western blot for myosin heavy chains and PRMT-I, ADMA measurement","journal":"European heart journal","confidence":"Low","confidence_rationale":"Tier 3 / Weak — siRNA knockdown was of both Ube2g1 and Ube2i simultaneously, so individual contributions cannot be separated; single study","pmids":["20965886"],"is_preprint":false},{"year":2026,"finding":"Elevated levels of Ube2g1 in young murine hematopoietic stem cells (HSCs) recapitulate hematopoietic aging hallmarks (increased myeloid-to-lymphoid ratio, reduced naïve T cells). Mechanistically, the effect was mediated through a Ube2g1–Shp2 axis that altered global tyrosine phosphorylation, rather than primarily through Ube2g1's ubiquitination function.","method":"Lentiviral overexpression of Ube2g1 in murine HSCs, bone marrow transplantation, flow cytometry for lineage output, phosphoproteomics/tyrosine phosphorylation analysis, Shp2 interaction studies","journal":"Haematologica","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — defined in vivo phenotype with mechanistic dissection of ubiquitination vs. phosphorylation axis; single study, no independent replication yet","pmids":["41641641"],"is_preprint":false}],"current_model":"UBE2G1 is a Lys-48-chain-extending E2 ubiquitin-conjugating enzyme that works downstream of an initial monoubiquitination step (performed by UBE2D-class E2s) to build K48-linked polyubiquitin chains on substrates of multiple cullin-RING ligases (CRL4CRBN, CRL4Cdt2, SCF, CUL2LRR1), with its acidic-loop tyrosines (Y102/Y104) mediating intramolecular donor-ubiquitin engagement required for efficient chain synthesis, and its backside surface required for E1-mediated charging; it also partners with the RING E3 TRAF7 to degrade the circadian factor DBP, and elevated levels in hematopoietic stem cells drive aging-like phenotypes partly through a non-canonical Shp2-mediated tyrosine phosphorylation axis."},"narrative":{"mechanistic_narrative":"UBE2G1 is a ubiquitin-conjugating (E2) enzyme that builds Lys-48-linked polyubiquitin chains, functioning as a dedicated chain-extending E2 downstream of an initial priming step performed by UBE2D-class enzymes for substrates of multiple cullin-RING ligases [PMID:30042095, PMID:31300418, PMID:34195792]. Across CRL4CRBN, CRL4Cdt2, SCF, and CUL2LRR1 complexes, UBE2G1 extends K48 chains on targets including IKZF3, the replication licensing factor Cdt1, the SCF substrates p27 and Cyclin E, the CUL2-RING substrate HIF1α, and the CMG helicase subunit MCM7, thereby committing these substrates to proteasomal degradation [PMID:30042095, PMID:31300418, PMID:21628527, PMID:31868589, PMID:34195792]. Its catalytic behavior is intrinsic: UBE2G1 can synthesize K48-linked chains autonomously in vitro, with acidic-loop tyrosines Tyr-102 and Tyr-104 promoting donor-ubiquitin engagement required for efficient chain synthesis, while the E2 backside surface (opposite the active site) is required for E1-mediated charging at the active-site cysteine [PMID:25471371, PMID:31634471]. Beyond cullin-RING ligases, UBE2G1 partners with the RING E3 TRAF7 to direct K48-linked polyubiquitination and degradation of the circadian transcription factor DBP, contributing to circadian period determination [PMID:39379486]. UBE2G1 has substrate-selective limits within ERAD-type degradation, as it cannot substitute for UBE2K in supporting US11-triggered retro-translocation and ubiquitination of MHC class I heavy chains [PMID:16868077].","teleology":[{"year":1996,"claim":"Established the molecular identity of UBE2G1 as a human ubiquitin-conjugating enzyme, providing the gene and protein foundation for all subsequent mechanistic work.","evidence":"cDNA cloning from fetal brain library, Northern blot, radiation-hybrid mapping","pmids":["8893823"],"confidence":"Medium","gaps":["No enzymatic activity or substrate defined","Tissue expression descriptive only, no functional role assigned"]},{"year":2006,"claim":"Tested whether UBE2G1 is interchangeable with other E2s in ERAD, showing it cannot substitute for UBE2K in US11-driven MHC class I degradation and thereby establishing substrate/pathway selectivity among related E2s.","evidence":"Permeabilized cell complementation with fractionated cytosol and purified recombinant E2s","pmids":["16868077"],"confidence":"Medium","gaps":["Negative result in a single system","Does not define which pathways UBE2G1 does support"]},{"year":2011,"claim":"Identified the first physiological CRL substrate context for UBE2G1, showing it cooperates with CRL4(Cdt2) to polyubiquitylate and degrade Cdt1 after UV, linking the enzyme to prevention of origin re-licensing.","evidence":"siRNA knockdown, proteomic analysis of Cdt2-associated proteins, in vivo ubiquitylation and cell-cycle assays","pmids":["21628527"],"confidence":"High","gaps":["Selectivity unexplained: not required for p21, Set8, or PCNA ubiquitylation","Did not resolve chain-priming versus chain-extension role"]},{"year":2014,"claim":"Resolved the intrinsic catalytic mechanism, demonstrating E3-independent K48 chain synthesis and defining acidic-loop tyrosines Y102/Y104 as donor-ubiquitin engagement determinants.","evidence":"In vitro ubiquitylation, NMR with E2~Ub thioester mimics, acidic-loop mutagenesis","pmids":["25471371"],"confidence":"High","gaps":["In vitro intrinsic activity not yet linked to a specific E3-driven cellular context","Acceptor-ubiquitin positioning not structurally resolved"]},{"year":2018,"claim":"Established the division of labor with UBE2D3 on CRL4CRBN substrates, showing UBE2D3 primes by monoubiquitination while UBE2G1 extends K48 chains, defining UBE2G1 as a dedicated chain-elongating E2.","evidence":"Genome-wide CRISPR-Cas9 screen with IKZF3 degron reporter plus functional E2 validation","pmids":["30042095","31300418"],"confidence":"High","gaps":["Mechanism of handoff between priming and extension E2s not detailed","Scope across other CRLs not yet tested here"]},{"year":2019,"claim":"Generalized the chain-extension role beyond CRL4 to SCF and CUL2 ligases and revealed redundancy with UBE2R1/2, while a second study defined the E2 backside as required for E1-mediated charging.","evidence":"CRISPR screen, in vitro reconstitution at physiological concentrations, siRNA with p27/CyclinE/HIF1α readouts; phage-display UbV plus crystal structure and charging assays","pmids":["31868589","31634471"],"confidence":"High","gaps":["Determinants of UBE2G1 versus UBE2R1/2 selection among substrates unclear","Backside-charging finding from inhibitory UbV, not a native partner"]},{"year":2021,"claim":"Demonstrated UBE2G1 acts in DNA replication termination, extending a K48 chain on monoubiquitylated CMG-MCM7 by CUL2LRR1 to convert CMG into a p97 substrate, integrating its extension role into replisome disassembly.","evidence":"In vitro reconstitution with purified human proteins including neddylated CUL2LRR1 and an E2 panel","pmids":["34195792"],"confidence":"High","gaps":["In vivo requirement in human cells not established here","Redundancy with UBE2G2 not quantitatively resolved"]},{"year":2024,"claim":"Extended UBE2G1's reach beyond cullin-RING ligases by pairing it with the RING E3 TRAF7 to degrade the circadian factor DBP, linking the enzyme to clock period control.","evidence":"Dominant-negative E2 screen, DBP interactome proteomics, co-IP, cell-based K48 ubiquitination assay, TRAF7 overexpression/knockdown/knockout","pmids":["39379486"],"confidence":"Medium","gaps":["Whether priming E2 is required upstream of TRAF7 not addressed","Single-lab characterization of the TRAF7–DBP axis"]},{"year":2026,"claim":"Uncovered a non-canonical, ubiquitination-independent function in which elevated Ube2g1 drives hematopoietic aging hallmarks through a Ube2g1–Shp2 tyrosine-phosphorylation axis.","evidence":"Lentiviral Ube2g1 overexpression in murine HSCs, bone marrow transplantation, lineage flow cytometry, phosphoproteomics, Shp2 interaction studies","pmids":["41641641"],"confidence":"Medium","gaps":["Molecular basis of the Ube2g1–Shp2 interaction undefined","Single study without independent replication","Relationship to canonical E2 activity not reconciled"]},{"year":null,"claim":"How UBE2G1 is selected over redundant chain-extending E2s (UBE2R1/2, UBE2G2) for specific substrates and ligases, and how its canonical K48-extension activity relates to the non-canonical Shp2 phosphorylation axis, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of UBE2G1 with a cognate cullin-RING ligase","Rules governing priming-E2 to extension-E2 handoff unknown","Physiological significance of the cardiomyocyte and HSC phenotypes not mechanistically separated from confounders"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,2,4,5,7]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[2,4]}],"localization":[],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,4,5,7]},{"term_id":"R-HSA-69306","term_label":"DNA Replication","supporting_discovery_ids":[1,5]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[1,4]},{"term_id":"R-HSA-9909396","term_label":"Circadian clock","supporting_discovery_ids":[7]}],"complexes":[],"partners":["TRAF7","CUL2","LRR1","CRBN","CDT2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P62253","full_name":"Ubiquitin-conjugating enzyme E2 G1","aliases":["E2 ubiquitin-conjugating enzyme G1","E217K","UBC7","Ubiquitin carrier protein G1","Ubiquitin-protein ligase G1"],"length_aa":170,"mass_kda":19.5,"function":"Accepts ubiquitin from the E1 complex and catalyzes its covalent attachment to other proteins. In vitro catalyzes 'Lys-48'-, as well as 'Lys-63'-linked polyubiquitination. May be involved in degradation of muscle-specific proteins. Mediates polyubiquitination of CYP3A4","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/P62253/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/UBE2G1","classification":"Not Classified","n_dependent_lines":21,"n_total_lines":1208,"dependency_fraction":0.0173841059602649},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"UBA52","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/UBE2G1","total_profiled":1310},"omim":[{"mim_id":"603124","title":"UBIQUITIN-CONJUGATING ENZYME E2 G2; UBE2G2","url":"https://www.omim.org/entry/603124"},{"mim_id":"602958","title":"SERUM/GLUCOCORTICOID-REGULATED KINASE 1; SGK1","url":"https://www.omim.org/entry/602958"},{"mim_id":"602434","title":"ANCIENT UBIQUITOUS PROTEIN 1; AUP1","url":"https://www.omim.org/entry/602434"},{"mim_id":"601569","title":"UBIQUITIN-CONJUGATING ENZYME E2 G1; UBE2G1","url":"https://www.omim.org/entry/601569"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"skeletal muscle","ntpm":190.2}],"url":"https://www.proteinatlas.org/search/UBE2G1"},"hgnc":{"alias_symbol":["UBC7"],"prev_symbol":["UBE2G"]},"alphafold":{"accession":"P62253","domains":[{"cath_id":"3.10.110.10","chopping":"4-166","consensus_level":"high","plddt":94.8865,"start":4,"end":166}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P62253","model_url":"https://alphafold.ebi.ac.uk/files/AF-P62253-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P62253-F1-predicted_aligned_error_v6.png","plddt_mean":94.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=UBE2G1","jax_strain_url":"https://www.jax.org/strain/search?query=UBE2G1"},"sequence":{"accession":"P62253","fasta_url":"https://rest.uniprot.org/uniprotkb/P62253.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P62253/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P62253"}},"corpus_meta":[{"pmid":"20965886","id":"PMC_20965886","title":"Signal transducer and activator 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alterations","date":"2025-04-01","source":"bioRxiv","url":"https://doi.org/10.1101/2025.03.31.25324887","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":20276,"output_tokens":3068,"usd":0.053424,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10328,"output_tokens":3494,"usd":0.069495,"stage2_stop_reason":"end_turn"},"total_usd":0.122919,"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\": 2018,\n      \"finding\": \"UBE2G1 plays a distinct role from UBE2D3 in substrate ubiquitination by CRL4CRBN: UBE2D3 acts to prime targets via monoubiquitination while UBE2G1 functions to extend polyubiquitin chains with lysine 48 linkages, as established by CRISPR-Cas9 genome-wide screening and functional validation.\",\n      \"method\": \"Genome-wide CRISPR-Cas9 screen with IKZF3 degron reporter, functional validation of E2 roles in CRL4CRBN-mediated substrate ubiquitination\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR screen plus functional validation with defined molecular readout, replicated in a second CRISPR screen (PMID:31300418)\",\n      \"pmids\": [\"30042095\", \"31300418\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"UBE2G1 (and UBE2G2), members of the UBE2G family, cooperate with the CRL4(Cdt2) E3 ubiquitin ligase to polyubiquitylate and degrade the replication licensing factor Cdt1 after UV irradiation, an activity critical for preventing origin re-licensing in DNA-damaged cells. In contrast, UBE2G1 was not required for CRL4(Cdt2)-mediated ubiquitylation of p21 or Set8, nor for PCNA monoubiquitylation.\",\n      \"method\": \"siRNA knockdown, proteomic analysis of Cdt2-associated proteins, in vivo ubiquitylation assays, cell cycle analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal proteomic identification plus siRNA depletion with defined substrate-specific phenotypic readouts and multiple substrates tested\",\n      \"pmids\": [\"21628527\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Ube2g1 synthesizes Lys-48-linked polyubiquitin chains without an E3 ligase; Tyr-102 and Tyr-104 in its acidic loop enhance ubiquitin binding and Lys-48-ubiquitylation activity, distinguishing Ube2g1 from the truncated form of Ube2r1. Intramolecular interaction between the acidic loop and the attached donor ubiquitin regulates this activity.\",\n      \"method\": \"In vitro ubiquitylation assays, NMR spectroscopy with oxyester and disulfide E2~UB thioester mimics, site-directed mutagenesis of acidic loop residues\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution combined with NMR structural analysis and mutagenesis in a single rigorous study\",\n      \"pmids\": [\"25471371\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"A ubiquitin variant (UbV) targeting the backside of Ube2G1 (opposite the active site) impeded the generation of thioester-linked ubiquitin at the active-site cysteine of Ube2G1 by the E1 enzyme, indicating that the E2 backside is required for efficient E1-mediated charging of Ube2G1.\",\n      \"method\": \"Phage display selection of UbVs, crystal structure of UbV–Ube2G1 complex, in vitro charging assays\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure plus functional in vitro charging assay with defined inhibitory mechanism in one rigorous study\",\n      \"pmids\": [\"31634471\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"UBE2G1 has robust in vitro K48-linked chain extension activity with SCF cullin-RING ligases and buffers against the loss of UBE2R1/2 in human cells; UBE2G1 knockdown in cells lacking UBE2R1/2 results in stabilization of SCF substrates p27 and CYCLIN E, and the CUL2-RING ligase substrate HIF1α.\",\n      \"method\": \"Genome-wide CRISPR screen, in vitro ubiquitylation reconstitution with purified proteins, mass spectrometry-based quantification of E2 levels, siRNA knockdown with substrate stability readouts\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro reconstitution at physiological concentrations plus CRISPR screen plus siRNA knockdown with multiple substrate readouts\",\n      \"pmids\": [\"31868589\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CUL2LRR1 uses UBE2G1 (or UBE2G2) to extend a single K48-linked ubiquitin chain on CMG helicase MCM7 subunit after initial monoubiquitylation by UBE2D-class E2 enzymes, converting CMG into a substrate for p97 during DNA replication termination.\",\n      \"method\": \"In vitro reconstitution of CMG-MCM7 ubiquitylation with purified human proteins including neddylated CUL2LRR1 and a panel of E2 enzymes\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — biochemical reconstitution with purified components and defined chain-linkage specificity in a single rigorous study\",\n      \"pmids\": [\"34195792\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"UBE2G1 cannot substitute for E2-25K (UBE2K) in supporting US11-triggered retro-translocation and polyubiquitination of MHC class I heavy chains in a permeabilized cell system, even though the related enzyme HsUbc7/Ube2G2 participates in ERAD.\",\n      \"method\": \"Permeabilized cell system with fractionated cytosol substitution, purified recombinant E2 complementation assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean biochemical complementation assay but this is a negative result (UBE2G1 unable to substitute) in a single study\",\n      \"pmids\": [\"16868077\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"UBE2G1 forms a complex with the RING-type E3 ligase TRAF7 and mediates K48-linked polyubiquitination and proteasomal degradation of the circadian transcription factor DBP, thereby contributing to circadian period determination.\",\n      \"method\": \"Dominant-negative E2 screen (19 E2s), proteomic analysis of DBP-interacting proteins, co-immunoprecipitation, ubiquitination assay in cultured cells, TRAF7 overexpression/knockdown/knockout\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — dominant-negative screen identified UBE2G1, co-IP confirmed TRAF7 complex, cell-based ubiquitination assay confirmed K48 linkage; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"39379486\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"UBE2G1 (originally named UBE2G) encodes a human ubiquitin-conjugating enzyme of 170 amino acids with 74% identity to C. elegans UBC7, strongly expressed in skeletal muscle, and maps to chromosome 17p13.3.\",\n      \"method\": \"cDNA cloning from fetal brain library, Northern blot, radiation-hybrid mapping\",\n      \"journal\": \"Cytogenetics and cell genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — original molecular cloning with tissue expression and chromosomal localization; sequence-based identification replicated by subsequent studies\",\n      \"pmids\": [\"8893823\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"siRNA-mediated knockdown of Ube2g1 (together with Ube2i) in neonatal rat cardiomyocytes causes downregulation of α- and β-myosin heavy chain expression, disruption of sarcomere structures, and increased PRMT-I expression and ADMA synthesis, implicating Ube2g1 in maintaining cardiomyocyte sarcomere integrity via the ubiquitin-proteasome system.\",\n      \"method\": \"siRNA knockdown in primary neonatal rat cardiomyocytes, immunofluorescence for sarcomere structure, Western blot for myosin heavy chains and PRMT-I, ADMA measurement\",\n      \"journal\": \"European heart journal\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — siRNA knockdown was of both Ube2g1 and Ube2i simultaneously, so individual contributions cannot be separated; single study\",\n      \"pmids\": [\"20965886\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Elevated levels of Ube2g1 in young murine hematopoietic stem cells (HSCs) recapitulate hematopoietic aging hallmarks (increased myeloid-to-lymphoid ratio, reduced naïve T cells). Mechanistically, the effect was mediated through a Ube2g1–Shp2 axis that altered global tyrosine phosphorylation, rather than primarily through Ube2g1's ubiquitination function.\",\n      \"method\": \"Lentiviral overexpression of Ube2g1 in murine HSCs, bone marrow transplantation, flow cytometry for lineage output, phosphoproteomics/tyrosine phosphorylation analysis, Shp2 interaction studies\",\n      \"journal\": \"Haematologica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — defined in vivo phenotype with mechanistic dissection of ubiquitination vs. phosphorylation axis; single study, no independent replication yet\",\n      \"pmids\": [\"41641641\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"UBE2G1 is a Lys-48-chain-extending E2 ubiquitin-conjugating enzyme that works downstream of an initial monoubiquitination step (performed by UBE2D-class E2s) to build K48-linked polyubiquitin chains on substrates of multiple cullin-RING ligases (CRL4CRBN, CRL4Cdt2, SCF, CUL2LRR1), with its acidic-loop tyrosines (Y102/Y104) mediating intramolecular donor-ubiquitin engagement required for efficient chain synthesis, and its backside surface required for E1-mediated charging; it also partners with the RING E3 TRAF7 to degrade the circadian factor DBP, and elevated levels in hematopoietic stem cells drive aging-like phenotypes partly through a non-canonical Shp2-mediated tyrosine phosphorylation axis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"UBE2G1 is a ubiquitin-conjugating (E2) enzyme that builds Lys-48-linked polyubiquitin chains, functioning as a dedicated chain-extending E2 downstream of an initial priming step performed by UBE2D-class enzymes for substrates of multiple cullin-RING ligases [#0, #5]. Across CRL4CRBN, CRL4Cdt2, SCF, and CUL2LRR1 complexes, UBE2G1 extends K48 chains on targets including IKZF3, the replication licensing factor Cdt1, the SCF substrates p27 and Cyclin E, the CUL2-RING substrate HIF1\\u03b1, and the CMG helicase subunit MCM7, thereby committing these substrates to proteasomal degradation [#0, #1, #4, #5]. Its catalytic behavior is intrinsic: UBE2G1 can synthesize K48-linked chains autonomously in vitro, with acidic-loop tyrosines Tyr-102 and Tyr-104 promoting donor-ubiquitin engagement required for efficient chain synthesis, while the E2 backside surface (opposite the active site) is required for E1-mediated charging at the active-site cysteine [#2, #3]. Beyond cullin-RING ligases, UBE2G1 partners with the RING E3 TRAF7 to direct K48-linked polyubiquitination and degradation of the circadian transcription factor DBP, contributing to circadian period determination [#7]. UBE2G1 has substrate-selective limits within ERAD-type degradation, as it cannot substitute for UBE2K in supporting US11-triggered retro-translocation and ubiquitination of MHC class I heavy chains [#6].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Established the molecular identity of UBE2G1 as a human ubiquitin-conjugating enzyme, providing the gene and protein foundation for all subsequent mechanistic work.\",\n      \"evidence\": \"cDNA cloning from fetal brain library, Northern blot, radiation-hybrid mapping\",\n      \"pmids\": [\"8893823\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": null,\n      \"gaps\": [\"No enzymatic activity or substrate defined\", \"Tissue expression descriptive only, no functional role assigned\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Tested whether UBE2G1 is interchangeable with other E2s in ERAD, showing it cannot substitute for UBE2K in US11-driven MHC class I degradation and thereby establishing substrate/pathway selectivity among related E2s.\",\n      \"evidence\": \"Permeabilized cell complementation with fractionated cytosol and purified recombinant E2s\",\n      \"pmids\": [\"16868077\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": null,\n      \"gaps\": [\"Negative result in a single system\", \"Does not define which pathways UBE2G1 does support\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identified the first physiological CRL substrate context for UBE2G1, showing it cooperates with CRL4(Cdt2) to polyubiquitylate and degrade Cdt1 after UV, linking the enzyme to prevention of origin re-licensing.\",\n      \"evidence\": \"siRNA knockdown, proteomic analysis of Cdt2-associated proteins, in vivo ubiquitylation and cell-cycle assays\",\n      \"pmids\": [\"21628527\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": null,\n      \"gaps\": [\"Selectivity unexplained: not required for p21, Set8, or PCNA ubiquitylation\", \"Did not resolve chain-priming versus chain-extension role\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Resolved the intrinsic catalytic mechanism, demonstrating E3-independent K48 chain synthesis and defining acidic-loop tyrosines Y102/Y104 as donor-ubiquitin engagement determinants.\",\n      \"evidence\": \"In vitro ubiquitylation, NMR with E2~Ub thioester mimics, acidic-loop mutagenesis\",\n      \"pmids\": [\"25471371\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": null,\n      \"gaps\": [\"In vitro intrinsic activity not yet linked to a specific E3-driven cellular context\", \"Acceptor-ubiquitin positioning not structurally resolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Established the division of labor with UBE2D3 on CRL4CRBN substrates, showing UBE2D3 primes by monoubiquitination while UBE2G1 extends K48 chains, defining UBE2G1 as a dedicated chain-elongating E2.\",\n      \"evidence\": \"Genome-wide CRISPR-Cas9 screen with IKZF3 degron reporter plus functional E2 validation\",\n      \"pmids\": [\"30042095\", \"31300418\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": null,\n      \"gaps\": [\"Mechanism of handoff between priming and extension E2s not detailed\", \"Scope across other CRLs not yet tested here\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Generalized the chain-extension role beyond CRL4 to SCF and CUL2 ligases and revealed redundancy with UBE2R1/2, while a second study defined the E2 backside as required for E1-mediated charging.\",\n      \"evidence\": \"CRISPR screen, in vitro reconstitution at physiological concentrations, siRNA with p27/CyclinE/HIF1\\u03b1 readouts; phage-display UbV plus crystal structure and charging assays\",\n      \"pmids\": [\"31868589\", \"31634471\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": null,\n      \"gaps\": [\"Determinants of UBE2G1 versus UBE2R1/2 selection among substrates unclear\", \"Backside-charging finding from inhibitory UbV, not a native partner\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrated UBE2G1 acts in DNA replication termination, extending a K48 chain on monoubiquitylated CMG-MCM7 by CUL2LRR1 to convert CMG into a p97 substrate, integrating its extension role into replisome disassembly.\",\n      \"evidence\": \"In vitro reconstitution with purified human proteins including neddylated CUL2LRR1 and an E2 panel\",\n      \"pmids\": [\"34195792\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": null,\n      \"gaps\": [\"In vivo requirement in human cells not established here\", \"Redundancy with UBE2G2 not quantitatively resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended UBE2G1's reach beyond cullin-RING ligases by pairing it with the RING E3 TRAF7 to degrade the circadian factor DBP, linking the enzyme to clock period control.\",\n      \"evidence\": \"Dominant-negative E2 screen, DBP interactome proteomics, co-IP, cell-based K48 ubiquitination assay, TRAF7 overexpression/knockdown/knockout\",\n      \"pmids\": [\"39379486\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": null,\n      \"gaps\": [\"Whether priming E2 is required upstream of TRAF7 not addressed\", \"Single-lab characterization of the TRAF7\\u2013DBP axis\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Uncovered a non-canonical, ubiquitination-independent function in which elevated Ube2g1 drives hematopoietic aging hallmarks through a Ube2g1\\u2013Shp2 tyrosine-phosphorylation axis.\",\n      \"evidence\": \"Lentiviral Ube2g1 overexpression in murine HSCs, bone marrow transplantation, lineage flow cytometry, phosphoproteomics, Shp2 interaction studies\",\n      \"pmids\": [\"41641641\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": null,\n      \"gaps\": [\"Molecular basis of the Ube2g1\\u2013Shp2 interaction undefined\", \"Single study without independent replication\", \"Relationship to canonical E2 activity not reconciled\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How UBE2G1 is selected over redundant chain-extending E2s (UBE2R1/2, UBE2G2) for specific substrates and ligases, and how its canonical K48-extension activity relates to the non-canonical Shp2 phosphorylation axis, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": null,\n      \"gaps\": [\"No structural model of UBE2G1 with a cognate cullin-RING ligase\", \"Rules governing priming-E2 to extension-E2 handoff unknown\", \"Physiological significance of the cardiomyocyte and HSC phenotypes not mechanistically separated from confounders\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 2, 4, 5, 7]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [2, 4]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 4, 5, 7]},\n      {\"term_id\": \"R-HSA-69306\", \"supporting_discovery_ids\": [1, 5]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [1, 4]},\n      {\"term_id\": \"R-HSA-9909396\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"TRAF7\", \"CUL2\", \"LRR1\", \"CRBN\", \"CDT2\"]\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":5,"faith_pct":80.0}}