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UBE2A

Ubiquitin-conjugating enzyme E2 A · UniProt P49459

Length
152 aa
Mass
17.3 kDa
Annotated
2026-06-10
35 papers in source corpus 13 papers cited in narrative 13 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

UBE2A (RAD6A/HHR6A) is an E2 ubiquitin-conjugating enzyme that channels ubiquitin to distinct E3 ligases to control chromatin modification, DNA damage tolerance, and mitochondrial quality control (PMID:10908344, PMID:23685073, PMID:41495224). Catalysis depends on an active-site glutamine, Q93, which deprotonates the incoming lysine nucleophile to enable ubiquitin transfer from the catalytic cysteine; the pathogenic Q93E substitution selectively blocks this aminolysis step (PMID:30531907). In DNA damage bypass, UBE2A forms an asymmetric ternary complex with a RAD18 dimer in which precise R6BD-mediated juxtaposition of a single RAD18 subunit is required for ligase activity (PMID:10908344, PMID:21967848). With RNF20/RNF40 it monoubiquitinates histone H2B at K120, a reaction allosterically stimulated when RAD6A directly contacts an H2B S112 GlcNAc moiety that raises the nucleophilicity of K120 (PMID:41495224); this histone-ubiquitination activity is further gated by CDK1/2 phosphorylation of Ser120, which boosts conjugating activity and peaks at G2/M (PMID:11953320). UBE2A is also recruited by the hemiRING module of the N-degron E3 ligase UBR4, whose UZI subdomain modestly activates Ub-loaded enzyme (PMID:38182926), and cooperates with the E3 Parkin to ubiquitinate mitochondrial proteins and drive mitophagy required for neuronal function (PMID:23685073). Genetically, UBE2A is an essential maternal factor needed for embryonic development beyond the two-cell stage (PMID:15169909) and is required for hippocampal mGluR-dependent long-term depression and spatial learning (PMID:26476408).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1996 Medium

    Established where UBE2A acts in the cell, linking it physically to transcriptionally active chromatin rather than a diffuse cytoplasmic role.

    Evidence Immunogold electron microscopy and expression profiling in testis

    PMID:8575614

    Open questions at the time
    • Does not identify the histone substrate or the E3 partner mediating chromatin association
    • Functional link to histone modification is contextual, not biochemical
  2. 2000 High

    Defined UBE2A's role in DNA damage tolerance by showing it forms a stable, conserved complex with the E3 ligase RAD18.

    Evidence Co-expression and complex purification in yeast, co-immunoprecipitation, with both paralogs

    PMID:10908344

    Open questions at the time
    • Does not resolve complex stoichiometry or the substrate ubiquitinated
    • No structural detail of the interaction interface
  3. 2002 High

    Revealed cell-cycle regulation of UBE2A activity, connecting CDK phosphorylation of Ser120 to a G2/M peak in histone H2B ubiquitylation.

    Evidence In vitro kinase assay, phosphomimetic/phospho-dead mutagenesis, cell-cycle immunoblot, yeast complementation

    PMID:11953320

    Open questions at the time
    • Structural basis of how Ser120 phosphorylation activates the enzyme not defined
    • Which E3 directs the cell-cycle H2B ubiquitylation not established here
  4. 2003 Medium

    Extended the UBE2A interactome by placing ZNF198 in a UBE2A/RAD18 repair complex with functional consequences for UV response.

    Evidence Yeast two-hybrid, co-immunoprecipitation, UV sensitivity assay

    PMID:12776193

    Open questions at the time
    • Direct vs. indirect ZNF198 association within the complex not dissected
    • Mechanism by which the fusion kinase acts dominant-negatively unresolved
  5. 2004 High

    Demonstrated a developmental requirement, showing maternal UBE2A is essential for embryos to progress past the two-cell stage.

    Evidence Mouse knockout, embryonic development assay, H3 methylation immunostaining control

    PMID:15169909

    Open questions at the time
    • The relevant ubiquitination substrate driving the arrest not identified
    • Redundancy with HR6B complicates assigning a unique molecular target
  6. 2011 High

    Resolved the architecture of the RAD6A–RAD18 ligase, showing an asymmetric RAD6A–(RAD18)2 complex where one R6BD-bearing subunit suffices for activity.

    Evidence Differential subunit tagging, co-IP, in vitro ubiquitin ligase assay, mutagenesis

    PMID:21967848

    Open questions at the time
    • No atomic structure of the ternary complex
    • Functional reason for the asymmetric dimer arrangement unexplained
  7. 2013 High

    Expanded UBE2A function beyond chromatin/DNA repair by showing it partners with Parkin to ubiquitinate mitochondrial proteins and drive mitophagy in neurons.

    Evidence Drosophila and mouse knockouts, patient cells, in vitro and in vivo ubiquitination assays, mitochondrial function assays

    PMID:23685073

    Open questions at the time
    • Specific mitochondrial substrates ubiquitinated by UBE2A–Parkin not enumerated
    • How UBE2A is recruited to depolarized mitochondria unclear
  8. 2015 Medium

    Linked UBE2A loss to a defined synaptic phenotype, placing it in the mGluR-dependent LTD pathway underlying spatial learning.

    Evidence Mouse knockout, Morris water maze, hippocampal LTP/LTD electrophysiology

    PMID:26476408

    Open questions at the time
    • Molecular substrate connecting UBE2A to mGluR-LTD signaling not identified
    • Single lab; mechanism downstream of the conjugating activity unresolved
  9. 2018 High

    Defined the chemical mechanism of ubiquitin transfer, showing Q93 deprotonates the acceptor lysine and that the pathogenic Q93E mutation selectively impairs aminolysis.

    Evidence In vitro ubiquitination, pH-dependent reactivity, chemical rescue with low-pKa amine, active-site mutagenesis, NMR context

    PMID:30531907

    Open questions at the time
    • Whether all E3-directed reactions share this Q93 dependence not tested across partners
    • Structural snapshot of the deprotonation transition state not provided
  10. 2023 Medium

    Identified UBE2A as a mechanosensitive transcriptional regulator that shuttles between nucleus and cytoplasm to control gene expression via histone ubiquitination.

    Evidence DHS-proteomics, nucleocytoplasmic fractionation, live-cell imaging, siRNA, NGS, histone ubiquitination assay

    PMID:37818922

    Open questions at the time
    • Pathway placement relies partly on correlative genomics
    • Mechanism coupling mechanical force to shuttling not defined
  11. 2024 High

    Provided the structural basis of E2–E3 selectivity, showing UBE2A is captured by the hemiRING module of UBR4 in the N-degron pathway.

    Evidence Cryo-EM of UBE2A–UBR4 complex, mutagenesis, in vitro ubiquitination

    PMID:38182926

    Open questions at the time
    • Physiological N-degron substrates handled through this complex in cells not catalogued
    • Extent of UZI-mediated activation relative to other E3s unclear
  12. 2026 High

    Explained allosteric control of H2B ubiquitylation, showing an H2B S112 GlcNAc directly contacts RAD6A to enhance K120 nucleophilicity.

    Evidence Cryo-EM of trapped RNF20/RNF40–RAD6A–Ub–H2BS112GlcNAc nucleosome, kinetics, mutagenesis, GlcNAc SAR

    PMID:41495224

    Open questions at the time
    • Cellular conditions controlling H2B S112 GlcNAcylation not defined
    • Crosstalk with Ser120 phosphorylation in the same reaction not integrated

Open questions

Synthesis pass · forward-looking unresolved questions
  • How UBE2A's multiple regulatory inputs — Ser120 phosphorylation, H2B GlcNAc allostery, and E3 partner identity — are coordinated to select among its chromatin, repair, and mitophagy roles in vivo remains unresolved.
  • No unifying model integrating cell-cycle, mechanosensing, and substrate-specific cues
  • Substrate-level distinction between UBE2A and paralog UBE2B in each pathway not fully resolved

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 3 GO:0031386 protein tag activity 2
Localization
GO:0005634 nucleus 2 GO:0000228 nuclear chromosome 1 GO:0005829 cytosol 1
Pathway
R-HSA-4839726 Chromatin organization 3 R-HSA-392499 Metabolism of proteins 2 R-HSA-73894 DNA Repair 2 R-HSA-1640170 Cell Cycle 1 R-HSA-9612973 Autophagy 1
Partners
PARKINRAD18RNF20RNF40UBR4ZNF198
Complex memberships
RAD6A–RAD18 (RAD6A–(RAD18)2) lesion-bypass complexRNF20/RNF40–RAD6A H2B ubiquitylation complexUBE2A–UBR4 E2–E3 N-degron complex

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 hHR6A (UBE2A) is phosphorylated by CDK1 and CDK2 on Ser120, resulting in a 4-fold increase in ubiquitin-conjugating activity in vitro; in vivo, phosphorylation peaks during G2/M phase with a concomitant increase in histone H2B ubiquitylation; mutation of Ser120 to alanine abolished activity while aspartate substitution (phosphomimetic) increased activity ~3-fold; genetic complementation in S. cerevisiae confirmed Ser120 is critical for cellular proliferation. Solid-phase phosphorylation screen, in vitro kinase assay, site-directed mutagenesis, cell cycle synchronization/immunoblot, yeast complementation The EMBO journal High 11953320
2000 Human RAD18 protein physically interacts with HHR6A (UBE2A) and HHR6B; co-expressed in yeast cells, stable RAD18–HHR6A and RAD18–HHR6B complexes were purified to near homogeneity, indicating UBE2A participates in a conserved RAD6–RAD18 lesion bypass complex. Co-expression in yeast, protein complex purification, co-immunoprecipitation Nucleic acids research High 10908344
2011 RAD6A (UBE2A) forms an asymmetric ternary complex with a RAD18 dimer (RAD6A–(RAD18)₂); only one of the two RAD18 subunits needs its RAD6-binding domain (R6BD) for complex formation and ligase activity; loss of both R6BDs abolishes activity even at high RAD6A concentrations, indicating that precise juxtaposition via R6BD is required; mutations in both RING or SAP domains strongly reduce activity, but inactivation of only one subunit is without effect. Differential tagging of RAD18 subunits, co-immunoprecipitation, in vitro ubiquitin ligase assay, site-directed mutagenesis Nucleic acids research High 21967848
2013 RAD6A (UBE2A) acts as an E2 ubiquitin-conjugating enzyme that, together with the E3 ligase Parkin, ubiquitinates mitochondrial proteins to facilitate clearance of dysfunctional mitochondria (mitophagy); Drosophila dRad6-deficient neurons show mitochondrial failure and synaptic dysfunction; mouse Ube2a KO and patient-derived mutant cells show defective mitochondria; in vitro and in vivo ubiquitination assays confirmed UBE2A–Parkin functional cooperation. Drosophila dRad6 knockout, mouse Ube2a knockout, patient-derived cell lines, in vitro ubiquitination assay, in vivo ubiquitination assay, mitochondrial function assays Molecular cell High 23685073
2003 ZNF198 protein interacts with HHR6A (UBE2A) and HHR6B as identified by yeast two-hybrid and confirmed by co-immunoprecipitation; human RAD18 is also present in the ZNF198/HHR6 protein complex; cells expressing the ZNF198/FGFR1 fusion kinase show increased UVB sensitivity, suggesting the fusion acts dominant-negatively on the DNA repair complex. Yeast two-hybrid, co-immunoprecipitation, UV sensitivity assay Oncogene Medium 12776193
1996 HHR6A (UBE2A) protein localizes to the nucleus, with preferential localization to euchromatin (transcriptionally active regions) as shown by immunogold electron microscopy; elevated expression in testis coincides with the replacement of histones by transition proteins, supporting a role in ubiquitin-mediated histone modification during spermatogenesis. Immunohistochemistry, immunogold electron microscopy, 2D immunoblot, Northern blot Developmental biology Medium 8575614
2004 mHR6A (Ube2a) is an essential maternal factor; mHR6A knockout females fail to produce offspring because oocyte-derived mHR6A is required for embryonic development beyond the two-cell stage; loss does not alter histone H3 methylation at this stage, but reveals a dose-dependent and redundant requirement for HR6A and HR6B in both somatic and germline cells. Mouse knockout, histological analysis, embryonic development assay, histone H3 methylation immunostaining Molecular and cellular biology High 15169909
2018 The pathogenic Q93E mutation in UBE2A impairs aminolysis (ubiquitin transfer to lysine) without preventing ubiquitin conjugation to the catalytic cysteine; the low reactivity is not rescued by the E3 ligase RAD18 in the context of PCNA ubiquitination; reactivity is restored at high pH or with a low-pKa amine nucleophile, indicating Q93 is essential for deprotonating the incoming lysine to enable ubiquitin transfer. In vitro ubiquitination assay, pH-dependent reactivity assay, chemical rescue with low-pKa amine, active-site mutagenesis, NMR (structural context noted) Nature chemical biology High 30531907
2015 Ube2a knockout mice show a major deficit in spatial learning but normal motor coordination and epilepsy thresholds; hippocampal electrophysiology reveals no deficit in basal synaptic transmission or LTP but a significant deficit in mGluR-dependent long-term depression (LTD), placing UBE2A in the mGluR-LTD signaling pathway relevant to neurodevelopmental disorders. Mouse Ube2a knockout, Morris water maze, hippocampal electrophysiology (LTP, mGluR-LTD recording) Human molecular genetics Medium 26476408
2024 UBE2A is specifically recruited by a hemiRING zinc finger module within the E3 ligase UBR4; cryo-EM structure of the UBE2A–UBR4 E2–E3 complex reveals atomic-level specificity determinants of the hemiRING for UBE2A/UBE2B; the UZI subdomain allosterically and modestly activates Ub-loaded UBE2A; the intrinsically high lysine reactivity of UBE2A cooperates with this activation to determine substrate specificity in the N-degron pathway. Cryo-EM structure determination, in vitro ubiquitination assay, mutagenesis, biochemical interaction assays Nature structural & molecular biology High 38182926
2026 Cryo-EM structure of a chemically trapped RNF20/RNF40–RAD6A(UBE2A)–Ub–H2BS112GlcNAc nucleosome complex shows that the H2BS112GlcNAc moiety directly contacts the E2 enzyme RAD6A (not the E3); mutagenesis and kinetics demonstrate that this interaction allosterically enhances the nucleophilicity of H2B K120, stimulating ubiquitin transfer; structure–activity analysis identified essential roles for the C2 N-acetyl group and β-configuration of C1 of the GlcNAc moiety. Chemical synthesis of GlcNAc-modified nucleosomes, cryo-EM, in vitro ubiquitination kinetics, mutagenesis, structure–activity relationship analysis Nature chemical biology High 41495224
2023 UBE2A/B undergoes force- and contact-inhibition-dependent nucleocytoplasmic shuttling, identified as a mechanosensing transcriptional trans-acting factor; DHS-proteomics and next-generation sequencing showed that UBE2A/B regulates downstream gene expression (including YAP target genes) through histone ubiquitination, defining a YAP-independent mechanotransduction/contact-inhibition pathway. DHS-proteomics, nucleocytoplasmic fractionation, live-cell imaging, siRNA knockdown, next-generation sequencing, histone ubiquitination assay The Biochemical journal Medium 37818922
2019 De novo UBE2A mutations acquired during chronic myeloid leukemia progression to blast crisis decrease UBE2A ubiquitin-conjugating activity in vitro, leading to impaired myeloid differentiation in CML cells. In vitro ubiquitin-conjugating activity assay, CML cell differentiation assay, parallel sequencing of patient samples Haematologica Medium 30819912

Source papers

Stage 0 corpus · 35 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2016 Deficiency in the Ubiquitin Conjugating Enzyme UBE2A in Alzheimer's Disease (AD) is Linked to Deficits in a Natural Circular miRNA-7 Sponge (circRNA; ciRS-7). Genes 268 27929395
2004 The ubiquitin-conjugating DNA repair enzyme HR6A is a maternal factor essential for early embryonic development in mice. Molecular and cellular biology 99 15169909
2006 UBE2A, which encodes a ubiquitin-conjugating enzyme, is mutated in a novel X-linked mental retardation syndrome. American journal of human genetics 85 16909393
1996 Expression of the ubiquitin-conjugating DNA repair enzymes HHR6A and B suggests a role in spermatogenesis and chromatin modification. Developmental biology 81 8575614
2013 Mutations in the intellectual disability gene Ube2a cause neuronal dysfunction and impair parkin-dependent mitophagy. Molecular cell 75 23685073
2002 Regulation of the ubiquitin-conjugating enzyme hHR6A by CDK-mediated phosphorylation. The EMBO journal 65 11953320
2000 The human RAD18 gene product interacts with HHR6A and HHR6B. Nucleic acids research 61 10908344
1992 Localization of two human homologs, HHR6A and HHR6B, of the yeast DNA repair gene RAD6 to chromosomes Xq24-q25 and 5q23-q31. Genomics 49 1559696
2010 Novel missense mutations in the ubiquitination-related gene UBE2A cause a recognizable X-linked mental retardation syndrome. Clinical genetics 47 20412111
2011 Asymmetric nature of two subunits of RAD18, a RING-type ubiquitin ligase E3, in the human RAD6A-RAD18 ternary complex. Nucleic acids research 32 21967848
2010 UBE2A deficiency syndrome: Mild to severe intellectual disability accompanied by seizures, absent speech, urogenital, and skin anomalies in male patients. American journal of medical genetics. Part A 32 21108393
2017 A novel UBE2A mutation causes X-linked intellectual disability type Nascimento. Human genome variation 27 28611923
2015 An essential role for UBE2A/HR6A in learning and memory and mGLUR-dependent long-term depression. Human molecular genetics 27 26476408
2018 Mechanistic insights revealed by a UBE2A mutation linked to intellectual disability. Nature chemical biology 24 30531907
2010 Novel deletion at Xq24 including the UBE2A gene in a patient with X-linked mental retardation. Journal of human genetics 24 20339384
2019 De novo UBE2A mutations are recurrently acquired during chronic myeloid leukemia progression and interfere with myeloid differentiation pathways. Haematologica 23 30819912
2003 ZNF198 protein, involved in rearrangement in myeloproliferative disease, forms complexes with the DNA repair-associated HHR6A/6B and RAD18 proteins. Oncogene 22 12776193
2024 UBE2A and UBE2B are recruited by an atypical E3 ligase module in UBR4. Nature structural & molecular biology 21 38182926
2014 UBE2A deficiency syndrome: a report of two unrelated cases with large Xq24 deletions encompassing UBE2A gene. American journal of medical genetics. Part A 20 25287747
2017 UBE2A deficiency in two siblings: A novel splicing variant inherited from a maternal germline mosaicism. American journal of medical genetics. Part A 11 29283210
2022 The circular RNA hsa_circ_0001394 promotes hepatocellular carcinoma progression by targeting the miR-527/UBE2A axis. Cell death discovery 10 35210429
2020 Delineation of Clinical Manifestations of the Inherited Xq24 Microdeletion Segregating with sXCI in Mothers: Two Novel Cases with Distinct Phenotypes Ranging from UBE2A Deficiency Syndrome to Recurrent Pregnancy Loss. Cytogenetic and genome research 10 32485717
2019 A novel splice site mutation in the UBE2A gene leads to aberrant mRNA splicing in a Chinese patient with X-linked intellectual disability type Nascimento. Molecular genetics & genomic medicine 9 31566921
2019 Alternative Splicing of RAD6B and Not RAD6A is Selectively Increased in Melanoma: Identification and Functional Characterization. Cells 7 31683936
2020 Refinement of the clinical and mutational spectrum of UBE2A deficiency syndrome. Clinical genetics 6 32415735
2023 UBE2A/B is the trans-acting factor mediating mechanotransduction and contact inhibition. The Biochemical journal 5 37818922
2020 A novel UBE2A mutation in a Chinese family with X-linked intellectual disability. The journal of gene medicine 5 32222108
2021 The Role of the Reanalysis of Genetic Test Results in the Diagnosis of Dysmorphic Syndrome Caused by Inherited xq24 Deletion including the UBE2A and CXorf56 Genes. Genes 4 33673493
2012 One stone, two birds: CDK9-directed activation of UBE2A regulates monoubiquitination of both H2B and PCNA. Cell cycle (Georgetown, Tex.) 4 22722497
2022 A novel UBE2A splice site variant causing intellectual disability type Nascimento. Clinical case reports 3 35846913
2021 A novel missense mutation in the UBE2A gene causes intellectual disability in the large X-linked family. The journal of gene medicine 2 33368912
2026 Allosteric activation of RNF20/RNF40-RAD6A-mediated H2BK120 monoubiquitylation by H2BS112 GlcNAcylation. Nature chemical biology 1 41495224
2025 Sudden infant death in a neonate with X-linked intellectual disability type Nascimento because of UBE2A deletion. Clinical dysmorphology 0 40156274
2025 [A large family of Nascimento form of syndromic X-linked intellectual developmental disorder caused by large segment deletion of the UBE2A gene: a case report and literature review]. Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics 0 40695520
2016 Identification and characterization of a ubiquitinconjugating enzyme UBE2A gene from lamprey. Fish physiology and biochemistry 0 26463350

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