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FLASH GENE
Symbol UBE3A contributors: mct/pgu/shn - updated : 05-07-2016
HGNC name ubiquitin protein ligase E3A
HGNC id 12496
Corresponding disease
AS Angelman syndrome
DUP15QP chromosome 15 interstitial duplication involving the Prader-Willi/Angelman critical region
Location 15q11.2      Physical location : 25.582.396 - 25.684.128
Synonym name
  • recognin
  • E6AP ubiquitin-protein ligase
  • oncogenic protein-associated protein E6-AP
  • human papillomavirus E6-associated protein
  • renal carcinoma antigen NY-REN-54
  • CTCL tumor antigen se37-2
    • Synonym symbol(s) E6AP, HPVE6A, AS, EPVE6AP, UE3A, ANCR, E6-AP, FLJ26981
    EC.number 6.3.2.19
    DNA
    TYPE like-sequence
    SPECIAL FEATURE overlapping, gene in gene, antisens
    text
  • an antisense overlapping transcript, oppositely imprinted with respect to the protein coding gene
    • STRUCTURE 101.73 kb     13 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    motif repetitive sequence
    text structure end repeats facilitating homologous recombination
    MAPPING cloned Y linked N status confirmed
    Map cen - D15S1021 - D15S128 - UBE3A - D15S122 - D15S210 - qter
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    11 splicing 4516 105 875 - -
    transcript variant 2
    15 splicing 4491 105 852 - -
    transcript variant 1
    13 splicing 5164 105 872 - -
    transcript variant 3
    EXPRESSION
    Type ubiquitous
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Digestiveintestinesmall intestine  moderately
     intestinelarge intestinecolon moderately
    Lymphoid/Immunespleen   lowly
     thymus   predominantly
    Reproductivefemale systemuterus  lowly
     male systemprostate  highly
     male systemtestis  highly
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Blood/Hematopoieticleukocyte
    cell lineage
    cell lines
    fluid/secretion sperm (ejaculated spermatozoa)
    at STAGE
    physiological period embryo
    Text at high levels in all structures
    IMPRINTING paternally
    text paternally imprinted in brain (neural precursor cells), in fibroblasts and lymphoblasts, biallelically expressed in other tissues
  • preferentially expressed from the maternal allele in central neurons but biallelicly expressed in glial cells
    • PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • C2 (Cal B) domain
  • two WW (phosphoserine or phosphothreonine binding) domains
  • a E6-AP-like C terminus domain (HECT)
    • HOMOLOGY
    interspecies ortholog to Ube3a, Mus musculus
    ortholog to UBE3A, Pan troglodytes
    ortholog to Ube3a, Rattus norvegicus
    ortholog to ube3a, Danio rerio
    Homologene
    FAMILY
  • E3 ubiquitin protein ligase
    • CATEGORY enzyme , regulatory
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,nucleus
    basic FUNCTION
  • mediating the interaction of the human papilloma virus E6 oncoprotein with TP53 nuclear hormone coactivator receptors
  • promotes the degradation of TP53 in association with papilloma E6 protein
  • involved in the degradation of short-lived and abnormal proteins
  • playing a major role in neural development
  • role in regulating growth of neuronal processes or synapse formation through the degradation or cellular localization of various proteins such as ECT2
  • mediating regulated proteasomal degradation of the nuclear receptor coactivator NCO3A in immortalized cells
  • acts to reduce the half-life of the PML protein by promoting its degradation in the proteasome, mediating its ubiquitination
  • regulates dendritic morphogenesis in a cell autonomous manner
  • necessary for maintaining plasticity during experience-dependent neocortical development - a role in maintaining
    • synaptic plasticity in the face of sensory processing
  • maternally expressed UBE3a is required for normal experience-dependent modification of cortical circuits during and after the critical period
  • regulates excitatory synapse development by controlling the degradation of ARC, a synaptic protein that promotes the internalization of the AMPA subtype of glutamate receptors
  • ligase that targets RNF2 for canonical ubiquitination and subsequent degradation
  • controls mammary gland development by regulating PGR isoform PR-B protein turnover via the ubiquitin proteasome pathway
  • UBE3A is able to induce MC1R promoter activity
  • plays a role in MC1R transcriptional regulation which can contribute to the development of hypopigmentation in AS patients
  • MECP2 and UBE3A play likely a role in the transcriptional control of common target gene expression
  • essential and conserved role of UBE3A in the regulation of the circadian system
    • CELLULAR PROCESS cell cycle
    protein, degradation
    protein, ubiquitin dependent proteolysis
    PHYSIOLOGICAL PROCESS
    text may be involved in the ubiquitin proteasome system in synaptic development and plasticity
    PATHWAY
    metabolism
    signaling
    a component
    INTERACTION
    DNA
    RNA
    small molecule
    protein
  • BPY2 (ubiquitination of UBE3A may be required for BPY2 function)
  • MYCBP2 (having an important role at the synapse)
  • ubiquitin-conjugating enzyme E2E 1 (UBC4/5 homolog, yeast) (UbcH6), ubiquitin-conjugating enzyme E2L 3 (UbcH7) and ubiquitin-conjugating enzyme E2D 1 (UBC4/5 homolog, yeast) (UbcH5)
  • ubiquitin-conjugating enzyme E2L 6, UBE2L6 and ubiquitin-conjugating enzyme E2L 3, UBE2L3
  • Human papillomavirus type 16, E6
  • minichromosome maintenance complex component 7, MCM7
  • human progesterone receptor (PR)
  • variable charge Y chromosome 2, VCD2Y
  • tumor suppressor p53
  • tuberous sclerosis 2, TSC2
  • interaction with HERC2 is mediated by the RCC1-like domain 2 of HERC2 and a region spanning amino acid residues 150-200 of UBE3A
  • several new UBE3A-interacting proteins, including HIF1AN, NEURL4, and mitogen-activated protein kinase 6 (MAPK6)
  • may negatively control adipogenesis by inhibiting CEBPA expression by targeting it to ubiquitin-proteasome pathway for degradation
  • UBE3A could bind to and degrade ARNTL in a ubiquitin ligase-dependent manner
  • RYBP modulates stability and function of RNF2 through targeting UBE3A
    • cell & other
    REGULATION
    induced by neuronal activity
    inhibited by topoisomerase I and topoisomerase II inhibitors, including topotecan, irinotecan, etoposide and dexrazoxane unsilence the paternal Ube3a allele
    repressed by MECP2 in the RETT syndrome, by changes in histone modifications resulting in loss of imprinting of the UBE3A antisense gene in the brain, increasing in UBE3A antisense RNA level and, consequently reduction in UBE3A production
    Other regulated by HERC2, that modulates the ubiquitin ligase activity of UBE3A
    ASSOCIATED DISORDERS
    corresponding disease(s) AS , DUP15QP
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional imprinting      
    included in PWS/AS typically deleted region, maternally expressed in brain
    constitutional     --over  
    in autism (by maternal duplication)
    constitutional imprinting      
    epigenetic aberrations at the PWS/AS imprinting center affecting UBE3A expression in RETT syndrome
    constitutional     --over  
    promoted NCO3A degradation
    constitutional       loss of function
    in neurons leads to an increase in ARC expression and a concomitant decrease in the number of AMPA receptors at excitatory synapses
    constitutional       loss of function
    results in an elevated level of ubiquitinated nucleosomal histone H2A and in increased global repressive transcriptional activity, which may contribute to the pathogenesis of Angelman syndrome
    constitutional     --over  
    in Hereditary spastic paraplegias (HSPs) with intellectual disability (ID)
    Susceptibility to autism
    Variant & Polymorphism
    Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    neurology  
    topotecan unsilences paternal Ube3a allele
    ANIMAL & CELL MODELS
  • mice with maternal deficiency (m-/p+) for Ube3a resemble human Anagelman Syndrome with motor dysfunction, inducible seizures, and a context-dependent learning deficit
  • E6-AP knockout mice display an elevated level of Rnf2 and ubiquitinated histone H2A in various tissues, including cerebellar Purkinje neurons, which may have implications to the pathogenesis of Angelman syndrome
  • mice deficient in maternal Ube3a show enetically reversible impairments in both learning and hippocampal long-term potentiation
  • Drosophila model for Angelman Sydrome appear normal externally, but display abnormal locomotive behavior and circadian rhythms, and defective long-term memory. Flies that overexpress Dube3a in the nervous system display locomotion defects
  • dUBE3A-null mutant Drosophila exhibit reduced dendritic branching of sensory neurons in the peripheral nervous system and slowed growth of terminal dendritic fine processes
  • experience-dependent maturation of excitatory cortical circuits is severely impaired and is associated with profound impairments in neocortical plasticity in Angelman syndrome model mice deficient in Ube3a .
  • topotecan unsilenced the paternal Ube3a allele in several regions of the mouse nervous system, including neurons in the hippocampus, neocortex, striatum, cerebellum and spinal cord