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UBE2G1

Ubiquitin-conjugating enzyme E2 G1 · UniProt P62253

Length
170 aa
Mass
19.5 kDa
Annotated
2026-06-10
30 papers in source corpus 12 papers cited in narrative 11 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 4/5 claims corpus-supported (80%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 1996 Medium

    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

    PMID:8893823

    Open questions at the time
    • No enzymatic activity or substrate defined
    • Tissue expression descriptive only, no functional role assigned
  2. 2006 Medium

    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

    PMID:16868077

    Open questions at the time
    • Negative result in a single system
    • Does not define which pathways UBE2G1 does support
  3. 2011 High

    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

    PMID:21628527

    Open questions at the time
    • Selectivity unexplained: not required for p21, Set8, or PCNA ubiquitylation
    • Did not resolve chain-priming versus chain-extension role
  4. 2014 High

    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

    PMID:25471371

    Open questions at the time
    • In vitro intrinsic activity not yet linked to a specific E3-driven cellular context
    • Acceptor-ubiquitin positioning not structurally resolved
  5. 2018 High

    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

    PMID:30042095 PMID:31300418

    Open questions at the time
    • Mechanism of handoff between priming and extension E2s not detailed
    • Scope across other CRLs not yet tested here
  6. 2019 High

    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

    PMID:31634471 PMID:31868589

    Open questions at the time
    • Determinants of UBE2G1 versus UBE2R1/2 selection among substrates unclear
    • Backside-charging finding from inhibitory UbV, not a native partner
  7. 2021 High

    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

    PMID:34195792

    Open questions at the time
    • In vivo requirement in human cells not established here
    • Redundancy with UBE2G2 not quantitatively resolved
  8. 2024 Medium

    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

    PMID:39379486

    Open questions at the time
    • Whether priming E2 is required upstream of TRAF7 not addressed
    • Single-lab characterization of the TRAF7–DBP axis
  9. 2026 Medium

    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

    PMID:41641641

    Open questions at the time
    • Molecular basis of the Ube2g1–Shp2 interaction undefined
    • Single study without independent replication
    • Relationship to canonical E2 activity not reconciled

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 6 GO:0016740 transferase activity 2
Pathway
R-HSA-392499 Metabolism of proteins 4 R-HSA-1640170 Cell Cycle 2 R-HSA-69306 DNA Replication 2 R-HSA-9909396 Circadian clock 1

Evidence

Reading pass · 11 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2018 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. Genome-wide CRISPR-Cas9 screen with IKZF3 degron reporter, functional validation of E2 roles in CRL4CRBN-mediated substrate ubiquitination Blood High 30042095 31300418
2011 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. siRNA knockdown, proteomic analysis of Cdt2-associated proteins, in vivo ubiquitylation assays, cell cycle analysis Molecular and cellular biology High 21628527
2014 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. In vitro ubiquitylation assays, NMR spectroscopy with oxyester and disulfide E2~UB thioester mimics, site-directed mutagenesis of acidic loop residues The Journal of biological chemistry High 25471371
2019 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. Phage display selection of UbVs, crystal structure of UbV–Ube2G1 complex, in vitro charging assays Journal of molecular biology High 31634471
2019 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. Genome-wide CRISPR screen, in vitro ubiquitylation reconstitution with purified proteins, mass spectrometry-based quantification of E2 levels, siRNA knockdown with substrate stability readouts eLife High 31868589
2021 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. In vitro reconstitution of CMG-MCM7 ubiquitylation with purified human proteins including neddylated CUL2LRR1 and a panel of E2 enzymes The Biochemical journal High 34195792
2006 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. Permeabilized cell system with fractionated cytosol substitution, purified recombinant E2 complementation assay Proceedings of the National Academy of Sciences of the United States of America Medium 16868077
2024 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. Dominant-negative E2 screen (19 E2s), proteomic analysis of DBP-interacting proteins, co-immunoprecipitation, ubiquitination assay in cultured cells, TRAF7 overexpression/knockdown/knockout Communications biology Medium 39379486
1996 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. cDNA cloning from fetal brain library, Northern blot, radiation-hybrid mapping Cytogenetics and cell genetics Medium 8893823
2010 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. siRNA knockdown in primary neonatal rat cardiomyocytes, immunofluorescence for sarcomere structure, Western blot for myosin heavy chains and PRMT-I, ADMA measurement European heart journal Low 20965886
2026 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. Lentiviral overexpression of Ube2g1 in murine HSCs, bone marrow transplantation, flow cytometry for lineage output, phosphoproteomics/tyrosine phosphorylation analysis, Shp2 interaction studies Haematologica Medium 41641641

Source papers

Stage 0 corpus · 30 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 Signal transducer and activator of transcription 3-mediated regulation of miR-199a-5p links cardiomyocyte and endothelial cell function in the heart: a key role for ubiquitin-conjugating enzymes. European heart journal 117 20965886
2018 Genome-wide screen identifies cullin-RING ligase machinery required for lenalidomide-dependent CRL4CRBN activity. Blood 109 30042095
2020 CircRNA-UBE2G1 regulates LPS-induced osteoarthritis through miR-373/HIF-1a axis. Cell cycle (Georgetown, Tex.) 74 32476580
1999 Regulation of components of the ubiquitin system by insulin-like growth factor I and growth hormone in skeletal muscle of rats made catabolic with dexamethasone. Endocrinology 64 10579327
2014 A method for gene-based pathway analysis using genomewide association study summary statistics reveals nine new type 1 diabetes associations. Genetic epidemiology 52 25371288
2013 TWIST1 regulates the activity of ubiquitin proteasome system via the miR-199/214 cluster in human end-stage dilated cardiomyopathy. International journal of cardiology 44 23360823
2011 Selective ubiquitylation of p21 and Cdt1 by UBCH8 and UBE2G ubiquitin-conjugating enzymes via the CRL4Cdt2 ubiquitin ligase complex. Molecular and cellular biology 43 21628527
2019 Robust cullin-RING ligase function is established by a multiplicity of poly-ubiquitylation pathways. eLife 41 31868589
2021 The plasma peptides of Alzheimer's disease. Clinical proteomics 33 34182925
2006 E2-25K mediates US11-triggered retro-translocation of MHC class I heavy chains in a permeabilized cell system. Proceedings of the National Academy of Sciences of the United States of America 31 16868077
2004 Analysis of transcripts from 17p13.3 in medulloblastoma suggests ROX/MNT as a potential tumour suppressor gene. European journal of cancer (Oxford, England : 1990) 29 15519529
2019 Genome-wide CRISPR screens reveal genetic mediators of cereblon modulator toxicity in primary effusion lymphoma. Blood advances 27 31300418
2019 Structural and Functional Analysis of Ubiquitin-based Inhibitors That Target the Backsides of E2 Enzymes. Journal of molecular biology 25 31634471
2014 Differential ubiquitin binding by the acidic loops of Ube2g1 and Ube2r1 enzymes distinguishes their Lys-48-ubiquitylation activities. The Journal of biological chemistry 25 25471371
2015 UBE2B is implicated in myofibrillar protein loss in catabolic C2C12 myotubes. Journal of cachexia, sarcopenia and muscle 24 27239408
2019 Transcriptome profiling of muscle in Nelore cattle phenotypically divergent for the ribeye muscle area. Genomics 22 31351181
1996 Molecular cloning of UBE2G, encoding a human skeletal muscle-specific ubiquitin-conjugating enzyme homologous to UBC7 of C. elegans. Cytogenetics and cell genetics 21 8893823
2022 Integration of RNA-seq and ATAC-seq identifies muscle-regulated hub genes in cattle. Frontiers in veterinary science 18 36032309
2020 Differential expression of microRNAs in the hippocampi of male and female rodents after chronic alcohol administration. Biology of sex differences 18 33228793
2014 Expression analysis of genes of ubiquitin-proteasome protein degradation system in MPTP-induced mice models of early stages of Parkinson's disease. Doklady. Biochemistry and biophysics 17 24993970
2022 UBE2G1 Is a Critical Component of Immune Response to the Infection of Pseudomonas Plecoglossicida in Large Yellow Croaker (Larimichthys crocea). International journal of molecular sciences 13 35955424
2019 MicroRNA-34a Acutely Regulates Synaptic Efficacy in the Adult Dentate Gyrus In Vivo. Molecular neurobiology 13 31754996
2021 Systems biology under heat stress in Indian cattle. Gene 11 34411649
2021 Reconstitution of human CMG helicase ubiquitylation by CUL2LRR1 and multiple E2 enzymes. The Biochemical journal 9 34195792
2020 Bioinformatics enrichment analysis of genes and pathways related to maternal type 1 diabetes associated with adverse fetal outcomes. Journal of diabetes and its complications 8 32046932
2024 Single-cell landscape of alternative polyadenylation in human lymphoid hematopoiesis. Journal of molecular cell biology 7 38982223
2024 TRAF7 determines circadian period through ubiquitination and degradation of DBP. Communications biology 3 39379486
2023 Abundance of proteins and genes associated with nutrient signaling, protein turnover, and transport of amino acids and glucose in fetuses from lactating Holstein cows. Research in veterinary science 2 37321013
2026 Elevated levels of Ube2g1 in hematopoietic stem cells lead to segmental aging of the hematopoietic system. Haematologica 0 41641641
2025 A Preliminary Study of circ-PNPT1/miR-144-3p/UBE2G1 Expression in Placental Tissues and Serum and Its Mechanism in Patients With Gestational Diabetes Mellitus. Molecular reproduction and development 0 40996425

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